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BACKGROUND: The choroid plexus (CP) produces and secretes most of the cerebrospinal fluid (CSF) of the central nervous system. The CP is suggested to be regulated by descending neurons and by circulating factors and is involved in the interaction between central and peripheral inflammation. Quantitative imaging has demonstrated volumetric CP changes in psychosis, schizophrenia and depression. This study histologically examines CP epithelial cell morphology in these illnesses to identify the biological source of such volumetric changes. METHODS: Formalin-fixed paraffin-embedded (FFPE) blocks were obtained bilaterally from the lateral ventricles of 13 cases of sex- and age-matched brains from each of schizophrenia (SZ) with psychosis, major depressive disorder (MDD) and matched controls (NPD). FFPE blocks were sectioned at 7 µm and routinely stained for H&E. Morphological analysis of 180 CP epithelia/case was conducted blindly on digital images collected at x600 magnification. Calcification was assessed in all CP regions manually. RESULTS: Analysis with a General Linear Model demonstrated a significant effect of diagnosis on somal width (p = 0.006, R2 = 0.33 R2(adj) = 0.25) demonstrating increased somal width in SZ without psychotic medication versus controls (p = 0.032), but not in medicated SZ cases. No effects were observed in calcification. DISCUSSION: The epithelial cells that were examined were attached to the CP fibrous surface, so width expansion describes the primary methods for these cells to expand with adherence to this surface in SZ. The interaction of antipsychotic medication and diagnosis demonstrates that this is an illness-specific change mediated through the DA-system with likely neuronal origin. CP alterations were not found in MDD where they are instead generally associated with heightened allostatic load that was unknown in this cohort.
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Transtorno Depressivo Maior , Esquizofrenia , Humanos , Esquizofrenia/metabolismo , Plexo Corióideo/metabolismo , Transtorno Depressivo Maior/metabolismo , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismoRESUMO
BACKGROUND: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. METHODS: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. RESULTS: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. CONCLUSIONS: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.
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Transcriptoma , Inibidores do Fator de Necrose Tumoral , Anti-Inflamatórios/farmacologia , Encéfalo , Humanos , Inflamação , Interferon-alfa/efeitos adversosRESUMO
In dynamic Positron Emission Tomography (PET) studies, compartmental models provide the richest information on the tracer kinetics of the tissue. Inverting such models at the voxel level is however quite challenging due to the low signal-to-noise ratio of the time activity curves. In this study, we propose the use of a Variational Bayesian (VB) approach to efficiently solve this issue and thus obtain robust quantitative parametric maps. VB was adapted to the non-uniform noise distribution of PET data. Moreover, we propose a novel hierarchical scheme to define the model parameter priors directly from the images in case such information are not available from the literature, as often happens with new PET tracers. VB was initially tested on synthetic data generated using compartmental models of increasing complexity, providing accurate (%bias<2%±2%, root mean square error<15%±5%) parameter estimates. When applied to real data on a paradigmatic set of PET tracers (L-[1-11C]leucine, [11C]WAY100635 and [18F]FDG), VB was able to generate reliable parametric maps even in presence of high noise in the data (unreliable estimates<11%±5%).
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Mapeamento Encefálico/métodos , Processamento de Imagem Assistida por Computador/métodos , Modelos Neurológicos , Tomografia por Emissão de Pósitrons/métodos , Algoritmos , Teorema de Bayes , Humanos , Modelos Teóricos , Razão Sinal-RuídoRESUMO
BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls. METHOD: Twelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory E max model we developed previously. RESULTS: The inhibitory E max model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), -5.67 (dorsal raphe nucleus)]. CONCLUSIONS: This result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD.
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Benzilaminas , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Encéfalo/metabolismo , Estudos de Casos e Controles , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/metabolismo , Citalopram/uso terapêutico , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/metabolismo , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Adulto JovemRESUMO
Schizophrenia is a chronic, disabling neuropsychiatric disorder characterised by positive, negative and cognitive symptoms. The aetiology is not known, although genetic, imaging and pathological studies have implicated both neurodevelopmental and neurodegenerative processes. The substantia nigra is a basal ganglia nucleus responsible for the production of dopamine and projection of dopaminergic neurons to the striatum. The substantia nigra is implicated in schizophrenia as dopamine has been heavily implicated in the dopamine hypothesis of schizophrenia and the prevalent psychotic symptoms and the monoamine theory of depression, and is a target for the development of new therapies. Studies into the major dopamine delivery pathways in the brain will therefore provide a strong base in improving knowledge of these psychiatric disorders. This post-mortem study examines the cytoarchitecture of dopaminergic neurons of the substantia nigra in schizophrenia (n = 12) and depression (n = 13) compared to matched controls (n = 13). Measures of nucleolar volume, nuclear length and nuclear area were taken in patients with chronic schizophrenia and major depressive disorder against matched controls. Astrocyte density was decreased in schizophrenia compared to controls (p = 0.030), with no change in oligodendrocyte density observed. Significantly increased nuclear cross-sectional area (p = 0.017) and length (p = 0.021), and increased nucleolar volume (p = 0.037) in dopaminergic neurons were observed in schizophrenia patients compared with controls, suggesting nuclear pleomorphic changes. No changes were observed in depression cases compared to control group. These changes may reflect pathological alterations in gene expression, neuronal structure and function in schizophrenia.
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Depressão/patologia , Esquizofrenia/patologia , Substância Negra/patologia , Adulto , Idoso , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Mudanças Depois da Morte , Substância Negra/metabolismoRESUMO
This paper investigates a new hierarchical method to apply basis function to mono- and multi-compartmental models (Hierarchical-Basis Function Method, H-BFM) at a voxel level. This method identifies the parameters of the compartmental model in its nonlinearized version, integrating information derived at the region of interest (ROI) level by segmenting the cerebral volume based on anatomical definition or functional clustering. We present the results obtained by using a two tissue-four rate constant model with two different tracers ([(11)C]FLB457 and [carbonyl-(11)C]WAY100635), one of the most complex models used in receptor studies, especially at the voxel level. H-BFM is robust and its application on both [(11)C]FLB457 and [carbonyl-(11)C]WAY100635 allows accurate and precise parameter estimates, good quality parametric maps and a low percentage of voxels out of physiological bound (<8%). The computational time depends on the number of basis functions selected and can be compatible with clinical use (~6h for a single subject analysis). The novel method is a robust approach for PET quantification by using compartmental modeling at the voxel level. In particular, different from other proposed approaches, this method can also be used when the linearization of the model is not appropriate. We expect that applying it to clinical data will generate reliable parametric maps.
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Encéfalo/metabolismo , Modelos Neurológicos , Piperazinas/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Piridinas/farmacocinética , Pirrolidinas/farmacocinética , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Dopaminérgicos/metabolismo , Salicilamidas/farmacocinética , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/farmacocinética , Simulação por Computador , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Serotonin (5-HT) neurotransmission is implicated in cognitive and emotional processes and a number of neuropsychiatric disorders. The use of positron emission tomography (PET) to measure ligand displacement has allowed estimation of endogenous dopamine release in the human brain; however, applying this methodology to assess central 5-HT release has proved more challenging. The aim of this study was to assess the sensitivity of a highly selective 5-HT(1A) partial agonist radioligand [(11)C]CUMI-101 to changes in endogenous 5-HT levels induced by an intravenous challenge with the selective 5-HT re-uptake inhibitor (SSRI), citalopram, in healthy human participants. We studied 15 healthy participants who underwent PET scanning in conjunction with [(11)C]CUMI-101 after receiving an intravenous infusion of citalopram 10 mg or placebo in a double-blind, crossover, randomized design. Regional estimates of binding potential (BP(ND)) were obtained by calculating total volumes of distribution (V(T)) for presynaptic dorsal raphe nucleus (DRN) and postsynaptic cortical regions. Relative to placebo, citalopram infusion significantly increased [(11)C]CUMI-101 BP(ND) at postsynaptic 5-HT(1A) receptors in several cortical regions, but there was no change in binding at 5-HT(1A) autoreceptors in the DRN. Across the postsynaptic brain regions, citalopram treatment induced a mean 7% in [(11)C]CUMI-101 BP(ND) (placebo 1.3 (0.2); citalopram 1.4 (0.2); paired t-test P=0.003). The observed increase in postsynaptic [(11)C]CUMI-101 availability identified following acute citalopram administration could be attributable to a decrease in endogenous 5-HT availability in cortical terminal regions, consistent with preclinical animal studies, in which acute administration of SSRIs decreases DRN cell firing through activation of 5-HT(1A) autoreceptors to reduce 5-HT levels in postsynaptic regions. We conclude that [(11)C]CUMI-101 may be sensitive to changes in endogenous 5-HT release in humans.
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Neuroimagem Funcional/métodos , Piperazinas , Tomografia por Emissão de Pósitrons/métodos , Neurônios Serotoninérgicos/metabolismo , Triazinas , Adulto , Radioisótopos de Carbono , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citalopram/administração & dosagem , Citalopram/farmacologia , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Núcleos da Rafe/diagnóstico por imagem , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Serotonina/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
We propose a general approach to generate parametric maps. It consists in a multi-stage hierarchical scheme where, starting from the kinetic analysis of the whole brain, we then cascade the kinetic information to anatomical systems that are akin in terms of receptor densities, and then down to the voxel level. A-priori classes of voxels are generated either by anatomical atlas segmentation or by functional segmentation using unsupervised clustering. Kinetic properties are transmitted to the voxels in each class using maximum a posteriori (MAP) estimation method. We validate the novel method on a [11C]diprenorphine (DPN) test-retest data-set that represents a challenge to estimation given [11C]DPN's slow equilibration in tissue. The estimated parametric maps of volume of distribution (VT) reflect the opioid receptor distributions known from previous [11C]DPN studies. When priors are derived from the anatomical atlas, there is an excellent agreement and strong correlation among voxel MAP and ROI results and excellent test-retest reliability for all subjects but one. Voxel level results did not change when priors were defined through unsupervised clustering. This new method is fast (i.e. 15 min per subject) and applied to [11C]DPN data achieves accurate quantification of VT as well as high quality VT images. Moreover, the way the priors are defined (i.e. using an anatomical atlas or unsupervised clustering) does not affect the estimates.
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Mapeamento Encefálico/métodos , Diprenorfina , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Algoritmos , Atlas como Assunto , Teorema de Bayes , Encéfalo/anatomia & histologia , Calibragem , Radioisótopos de Carbono , Análise por Conglomerados , Humanos , Processamento de Imagem Assistida por Computador , Cinética , Imageamento por Ressonância Magnética , Modelos Estatísticos , Dinâmica não Linear , Distribuição Normal , Reprodutibilidade dos TestesRESUMO
RATIONALE: (11)C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be present in genetic Alzheimer's (AD), cerebral amyloid angiopathy and prion diseases. Therefore, we investigated whether the pons could be used as an alternative reference region for the analysis of [(11)C]PIB binding in AD. The aims of the study were to: 1) Evaluate the pons as a reference region using arterial plasma input function and Logan graphical analysis of binding. 2) Assess the power of target-to-pons ratios to discriminate controls from AD subjects. 3) Determine the test-retest reliability in AD subjects. 4) Demonstrate the application of target-to-pons ratio in subjects with elevated cerebellar [(11)C]PIB binding. METHODS: 12 sporadic AD subjects aged 65 ± 4.5 yrs with a mean MMSE 21.4 ± 4 and 10 age-matched control subjects had [(11)C]PIB PET with arterial blood sampling. Three additional subjects (two subjects with pre-symptomatic presenilin-1 mutation carriers and one probable familial AD) were also studied. Object maps were created by segmenting individual MRIs and spatially transforming the gray matter images into standard stereotaxic MNI space and then superimposing a probabilistic atlas. Cortical [(11)C]PIB binding was assessed with an ROI (region of interest) analysis. Parametric maps of the volume of distribution (V(T)) were generated with Logan analysis. Additionally, parametric maps of the 60-90 min target-to-cerebellar ratio (RATIO(CER)) and the 60-90 min target-to-pons ratio (RATIO(PONS)) were computed. RESULTS: All three approaches were able to differentiate AD from controls (p<0.0001, nonparametric Wilcoxon rank sum test) in the target regions with RATIO(CER) and RATIO(PONS) differences higher than V(T) with use of an arterial input function. All methods had a good reproducibility (intraclass correlation coefficient>0.83); RATIO(CER) performed best closely followed by RATIO(PONS). The two subjects with presenilin-1 mutations and the probable familial AD case showed no significant differences in cortical binding using RATIO(CER), but the RATIO(PONS) approach revealed higher [(11)C]PIB binding in cortex and cerebellum. CONCLUSION: This study established 60-90 min target-to-pons RATIOs as a reliable method of analysis in [(11)C]PIB PET studies where cerebellum is not an appropriate reference region.
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Doença de Alzheimer/diagnóstico por imagem , Benzotiazóis/farmacocinética , Cerebelo/diagnóstico por imagem , Marcadores Fiduciais/normas , Ponte/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/normas , Doença de Alzheimer/metabolismo , Compostos de Anilina , Cerebelo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ponte/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tiazóis , Reino UnidoRESUMO
Aberrant emotion processing is a well-established component of psychotic disorders and is already present at the first episode of psychosis (FEP). However, the role of emotion processing abnormalities in the emergence of psychosis and the underlying neurobiology remain unclear. Here, we systematically reviewed functional magnetic resonance studies that used emotion processing task paradigms in FEP patients, and in people at clinical high-risk for psychosis (CHRp). Image-based meta-analyses with Seed-based d Mapping on available studies (n = 6) were also performed. Compared to controls, FEP patients showed decreased neural responses to emotion, particularly in the amygdala and anterior cingulate cortex. There were no significant differences between CHRp subjects and controls, but a high degree of heterogeneity was identified across studies. The role of altered emotion processing in the early phase of psychosis may be clarified through more homogenous experimental designs, particularly in the CHRp population.
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Imageamento por Ressonância Magnética , Transtornos Psicóticos , Tonsila do Cerebelo , Encéfalo/diagnóstico por imagem , Emoções , Giro do Cíngulo , Humanos , Transtornos Psicóticos/diagnóstico por imagemRESUMO
Depression is associated with peripheral inflammation, but its link with brain microglial activity remains unclear. In seven healthy males, we used repeated translocator protein-Positron Emission Tomography (TSPO-PET) dynamic scans with [11C]PBR28 to image brain microglial activation before and 24 h after the immune challenge interferon (IFN)-α. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-α administration decreased [11C]PBR28 PET tissue volume of distribution (Vt) across the brain (-20 ± 4%; t6 = 4.1, p = 0.01), but after correction for radioligand free-plasma fraction there were no longer any changes (+23 ± 31%; t = 0.1, p = 0.91). IFN-α increased serum IL-6 (1826 ± 513%, t6 = -7.5, p < 0.001), IL-7 (39 ± 12%, t6 = -3.6, p = 0.01), IL-10 (328 ± 48%, t6 = -12.8, p < 0.001), and IFN-γ (272 ± 64%, t6 = -7.0, p < 0.001) at 4-6 h, and increased serum TNF-α (49 ± 7.6%, t6 = -7.5, p < 0.001), IL-8 (39 ± 12%, t6 = -3.5, p = 0.013), and C-reactive protein (1320 ± 459%, t6 = -7.2, p < 0.001) at 24 h. IFN-α induced temporary mood changes and sickness symptoms after 4-6 h, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p ≤ 0.04). No association was found between changes in peripheral inflammation and changes in PET or mood measures. Our work suggests that brain TSPO-PET signal is highly dependent of inflammation-induced changes in ligand binding to plasma proteins. This limits its usefulness as a sensitive marker of neuroinflammation and consequently, data interpretation. Thus, our results can be interpreted as showing either that [11C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.
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Tomografia por Emissão de Pósitrons , Receptores de GABA , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Microglia/metabolismo , Receptores de GABA/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
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Alzheimer's disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.
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Doença de Alzheimer/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Doença de Alzheimer/complicações , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Modelos Biológicos , Apneia Obstrutiva do Sono/complicações , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/fisiopatologiaAssuntos
Encéfalo/patologia , Polimorfismo Genético/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Alelos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
Corpo Estriado/metabolismo , Dopamina/biossíntese , Neuroimagem Funcional/psicologia , Transtornos Psicóticos/metabolismo , Adulto , Corpo Estriado/diagnóstico por imagem , Di-Hidroxifenilalanina/análogos & derivados , Feminino , Radioisótopos de Flúor , Neuroimagem Funcional/métodos , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Transtornos Psicóticos/diagnóstico por imagemRESUMO
Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicer under resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two 18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two 18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg-1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=-0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=-0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinson's disease.
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Apomorfina/farmacologia , Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto JovemRESUMO
We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.
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Encéfalo/metabolismo , Microglia/metabolismo , Transtornos Psicóticos/complicações , Transtornos Psicóticos/metabolismo , Receptores de GABA/metabolismo , Esquizofrenia/complicações , Esquizofrenia/metabolismo , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Feminino , Humanos , Isoquinolinas , Masculino , Tomografia por Emissão de Pósitrons , Fatores de Risco , Esquizofrenia/diagnóstico , Adulto JovemRESUMO
This article develops a theoretical framework for the use of the wavelet transform in the estimation of emission tomography images. The solution of the problem of estimation addresses the equivalent problems of optimal filtering, maximum compression, and statistical testing. In particular, new theory and algorithms are presented that allow current wavelet methodology to deal with the two main characteristics of nuclear medicine images: low signal-to-noise ratios and correlated noise. The technique is applied to synthetic images, phantom studies, and clinical images. Results show the ability of wavelets to model images and to estimate the signal generated by cameras of different resolutions in a wide variety of noise conditions. Moreover, the same methodology can be used for the multiscale analysis of statistical maps. The relationship of the wavelet approach to current hypothesis-testing methods is shown with an example and discussed. The wavelet transform is shown to be a valuable tool for the numerical treatment of images in nuclear medicine. It is envisaged that the methods described here may be a starting point for further developments in image reconstruction and image processing.