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Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.
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Modelos Animales de Enfermedad , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , alfa-Sinucleína , Animales , alfa-Sinucleína/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/diagnóstico por imagen , Humanos , Ratones , Tomografía de Emisión de Positrones/métodos , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Callithrix , Masculino , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Anciano , Ratones Endogámicos C57BLRESUMEN
PURPOSE: Information about developed positron emission tomography (PET) tracers and obtained clinical PET images is publicly available in a database. However, findings regarding the kinetic parameters of PET tracers are yet to be summarized. Therefore, in this study, we created an open-access database of central nervous system (CNS) kinetic parameters in the healthy human brain for existing PET tracers (DOCK-PET). METHODS: Our database includes information on the kinetic parameters and compounds of existing CNS-PET tracers. The kinetic parameter dataset comprises the analysis methods, VT, BPND, K parameters, relevant literature, and study details. The list of PET tracers and kinetic parameter information was compiled through keyword-based searches of PubMed and the Molecular Imaging and Contrast Agent Database (MICAD). The kinetic parameters obtained, including VT, BPND, and K parameters, were reorganized based on the defined brain anatomical regions. All data were rigorously double-checked before being summarized in Microsoft Excel and JavaScript Object Notation (JSON) formats. RESULTS: Of the 247 PET tracers identified through searches using the PubMed and MICAD websites, the kinetic parameters of 120 PET tracers were available. Among the 120 PET tracers, compound structures with chemical and physical properties were obtained from the PubChem website or the ChemDraw software. Furthermore, the affinity information of the 104 PET tracers was gathered from PubChem or extensive literature surveys of the 120 PET tracers. CONCLUSIONS: We developed a comprehensive open-access database, DOCK-PET, that includes both kinetic parameters of healthy humans and compound information for existing CNS-PET tracers.
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Encéfalo , Bases de Datos Factuales , Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Cinética , Trazadores Radiactivos , Sistema Nervioso Central/diagnóstico por imagen , Sistema Nervioso Central/metabolismoRESUMEN
Frontotemporal dementia refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of frontotemporal dementia at an individual level have hitherto not been successful. In this study, we aim to classify patients with frontotemporal dementia based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607 and 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer's disease as well as in non-Alzheimer's disease tauopathies. Twenty-six patients with frontotemporal dementia, 15 with behavioural variant frontotemporal dementia and 11 with other frontotemporal dementia phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the patients with behavioural variant frontotemporal dementia were classified into the following subgroups: (i) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = 3), (ii) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = 4); (iii) amyloid and tau accumulations consistent with Alzheimer's disease (n = 4); and (iv) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioural variant frontotemporal dementia subgroups. The patients with other frontotemporal dementia phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with frontotemporal dementia on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.
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In Alzheimer's disease (AD), aggregated abnormal proteins induce neuronal dysfunction. Despite the evidence supporting the association between tau proteins and brain atrophy, further studies are needed to explore their link to neuronal dysfunction in the human brain. To clarify the relationship between neuronal dysfunction and abnormal proteins in AD-affected brains, we conducted magnetic resonance spectroscopic imaging (MRSI) and assessed the neurofilament light chain plasma levels (NfL). We evaluated tau and amyloid-ß depositions using standardized uptake value ratios (SUVRs) of florzolotau (18F) for tau and 11C-PiB for amyloid-ß positron emission tomography in the same patients. Heatmaps were generated to visualize Z scores of glutamate to creatine (Glu/Cr) and N-acetylaspartate to creatine (NAA/Cr) ratios using data from healthy controls. In AD brains, Z score maps revealed reduced Glu/Cr and NAA/Cr ratios in the gray matter, particularly in the right dorsolateral prefrontal cortex (rDLPFC) and posterior cingulate cortex (PCC). Glu/Cr ratios were negatively correlated with florzolotau (18F) SUVRs in the PCC, and plasma NfL levels were elevated and negatively correlated with Glu/Cr (P = 0.040, r = -0.50) and NAA/Cr ratios (P = 0.003, r = -0.68) in the rDLPFC. This suggests that the abnormal tau proteins in AD-affected brains play a role in diminishing glutamate levels. Furthermore, neuronal dysfunction markers including Glu/tCr and NAA/tCr could potentially indicate favorable clinical outcomes. Using MRSI provided spatial information about neural dysfunction in AD, enabling the identification of vulnerabilities in the rDLPFC and PCC within the AD's pathological context.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Creatina/metabolismo , Estudios de Casos y Controles , Imagen por Resonancia Magnética , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones , Encéfalo/patología , Ácido Glutámico/metabolismo , Espectroscopía de Resonancia Magnética , Biomarcadores/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
BACKGROUND: Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer's disease (AD) has been reported; RIPK1 is involved in microglia's phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1. RESULTS: (S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK'963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK'963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK'963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK'963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47-115 GBq/µmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively. CONCLUSIONS: We synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK'963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required.
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PURPOSE: The topological distribution of dopamine-related proteins is determined by gene transcription and subsequent regulations. Recent research strategies integrating positron emission tomography with a transcriptome atlas have opened new opportunities to understand the influence of regulation after transcription on protein distribution. Previous studies have reported that messenger (m)-RNA expression levels spatially correlate with the density maps of serotonin receptors but not with those of transporters. This discrepancy may be due to differences in regulation after transcription between presynaptic and postsynaptic proteins, which have not been studied in the dopaminergic system. Here, we focused on dopamine D1 and D2/D3 receptors and dopamine transporters and investigated their region-wise relationship between mRNA expression and protein distribution. METHODS: We examined the region-wise correlation between regional binding potentials of the target region relative to that of non-displaceable tissue (BPND) values of 11C-SCH-23390 and mRNA expression levels of dopamine D1 receptors (D1R); regional BPND values of 11C-FLB-457 and mRNA expression levels of dopamine D2/D3 receptors (D2/D3R); and regional total distribution volume (VT) values of 18F-FE-PE2I and mRNA expression levels of dopamine transporters (DAT) using Spearman's rank correlation. RESULTS: We found significant positive correlations between regional BPND values of 11C-SCH-23390 and the mRNA expression levels of D1R (r = 0.769, p = 0.0021). Similar to D1R, regional BPND values of 11C-FLB-457 positively correlated with the mRNA expression levels of D2R (r = 0.809, p = 0.0151) but not with those of D3R (r = 0.413, p = 0.3095). In contrast to D1R and D2R, no significant correlation between VT values of 18F-FE-PE2I and mRNA expression levels of DAT was observed (r = -0.5934, p = 0.140). CONCLUSION: We found a region-wise correlation between the mRNA expression levels of dopamine D1 and D2 receptors and their respective protein distributions. However, we found no region-wise correlation between the mRNA expression levels of dopamine transporters and their protein distributions, indicating different regulatory mechanisms for the localization of pre- and postsynaptic proteins. These results provide a broader understanding of the application of the transcriptome atlas to neuroimaging studies of the dopaminergic nervous system.
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Encéfalo , Dopamina , Humanos , Dopamina/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Expresión GénicaRESUMEN
Objective.Tumour response to radiation therapy appears as changes in tumour vascular condition. There are several methods for analysing tumour blood circulatory changes one of which is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), but there is no method that can observe the tumour vascular condition and physiological changes at the site of radiation therapy. Positron emission tomography (PET) has been applied for treatment verification in charged particle therapy, which is based on the detection of positron emitters produced through nuclear fragmentation reactions in a patient's body. However, the produced positron emitters are washed out biologically depending on the tumour vascular condition. This means that measuring the biological washout rate may allow evaluation of the tumour radiation response, in a similar manner to DCE-MRI. Therefore, this study compared the washout rates in rats between in-beam PET during12C ion beam irradiation and DCE-MRI.Approach.Different vascular conditions of the tumour model were prepared for six nude rats. The tumour of each nude rat was irradiated by a12C ion beam with simultaneous in-beam PET measurement. In 10-12 h, the DCE-MRI experiment was performed for the same six nude rats. The biological washout rate of the produced positron emitters (k2,1st) and the MRI contrast agent (k2a) were derived using the single tissue compartment model.Main results.A linear correlation was observed betweenk2,1standk2a, and they were inversely related to fractional necrotic volume.Significance.This is the first animal study which confirmed the biological washout rate of in-beam PET correlates closely with tumour vascular condition measured with the MRI contrast agent administrated intravenously.
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Medios de Contraste , Tomografía Computarizada por Rayos X , Animales , Ratas , Ratas Desnudas , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , CarbonoRESUMEN
Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = - 0.55, p = 0.022; r = - 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.
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Trastorno Autístico , Glutamina , Masculino , Adulto , Humanos , Glutamina/metabolismo , Ácido Glutámico/metabolismo , Trastorno Autístico/metabolismo , Astrocitos/metabolismo , Dopamina/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/metabolismoRESUMEN
BACKGROUND AND HYPOTHESIS: Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels. STUDY DESIGN: This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy. STUDY RESULTS: Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group. CONCLUSIONS: The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia.
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Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagen , Hidrolasas Diéster Fosfóricas/metabolismo , Tomografía de Emisión de Positrones/métodos , Ganglios Basales , GlutamatosRESUMEN
Patients with progressive supranuclear palsy (PSP) frequently exhibit apathy but the neuropathological processes leading to this phenotype remain elusive. We aimed to examine the involvement of tau protein depositions, oxidative stress (OS), and neuronal loss in the apathetic manifestation of PSP. Twenty patients with PSP and twenty-three healthy controls were enrolled. Tau depositions and brain volumes were evaluated via positron-emission tomography (PET) using a specific probe, 18F-PM-PBB3, and magnetic resonance imaging, respectively. Glutathione (GSH) levels in the anterior and posterior cingulate cortices were quantified by magnetic resonance spectroscopy. Tau pathologies were observed in the subcortical and cortical structures of the patient brains. The angular gyrus exhibited a positive correlation between tau accumulations and apathy scale (AS). Although PSP cases did not show GSH level alterations compared with healthy controls, GSH levels in posterior cingulate cortex were correlated with AS and tau depositions in the angular gyrus. Marked atrophy was observed in subcortical areas, and gray matter volumes in the inferior frontal gyrus and anterior cingulate cortex were positively correlated with AS but showed no correlation with tau depositions and GSH levels. Path analysis highlighted synergistic contributions of tau pathologies and GSH reductions in the posterior cortex to AS, in parallel with associations of gray matter atrophy in the anterior cortex with AS. Apathetic phenotypes may arise from PET-visible tau aggregation and OS compromising the neural circuit resilience in the posterior cortex, along with neuronal loss, with neither PET-detectable tau pathologies nor OS in the anterior cortex.
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Apatía , Parálisis Supranuclear Progresiva , Humanos , Proteínas tau/metabolismo , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/complicaciones , Encéfalo/patología , Tomografía de Emisión de Positrones/métodos , Estrés OxidativoRESUMEN
Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.
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Cerebelo , Tomografía de Emisión de Positrones , Tauopatías , Proteínas tau , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/patología , Tomografía de Emisión de Positrones/normas , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/patología , Proteínas tau/análisis , Proteínas tau/metabolismo , Tauopatías/diagnóstico por imagen , Tauopatías/patología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Estándares de ReferenciaRESUMEN
BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Alzheimer , Trastornos del Movimiento , Parálisis Supranuclear Progresiva , Tauopatías , Humanos , Proteínas tau/metabolismo , Encéfalo/patología , Tauopatías/diagnóstico por imagen , Tauopatías/patología , Parálisis Supranuclear Progresiva/patología , Tomografía de Emisión de Positrones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Aprendizaje AutomáticoRESUMEN
PURPOSE: Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer's disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies. METHODS: A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, 18F-PM-PBB3, and MRI at various ages (1.8-12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations. RESULTS: 18F-PM-PBB3 SUVR at 40-60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4-5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivo 18F-PM-PBB3 binding was blocked by non-radioactive PM-PBB3. 18F-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor, 11C-PBB3. CONCLUSION: Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.
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Enfermedad de Alzheimer , Neocórtex , Fármacos Neuroprotectores , Animales , Ratones , Proteínas tau/metabolismo , Plata/metabolismo , Tomografía Computarizada por Rayos X , Tomografía de Emisión de Positrones/métodos , Enfermedad de Alzheimer/metabolismo , Modelos Animales de Enfermedad , Encéfalo/metabolismo , Ratones Transgénicos , Neocórtex/patologíaRESUMEN
Objective.The biological washout of positron emitters should be modeled and corrected in order to achieve quantitative dose range verification in charged particle therapy based on positron emission tomography (PET). This biological washout effect is affected by physiological environmental conditions such as blood perfusion and metabolism, but the correlation to tumour pathology has not been studied yet.Approach.The aim of this study was to investigate the dependence of the biological washout rate on tumour vascular status in rat irradiation. Two types of tumour vascularity conditions, perfused and hypoxic, were modelled with nude rats. The rats were irradiated by a radioactive15O ion beam and time activity curves were acquired by dynamic in-beam PET measurement. Tumour tissue sections were obtained to observe the histology as well. The biological washout rate was derived using a single-compartment model with two decay components (medium decay,k2mand slow decay,k2s).Main results.Allk2mvalues in the vascular perfused tumour tissue were higher than the values of the normal tissue. Allk2mvalues in the hypoxic tumour tissue were much lower than the values of the vascular perfused tumour tissue and slightly lower than the values of the normal tissue.Significance.The dependency of the biological washout on the tumour vasculature conditions was experimentally shown.
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Neoplasias , Tomografía de Emisión de Positrones , Animales , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Tomografía de Emisión de Positrones/métodos , RatasRESUMEN
Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.
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The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.
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Imagen por Resonancia Magnética , Receptor de Serotonina 5-HT2A , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Humanos , Inhibición Psicológica , Imagen por Resonancia Magnética/métodos , Masculino , Redes Neurales de la Computación , Vías NerviosasRESUMEN
PURPOSE: Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. METHODS: Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test-retest reproducibility of 18F-T-401-PET were also evaluated. RESULTS: 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. CONCLUSIONS: Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.
Asunto(s)
Cannabinoides , Monoacilglicerol Lipasas , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Cannabinoides/metabolismo , Humanos , Masculino , Monoacilglicerol Lipasas/metabolismo , Tomografía de Emisión de Positrones/métodos , Reproducibilidad de los Resultados , Distribución TisularRESUMEN
PURPOSE: Histamine H3 receptor antagonists and inverse agonists have been extensively developed to treat sleep-wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H3 receptors. METHODS: To measure the histamine H3 receptor occupancy by enerisant, positron emission tomography studies using [11C]TASP457, a specific radioligand for histamine H3 receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. RESULTS: Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. CONCLUSION: The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H3 receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill's plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug's unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.