International consensus on clinical use of presynaptic dopaminergic positron emission tomography imaging in parkinsonism.

PURPOSE: Presynaptic dopaminergic positron emission tomography (PET) imaging serves as an essential tool in diagnosing and differentiating patients with suspected parkinsonism, including idiopathic Parkinson's disease (PD) and other neurodegenerative and non-neurodegenerative diseases. The PET tracers most commonly used at the present time mainly target dopamine transporters (DAT), aromatic amino acid decarboxylase (AADC), and vesicular monoamine type 2 (VMAT2). However, established standards for the imaging procedure and interpretation of presynaptic dopaminergic PET imaging are still lacking. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform presynaptic dopaminergic PET imaging. METHOD: A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for presynaptic dopaminergic PET imaging in parkinsonism, focusing on standardized recommendations, procedures, interpretation, and reporting. CONCLUSION: This international consensus and practice guideline will help to promote the standardized use of presynaptic dopaminergic PET imaging in parkinsonism. It will become an international standard for this purpose in clinical practice.

Novel strategy of liver cancer treatment with modified antisense oligonucleotides targeting human vasohibin-2.

Vasohihibin-2 (VASH2) is a homolog of vasohibin-1 (VASH1) and is overexpressed in various cancers. Vasohihibin-2 acts on both cancer cells and cancer microenvironmental cells. Previous analyses have shown that VASH2 promotes cancer progression and abrogation of VASH2 results in significant anticancer effects. We therefore propose VASH2 to be a practical molecular target for cancer treatment. Modifications of antisense oligonucleotide (ASO) such as bridged nucleic acids (BNA)-based modification increases the specificity and stability of ASO, and are now applied to the development of a number of oligonucleotide-based drugs. Here we designed human VASH2-ASOs, selected an optimal one, and developed 2',4'-BNA-based VASH2-ASO. When systemically administered, naked 2',4'-BNA-based VASH2-ASO accumulated in the liver and showed its gene-silencing activity. We then examined the effect of 2',4'-BNA-based VASH2-ASO in liver cancers. Intraperitoneal injection of naked 2',4'-BNA-based VASH2-ASO exerted a potent antitumor effect on orthotopically inoculated human hepatocellular carcinoma cells. The same manipulation also showed potent antitumor activity on the splenic inoculation of human colon cancer cells for liver metastasis. These results provide a novel strategy for the treatment of primary as well as metastatic liver cancers by using modified ASOs targeting VASH2.

Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe.

Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges into the systemic circulation, indicating that tcHGF is an excellent target for molecular imaging using positron emission tomography (PET). We recently discovered HGF-inhibitory peptide-8 (HiP-8) that binds specifically to human tcHGF with nanomolar affinity. The purpose of this study was to investigate the usefulness of HiP-8-based PET probes in human HGF knock-in humanized mice. 64Cu-labeled HiP-8 molecules were synthesized using a cross-bridged cyclam chelator, CB-TE1K1P. Radio-high-performance liquid chromatography-based metabolic stability analyses showed that more than 90% of the probes existed in intact form in blood at least for 15 min. In PET studies, significantly selective visualization of hHGF-overexpressing tumors versus hHGF-negative tumors was observed in double-tumor-bearing mice. The accumulation of labeled HiP-8 into the hHGF-overexpressing tumors was significantly reduced by competitive inhibition. In addition, the radioactivity and distribution of phosphorylated MET/HGF receptor were colocalized in tissues. These results demonstrate that the 64Cu-labeled HiP-8 probes are suitable for tcHGF imaging in vivo, and secretory proteins like tcHGF can be a target for PET imaging.

Characteristic Evaluation of a 11C-Labeled Leucine Analog, l-α-[5-11C]methylleucine, as a Tracer for Brain Tumor Imaging by Positron Emission Tomography.

Amino acid transporters are upregulated in many cancer cells, and system L amino acid transporters (LAT1-4), in particular, LAT1, which preferentially transports large, neutral, and branched side-chain amino acids, are considered a primary target for cancer positron emission tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step reaction of Pd0-mediated 11C-methylation and microfluidic hydrogenation. In this study, we evaluated the characteristics of [5-11C]MeLeu and also compared the sensitivity to brain tumors and inflammation with l-[11C]methionine ([11C]Met) to determine its potential for brain tumor imaging. Competitive inhibition experiments, protein incorporation, and cytotoxicity experiments of [5-11C]MeLeu were performed in vitro. Further, metabolic analyses of [5-11C]MeLeu were performed using a thin-layer chromatogram. The accumulation of [5-11C]MeLeu in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen methyl ester by PET imaging, respectively. Transporter assay with various inhibitors revealed that [5-11C]MeLeu is mainly transported via system L amino acid transporters, especially LAT1, into A431 cells. The protein incorporation assay and metabolic assay in vivo demonstrated that [5-11C]MeLeu was neither used for protein synthesis nor metabolized. These results indicate that MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells with various concentrations of MeLeu did not change their viability, even at high concentrations (∼10 mM). In brain tumors, the tumor-to-normal ratio of [5-11C]MeLeu was more elevated than that of [11C]Met. However, the accumulation levels of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06, respectively). In brain inflammation, no significant accumulation of [5-11C]MeLeu was observed at the inflamed brain area. These data suggested that [5-11C]MeLeu was identified as a stable and safe agent for PET tracers and could help detect brain tumors, which overexpress the LAT1 transporter.

Acute nicotine exposure blocks aromatase in the limbic brain of healthy women: A [11C]cetrozole PET study.

BACKGROUND: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain. METHODS: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI-based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential. RESULTS: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d = -0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend. CONCLUSIONS: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.

Lysophosphatidic acid receptor type-1 mediates brain activation in micro-positron emission tomography analysis in a fibromyalgia-like mouse model.

The intermittent cold stress-induced generalized pain response mimics the pathophysiological and pharmacotherapeutic features reported for fibromyalgia patients, including the presence of chronic generalized pain and female dominance. In addition, the intermittent cold stress-induced generalized pain is abolished in lysophosphatidic acid receptor type-1 knockout mice, as reported in many cases of neuropathic pain models. This study aimed to identify the brain loci involved in the intermittent cold stress generalized pain response and test their dependence on the lysophosphatidic acid receptor type-1. Positron emission tomography analyses using 2-deoxy-2-[18 F]fluoro-d-glucose in the presence of a pain stimulus showed that intermittent cold stress causes a significant increase in uptake in the ipsilateral regions, including the salience networking-related anterior cingulate cortex and insular cortex and the cognition-related hippocampus. A significant decrease was observed in the default mode network-related posterior cingulate cortex. Almost these intermittent cold stress-induced changes were abolished in lysophosphatidic acid receptor type-1 knockout mice. There results suggest that the intermittent cold stress-induced generalized pain response is mediated by the lysophosphatidic acid receptor type-1 in specific brain loci related to salience networking and cognition, which may lead to further developments in the treatment of fibromyalgia.

First-in-human assessment of the novel LAT1 targeting PET probe 18F-FIMP.

In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl-11C]methionine (11C-MET) and 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG). 18F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11C-MET and 18F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11C-MET and 18F-FDG. 18F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma.

[18F]DPA-714 PET imaging for the quantitative evaluation of early spatiotemporal changes of neuroinflammation in rat brain following status epilepticus.

BACKGROUND: Most antiepileptic drug therapies are symptomatic and adversely suppress normal brain function by nonspecific inhibition of neuronal activity. In recent times, growing evidence has suggested that neuroinflammation triggered by epileptic seizures might be involved in the pathogenesis of epilepsy. Although the potential effectiveness of anti-inflammatory treatment for curing epilepsy has been extensively discussed, the limited quantitative data regarding spatiotemporal characteristics of neuroinflammation after epileptic seizures makes it difficult to be realized. We quantitatively analyzed the spatiotemporal changes in neuroinflammation in the early phase after status epilepticus in rats, using translocator protein (TSPO) positron emission tomography (PET) imaging, which has been widely used for the quantitative evaluation of neuroinflammation in several animal models of CNS disease. METHODS: The second-generation TSPO PET probe, [18F]DPA-714, was used for brain-wide quantitative analysis of neuroinflammation in the brains of rats, when the status epilepticus was induced by subcutaneous injection of kainic acid (KA, 15 mg/kg) into those rats. A series of [18F]DPA-714 PET scans were performed at 1, 3, 7, and 15 days after status epilepticus, and the corresponding histological changes, including activation of microglia and astrocytes, were confirmed by immunohistochemistry. RESULTS: Apparent accumulation of [18F]DPA-714 was observed in several KA-induced epileptogenic regions, such as the amygdala, piriform cortex, ventral hippocampus, mediodorsal thalamus, and cortical regions 3 days after status epilepticus, and was reversibly displaced by unlabeled PK11195 (1 mg/kg). Consecutive [18F]DPA-714 PET scans revealed that accumulation of [18F]DPA-714 was focused in the KA-induced epileptogenic regions from 3 days after status epilepticus and was further maintained in the amygdala and piriform cortex until 7 days after status epilepticus. Immunohistochemical analysis revealed that activated microglia but not reactive astrocytes were correlated with [18F]DPA-714 accumulation in the KA-induced epileptogenic regions for at least 1 week after status epilepticus. CONCLUSIONS: These results indicate that the early spatiotemporal characteristics of neuroinflammation quantitatively evaluated by [18F]DPA-714 PET imaging provide valuable evidence for developing new anti-inflammatory therapies for epilepsy. The predominant activation of microglia around epileptogenic regions in the early phase after status epilepticus could be a crucial therapeutic target for curing epilepsy.

International consensus on the use of tau PET imaging agent 18F-flortaucipir in Alzheimer's disease.

PURPOSE: Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. METHOD: A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18F-flortaucipir PET imaging in Alzheimer's disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. CONCLUSION: This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.

Neural correlates of beneficial effects of young plasma treatment in aged mice: PET-SPM analyses and neuro-behavioural/molecular biological studies.

PURPOSE: To investigate the in vivo neurofunctional changes and therapeutic effects of young blood plasma (YBP) in aged mice, as well as the molecular mechanisms underlying the therapeutic effects of YBP ex vivo and in vitro. METHODS: Aged C57/BL6 mice received systemic administrations of phosphate-buffered saline (PBS) or YBP twice a week, for 4 weeks. In vivo 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) under conscious state and cognitive behavioural tests were performed after 4-week treatment. In addition, an in vitro senescent model was established, and the expressions of key cognition-associated proteins and/or the alterations of key neuronal pathways were analysed in both brain tissues and cultured cells. RESULTS: Aged mice treated with YBP demonstrated higher glucose metabolism in the right hippocampus and bilateral somatosensory cortices, and lower glucose metabolism in the right bed nucleus of stria terminalis and left cerebellum. YBP treatment exerted beneficial effects on the spatial and long-term social recognition memory, and significantly increased the expressions of several cognition-related proteins and altered the key neuronal signalling pathways in the hippocampus and somatosensory cortex. Further in vitro studies suggested that YBP but not aged blood plasma significantly upregulated the expressions of several cognition-associated proteins. CONCLUSION: Our results highlight the role of the hippocampus and somatosensory cortex in YBP-induced beneficial effects on recognition memory in aged mice. 18F-FDG PET imaging under conscious state provides a new avenue for exploring the mechanisms underlying YBP treatment against age-related cognitive decline.

Alleviation of the chronic stress response attributed to the antioxidant and anti-inflammatory effects of electrolyzed hydrogen water.

Reactive oxygen species (ROS) are highly reactive and directly attack surrounding biomolecules to deteriorate cellular and tissue functions. Meanwhile, ROS also serve as signaling mediators to upregulate pro-inflammatory cytokine expression via activation of the nuclear factor kappa B signaling pathway, and the increased pro-inflammatory cytokines trigger respiratory burst of inflammatory cells that further accelerates ROS production in the inflamed tissue. Such crosstalk between ROS and inflammatory responses leads to a chain reaction of negativity, and cause progression of several chronic pathologies. Since molecular hydrogen is known to preferentially remove cytotoxic hydroxyl radicals and peroxynitrites, and to prevent cell and tissue damage, we here examined whether electrolyzed hydrogen water (EHW) enriched with molecular hydrogen and reactive hydrogen storing platinum nanoparticles dissolved from an electrode could alleviate oxidative stress and inflammation induced by continuous stress challenges. Five-day continuous stress loading to rats elevated reactive oxygen metabolites-derived compounds (d-ROMs), interleukin (IL)-1ß, and adrenocorticotropic hormone (ACTH) levels and decreased the biological antioxidant potential (BAP) level. Drinking EHW during 5-day continuous stress loading significantly alleviated all of these changes. The results suggest that EHW could suppress stress-response-associated oxidative stress and IL-1ß level elevation in vivo, and that drinking of EHW is effective for controlling stress responses via its antioxidant potential.

PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study.

Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 µSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

International consensus on the use of [18F]-FDG PET/CT in pediatric patients affected by epilepsy.

PURPOSE: Positron emission tomography (PET) with 18F-fluorodeoxyglucose ([18F]-FDG) has been increasingly applied in precise localization of epileptogenic focus in epilepsy patients, including pediatric patients. The aim of this international consensus is to provide the guideline and specific considerations for [18F]-FDG PET in pediatric patients affected by epilepsy. METHODS: An international, multidisciplinary task group is formed, and the guideline for brain [18F]-FDG PET/CT in pediatric epilepsy patients has been discussed and approved, which include but not limited to the clinical indications, patient preparation, radiopharmaceuticals and administered activities, image acquisition, image processing, image interpretation, documentation and reporting, etc. CONCLUSION: This is the first international consensus and practice guideline for brain [18F]-FDG PET/CT in pediatric epilepsy patients. It will be an international standard for this purpose in clinical practice.

PET imaging of neural activity, ß-amyloid, and tau in normal brain aging.

Normal brain aging is commonly associated with neural activity alteration, ß-amyloid (Aß) deposition, and tau aggregation, driving a progressive cognitive decline in normal elderly individuals. Positron emission tomography (PET) with radiotracers targeting these age-related changes has been increasingly employed to clarify the sequence of their occurrence and the evolution of clinically cognitive deficits. Herein, we reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aß, and tau. Neural hypoactivity reflected by decreased glucose utilization with PET imaging has been predominately reported in the frontal, cingulate, and temporal lobes of the normal aging brain. Aß PET imaging uncovers the pathophysiological association of Aß deposition with cognitive aging, as well as the potential mechanisms. Tau-associated cognitive changes in normal aging are likely independent of but facilitated by Aß as indicated by tau and Aß PET imaging. Future longitudinal studies using multi-radiotracer PET imaging combined with other neuroimaging modalities, such as magnetic resonance imaging (MRI) morphometry, functional MRI, and magnetoencephalography, are essential to elucidate the neuropathological underpinnings and interactions in normal brain aging.

Systematic imaging in medicine: a comprehensive review.

Systematic imaging can be broadly defined as the systematic identification and characterization of biological processes at multiple scales and levels. In contrast to "classical" diagnostic imaging, systematic imaging emphasizes on detecting the overall abnormalities including molecular, functional, and structural alterations occurring during disease course in a systematic manner, rather than just one aspect in a partial manner. Concomitant efforts including improvement of imaging instruments, development of novel imaging agents, and advancement of artificial intelligence are warranted for achievement of systematic imaging. It is undeniable that scientists and radiologists will play a predominant role in directing this burgeoning field. This article introduces several recent developments in imaging modalities and nanoparticles-based imaging agents, and discusses how systematic imaging can be achieved. In the near future, systematic imaging which combines multiple imaging modalities with multimodal imaging agents will pave a new avenue for comprehensive characterization of diseases, successful achievement of image-guided therapy, precise evaluation of therapeutic effects, and rapid development of novel pharmaceuticals, with the final goal of improving human health-related outcomes.

Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor.

Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF-MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.

Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.

A Strategy for Tumor Targeting by Higher-Order Glycan Pattern Recognition: Synthesis and In Vitro and In Vivo Properties of Glycoalbumins Conjugated with Four Different N-Glycan Molecules.

Natural glycoconjugates that form glycocalyx play important roles in various biological processes based on cell surface recognition through pattern recognition mechanisms. This work represents a new synthesis-based screening strategy to efficiently target the cancer cells by higher-order glycan pattern recognition in both cells and intact animals (mice). The use of the very fast, selective, and effective RIKEN click reaction (6π-azaelectrocyclization of unsaturated imines) allows to synthesize and screen various structurally well-defined glycoalbumins containing two and eventually four different N-glycan structures in a very short time. The importance of glycan pattern recognition is exemplified in both cell- and mouse-based experiments. The use of pattern recognition mechanisms for cell targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases including cancers.

Quantification of aromatase binding in the female human brain using [11 C]cetrozole positron emission tomography.

Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [11 C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [11 C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [11 C]cetrozole time-activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BPND ), with cerebellum as reference region, can be used to estimate [11 C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BPND at the voxel level. As PET tracer, [11 C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.

Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.