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Aims The liver is the major organ shown to remove oxidized low-density lipoprotein (oxLDL) from the circulation. Given increased evidence that thermogenic adipose tissue has anti-effects, we used 123I-labelled oxLDL as a tracer to reveal oxLDL accumulation in the brown adipose tissue (BAT) of mice. We also explored the mechanisms of oxLDL accumulation in BAT. Methods and results We used high-resolution nanoSPECT/CT to investigate the tissue distribution of 123I-oxLDL and 123I-LDL (control) following intravenous injection into conscious mice. 123I-oxLDL distribution was discovered in BAT at an intensity equivalent to that in the liver, whereas 123I-LDL was detected mostly in the liver. Consistent with the function of BAT related to sympathetic nerve activity, administering anaesthesia in mice almost completely eliminated the accumulation of 123I-oxLDL in BAT, and this effect was reversed by administering β3-agonist. Furthermore, exposing mice to cold stress at 4°C enhanced 123I-oxLDL accumulation in BAT. Because in 123I-oxLDL, the protein of oxLDL was labelled, we performed additional experiments with DiI-oxLDL in which the lipid phase of oxLDL was fluorescently labelled and observed similar results, suggesting that the whole oxLDL particle was taken up by BAT. To identify the receptor responsible for oxLDL uptake in BAT, we analysed the expression of known oxLDL receptors (e.g. SR-A, CD36, and LOX-1) in cultured brown adipocyte cell line and primary brown adipocytes and found that CD36 was the major receptor expressed. Treatment of cells with CD36 siRNA or CD36 neutralizing antibody significantly inhibited DiI-oxLDL uptake. Finally, CD36 deletion in mice abolished the accumulation of 123I-oxLDL and DiI-oxLDL in BAT, indicating that CD36 is the major receptor for oxLDL in BAT. Conclusion We show novel evidence for the CD36-mediated accumulation of oxLDL in BAT, suggesting that BAT may exert its anti-atherogenic effects by removing atherogenic LDL from the circulation.

Purpose Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ([18F]F-DPA) imaging for detecting spinal cord microglial activation after partial sciatic nerve ligation (PSNL) in rats. Procedures Neuropathic pain was induced in rats (n = 20) by PSNL, and pain sensation tests were conducted before surgery and 3 and 7 days post-injury. On day 7, in vivo PET imaging and ex vivo autoradiography were performed using [18F]F-DPA or [11C]PK11195. Ex vivo biodistribution and PET imaging of the removed spinal cord were carried out with [18F]F-DPA. Sham-operated and PK11195-pretreated animals were also examined. Results Mechanical allodynia was confirmed in the PSNL rats from day 3 through day 7. Ex vivo autoradiography showed a higher lesion-to-background uptake with [18F]F-DPA compared with [11C]PK11195. Ex vivo PET imaging of the removed spinal cord showed [18F]F-DPA accumulation in the inflammation site, which was immunohistochemically confirmed to coincide with microglia activation. Pretreatment with PK11195 eliminated the uptake. The SUV values of in vivo [18F]F-DPA and [11C]PK11195 PET were not significantly increased in the lesion compared with the reference region, and were fivefold higher than the values obtained from the ex vivo data. Ex vivo biodistribution revealed a twofold higher [18F]F-DPA uptake in the vertebral body compared to that seen in the bone from the skull. Conclusions [18F]F-DPA aided visualization of the spinal cord inflammation site in PSNL rats on ex vivo autoradiography and was superior to [11C]PK11195. In vivo [18F]F-DPA PET did not allow for visualization of tracer accumulation even using a high-spatial-resolution PET scanner. The main reason for this result was due to insufficient SUVs in the spinal cord region as compared with the background noise, in addition to a spillover from the vertebral body.

While brown adipose tissue (BAT) activity is known to be associated with both muscle and adipose tissue volumes, the association between BAT and muscle composition remains unclear, especially in adults. Therefore, the present study aimed to examine the association between BAT parameters (glucose uptake and fat-fraction) and muscle volumes and intramuscular adipose tissue contents among healthy young and middle-aged men. BAT glucose uptake was determined using positron emission tomography with [18F]-2-deoxy-2-fluoro-D-glucose (18F-FDG) during cold exposure in 19 young and middle-aged men (36.3 ± 10.7 years). The fat-fraction of BAT was determined from volumes of interest set in cervical and supraclavicular adipose tissue depots using signal fat-fraction maps via magnetic resonance imaging (MRI). Muscle volumes and intramuscular adipose tissue contents of m. tibialis anterior and m. multifidus lumborum were measured using MRI. The fat-fraction of BAT was significantly associated with intramuscular adipose tissue content in m. tibialis anterior (n = 13, rs = 0.691, P = 0.009). A similar trend was also observed in m. multifidus lumborum (n = 19, rs = 0.454, P = 0.051). However, BAT glucose uptake was not associated with intramuscular adipose tissue contents in both muscles, nor were muscle volumes associated with the BAT glucose uptake and fat-fraction. The fat-fraction of BAT increases with skeletal muscle adiposity, especially in the lower leg, among healthy young and middle-aged men.

Studying renal glucose metabolism non-invasively in humans is an unmet need. Positron emission tomography (PET) is the current gold standard for measuring regional tissue glucose uptake rates, but the most widely used glucose analog ([We measured individual [We found that the corrected glucose uptake is consistently higher in the medulla than cortex and that both cortical and medullary glucose uptake are higher in lean than obese participants under both fasting and insulinized conditions. Moreover, cortical but not medullary glucose uptake is increased from the fasting to the insulinized condition.The data show for the first time that [

Abstract In Myocardial Perfusion Imaging (MPI) with Positron Emission Tomography/Computed Tomography (PET/CT) systems, accurate quantification is essential. We assessed flow quantification accuracy over various injected activities using a flow phantom. Methods The study was performed on the digital 4-ring Discovery MI (DMI-20) and analog Discovery 690 (D690) PET/CT systems, using 325-1257 MBq of [15O]H2O. PET performance and flow quantification accuracy were assessed in terms of count-rates, dead-time factors (DTF), scatter fractions (SF), time-activity curves (TACs), areas-under-the-curves (AUCs) and flow values. Results On DMI-20, prompts of 12.8 Mcps, DTF of 2.06 and SF of 46.1% were measured with 1257 MBq of activity. On the D690, prompts of 6.85 Mcps, DTF of 1.57 and SF of 32.5% were measured with 1230 MBq of activity. AUC values were linear over all activities. Mean wash-in flow error was − 9% for both systems whereas wash-out flow error was − 5% and − 6% for DMI-20 and D690. With the highest activity, wash-out flow error was − 12% and − 7% for the DMI-20 and D690. Conclusion DMI-20 and D690 preserved accurate flow quantification over all injected activities, with maximum error of − 12%. In the future, flow quantification accuracy over the activities and count-rates evaluated in this study should be assessed.

Perinatal hypoxic ischemic encephalopathy (HIE) results in serious neurological dysfunction and mortality. Clinical trials of multilineage-differentiating stress enduring cells (Muse cells) have commenced in stroke using intravenous delivery of donor-derived Muse cells. Here, we investigated the therapeutic effects of human Muse cells in an HIE model. Seven-day-old rats underwent ligation of the left carotid artery then were exposed to 8% oxygen for 60 min, and 72 hours later intravenously transplanted with 1 × 104 of human-Muse and -non-Muse cells, collected from bone marrow-mesenchymal stem cells as stage-specific embryonic antigen-3 (SSEA-3)+ and −, respectively, or saline (vehicle) without immunosuppression. Human-specific probe revealed Muse cells distributed mainly to the injured brain at 2 and 4 weeks, and expressed neuronal and glial markers until 6 months. In contrast, non-Muse cells lodged in the lung at 2 weeks, but undetectable by 4 weeks. Magnetic resonance spectroscopy and positron emission tomography demonstrated that Muse cells dampened excitotoxic brain glutamatergic metabolites and suppressed microglial activation. Muse cell-treated group exhibited significant improvements in motor and cognitive functions at 4 weeks and 5 months. Intravenously transplanted Muse cells afforded functional benefits in experimental HIE possibly via regulation of glutamate metabolism and reduction of microglial activation.

PET with (18)F-FDG has been increasingly applied, predominantly in the research setting, to study drug effects and pulmonary biology and to monitor disease progression and treatment outcomes in lung diseases that interfere with gas exchange through alterations of the pulmonary parenchyma, airways, or vasculature. To date, however, there are no widely accepted standard acquisition protocols or imaging data analysis methods for pulmonary (18)F-FDG PET/CT in these diseases, resulting in disparate approaches. Hence, comparison of data across the literature is challenging. To help harmonize the acquisition and analysis and promote reproducibility, we collated details of acquisition protocols and analysis methods from 7 PET centers. From this information and our discussions, we reached the consensus recommendations given here on patient preparation, choice of dynamic versus static imaging, image reconstruction, and image analysis reporting.

Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([Neuropathic pain was induced in rats (n = 20) by PSNL, and pain sensation tests were conducted before surgery and 3 and 7 days post-injury. On day 7, in vivo PET imaging and ex vivo autoradiography were performed using [Mechanical allodynia was confirmed in the PSNL rats from day 3 through day 7. Ex vivo autoradiography showed a higher lesion-to-background uptake with [[

Human studies of renal hemodynamics and metabolism in obesity are insufficient. We hypothesized that renal perfusion and renal free fatty acid (FFA) uptake are higher in subjects with morbid obesity compared with lean subjects and that they both decrease after bariatric surgery. Cortical and medullary hemodynamics and metabolism were measured in 23 morbidly obese women and 15 age- and sex-matched nonobese controls by PET scanning of [15O]-H2O (perfusion) and 14( R,S)-[18F]fluoro-6-thia-heptadecanoate (FFA uptake). Kidney volume and radiodensity were measured by computed tomography, cardiac output by MRI. Obese subjects were re-studied 6 mo after bariatric surgery. Obese subjects had higher renal volume but lower radiodensity, suggesting accumulation of water and/or lipid. Both cardiac output and estimated glomerular filtration rate (eGFR) were increased by ~25% in the obese. Total renal blood flow was higher in the obese [885 (317) (expressed as median and interquartile range) vs. 749 (300) (expressed as means and SD) ml/min of controls, P = 0.049]. In both groups, regional blood perfusion was higher in the cortex than medulla; in either region, FFA uptake was ~50% higher in the obese as a consequence of higher circulating FFA levels. Following weight loss (26 ± 8 kg), total renal blood flow was reduced ( P = 0.006). Renal volume, eGFR, cortical and medullary FFA uptake were decreased but not fully normalized. Obesity is associated with renal structural, hemodynamic, and metabolic changes. Six months after bariatric surgery, the hemodynamic changes are reversed and the structural changes are improved. On the contrary, renal FFA uptake remains increased, driven by high substrate availability.

We developed and validated the accuracy of a method to calculate the arterial input function (AIF) from PET images only, without the need for the arterial blood sampling, in the absolute quantitation of functional parametric values inWe extended the method reported by Iguchi et al. (2013) to derive the arterial input function, thus absolute quantitative functional parametric images of cerebral perfusion and oxygen metabolism by a reference tissue approach. We compared shapes of the AIF and reproducibility of the absolute functional values. Existing test data that were carried out with the continuous arterial blood sampling were used for this study.The estimated AIF shapes agreed well with those estimated from the continuous arterial blood sampling. The error range of the absolute quantitative values was approximately ±20%, with a fairly well reproducibility in the relative values being less than 3%.The AIFs by this method were reproducible. Although the absolute quantitative values varied depending on the assumed functional values in the reference region in individual cases, the relative images showed fairly good agreement with the results from the standard technique that employed the arterial blood sampling. The present technique may provide significant contribution to clinical examination.

While brown adipose tissue (BAT) activity is known to be associated with both muscle and adipose tissue volumes, the association between BAT and muscle composition remains unclear, especially in adults. Therefore, the present study aimed to examine the association between BAT parameters (glucose uptake and fat-fraction) and muscle volumes and intramuscular adipose tissue contents among healthy young and middle-aged men.BAT glucose uptake was determined using positron emission tomography with [The fat-fraction of BAT was significantly associated with intramuscular adipose tissue content in m. tibialis anterior (n = 13, rThe fat-fraction of BAT increases with skeletal muscle adiposity, especially in the lower leg, among healthy young and middle-aged men.

Head trauma is a well-established epidemiological risk factor for Alzheimer's disease, but a study of early detection of its pathology has not yet been performed in human patients in vivo. To address this issue, we performed 11 C-labelled Pittsburgh compound B-positron emission tomography on a right-handed 30-year-old man with cognitive deterioration after repetitive head trauma during karate matches. Structural magnetic resonance imaging was also performed on this patient. The same positron emission tomography analysis was performed on elderly healthy controls (15 men, mean age: 70.7 ± 6.2 years). To analyze grey matter volume, structural magnetic resonance imaging was performed on age-matched healthy controls (15 men, mean age: 28.5 ± 3.6 years). The cognitive deterioration in our patient was fixed and partially improved in the 10 years after the repetitive head trauma. However, Pittsburgh compound B-non-displaceable binding potential was significantly elevated in the patient. Volume reduction was shown in the medial temporal region, cerebellum, and the basal frontal cortex, while amyloid-β increase was shown in the bilateral prefrontal cortex. This is the first study to show an early degenerative process due to head trauma in the prefrontal cortex, where structural damage is not yet visible. Early recognition of the degenerative pathology due to repetitive head trauma by amyloid and possibly tau imaging would help clinicians determine how to treat those with early symptoms.

Introduction Lactate could serve as an energy source and signaling molecule in the brain, although there is insufficient in vivo evidence to support this possibility. Here we aimed to use a one-pot enzymatic synthetic procedure to synthesize l -[3-11C]lactate that can be used to evaluate chemical forms in the blood after intravenous administration, and as a probe for pharmacokinetic analysis of lactate metabolism in in vivo positron emission tomography (PET) scans with normal and fasted rats. Methods Racemic [3-11C]alanine obtained from 11C-methylation of a precursor and deprotection was reacted with an enzyme mixture consisting of alanine racemase, d -amino acid oxidase, catalase, and lactate dehydrogenase to yield l -[3-11C]lactate via [3-11C]pyruvate. The optical purity was measured by HPLC. Radioactive chemical forms in the arterial blood of Sprague Dawley rats with or without insulin pretreatment were evaluated by HPLC 10 min after bolus intravenous injection of l -[3-11C]lactate. PET scans were performed on normal and fasted rats administered with l -[3-11C]lactate. Results l -[3-11C]Lactate was synthesized within 50 min and had decay corrected radiochemical yield, radiochemical purity, and optical purity of 13.4%, >95%, and >99%, respectively. The blood radioactivity peaked immediately after l -[3-11C]lactate injection, rapidly decreased to the minimum value within 90 s, and slowly cleared thereafter. HPLC analysis of blood samples revealed the presence of [11C]glucose (78.9%) and l -[3-11C]lactate (12.1%) 10 min after administration of l -[3-11C]lactate. Insulin pretreatment partly inhibited glyconeogenesis conversion leading to 55.4% as [11C]glucose and 38.9% as l -[3-11C]lactate simultaneously. PET analysis showed a higher SUV in the brain tissue of fasted rats relative to non-fasted rats. Conclusions We successfully synthesized l -[3-11C]lactate in a one-pot enzymatic synthetic procedure and showed rapid metabolic conversion of l -[3-11C]lactate to [11C]glucose in the blood. PET analysis of l -[3-11C]lactate indicated the possible presence of active lactate usage in rat brains in vivo.

Prolongation of the T2 relaxation time, an increase in T2-weighted signal intensity (T2-SI), and a decrease in the apparent diffusion coefficient (ADC) calculated from diffusion-weighted images (DWI) on magnetic resonance imaging (MRI) are conventional indicators of the vasogenic (interstitial) or cytotoxic (cellular) cerebral edema that develops after ischemic stroke. However, these parameters obtained on stroke imaging have not given us a precise threshold at which we can determine the viability or vulnerability of the tissue, allowing us to decide on an intervention that will help reversible tissue in the acute phase. Here, we introduce a new indicator—the essential diffusion coefficient or EDC, calculated from the T2-SI and ADC—that permits detection of irreversible brain damage after induction of experimental, focal cerebral ischemia. Our three-vessel occlusion (3-VO) method (Yang et al. Eur Neurol 71:4–18, 2014) was applied to investigate early changes on 7-T MRI. In the 3-VO model, which targets only a part of the cortex, animals seldom die at least within 24 h. The T2-SI and the ADC value were monitored, starting at 60 min after reperfusion, and every 30–60 min, for 10 h after the induction of focal ischemia. The region of interest (ROI) was set in each of the following: (1) the ischemic core (the dead zone); (2) the medial border area (the dying/dead mixed zone, including the ischemic penumbra); (3) the lateral border area (the surviving zone after the ischemic stress, where the rCBF is above the threshold for death); and (4) The intact area (outside the ischemic zone). The diagnosis was made by histological analysis performed 24 h after reperfusion. Significant increases in the T2-SI were observed, in ROI-1 at 1 h, in ROI-2 at 2.5 h, and in ROI-3 at 4 h post-reperfusion (1.10, 1.11, or 1.11; > 1.10, respectively, p

As matrix metalloproteinases (MMPs), especially MMP-9 and MMP-12 are involved in the pathological processes associated with chronic obstructive pulmonary disease (COPD), we developed a novel radiofluorinated probe, 18F-IPFP, for MMPs-targeted positron emission tomography (PET). 18F-IPFP was designed by iodination of MMP inhibitor to enhance the affinity, and labelled with a compact prosthetic agent, 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP). As a result, IPFP demonstrated the highest affinity toward MMP-12 (IC50 = 1.5 nM) among existing PET probes. A COPD model was employed by exposing mice to cigarette smoke and the expression levels of MMP-9 and MMP-12 were significantly increased in the lungs. Radioactivity accumulation in the lungs 90 min after administration of 18F-IPFP was 4× higher in COPD mice than normal mice, and 10× higher than in the heart, muscle, and blood. Ex vivo PET confirmed the radioactivity distribution in the tissues and autoradiography analysis demonstrated that accumulation differences in the lungs of COPD mice were 2× higher than those of normal mice. These results suggest that 18F-IPFP is a promising probe for pulmonary imaging and expected to be applied to various MMP-related diseases for early diagnosis, tracking of therapeutic effects, and new drug development in both preclinical and clinical applications.

PURPOSE: Oxidized low-density lipoprotein (oxLDL) plays a key role in endothelial dysfunction, vascular inflammation, and atherogenesis. The aim of this study was to assess blood clearance and in vivo kinetics of radiolabeled oxLDL in mice. METHODS: We synthesized (123)I–oxLDL by the iodine monochloride method, and performed an uptake study in CHO cells transfected with lectin-like oxLDL receptor-1 (LOX-1). In addition, we evaluated the consistency between the (123)I–oxLDL autoradiogram and the fluorescence image of DiI-oxLDL after intravenous injection for both spleen and liver. Whole-body dynamic planar images were acquired 10 min post injection of (123)I–oxLDL to generate regional time-activity curves (TACs) of the liver, heart, lungs, kidney, head, and abdomen. Regional radioactivity for those excised tissues as well as the bladder, stomach, gut, and thyroid were assessed using a gamma counter, yielding percent injected dose (%ID) and dose uptake ratio (DUR). The presence of (123)I–oxLDL in serum was assessed by radio-HPLC. RESULTS: The cellular uptakes of (123)I–oxLDL were identical to those of DiI-oxLDL, and autoradiograms and fluorescence images also exhibited consistent distributions. TACs after injection of (123)I–oxLDL demonstrated extremely fast kinetics. The radioactivity uptake at 10 min post-injection was highest in the liver (40.8 ± 2.4% ID). Notably, radioactivity uptake was equivalent throughout the rest of the body (39.4 ± 2.7% ID). HPLC analysis revealed no remaining (123)I–oxLDL or its metabolites in the blood. CONCLUSION: (123)I–OxLDL was widely distributed not only in the liver, but also throughout the whole body, providing insight into the pathophysiological effects of oxLDL.

11C-Pittsburgh compound-B (11C-PIB) positron emission tomography (PET) is used to visualize and quantify amyloid deposition in the brain cortex in pathological conditions such as Alzheimer’s disease (AD). Intense 11C-PIB retention is also observed in the white matter (WM) of both healthy individuals and AD patients. However, the clinical implications of this retention in brain WM have not been clarified. We investigated the relationship between the extent of white matter lesions (WMLs) and the binding potential of 11C-PIB (BPND) in the WM in patients with hypertensive small vessel disease. We further examined the relationship between the extent of WMLs and BPND in WML and in normal-appearing white matter (NAWM). Twenty-one hypertensive vasculopathy patients, without AD and major cerebral arterial stenosis and/or occlusion, were enrolled (9 women, 68 ± 7 years). Regions of WML and NAWM were extracted using magnetization-prepared rapid gradient-echo and fluid-attenuated inversion recovery of magnetic resonance images. Volumes of interest (VOIs) were set in the cortex-subcortex, basal ganglia, and centrum semiovale (CS). BPND in the cortex-subcortex, basal ganglia, CS, WML, and NAWM were estimated on 11C-PIB PET using Logan graphical analysis with cerebellar regions as references. The relationships between WML volume and BPND in each region were examined by linear regression analysis. BPND was higher in the CS and basal ganglia than in the cortex-subcortex regions. WML volume had a significant inverse correlation with BPND in the CS (Slope = −0.0042, R 2 = 0.44, P

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20972656 for Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy by Toshihiko Suzuki, Yoshiaki Sato, Yoshihiro Kushida, Masahiro Tsuji, Shohei Wakao, Kazuto Ueda, Kenji Imai, Yukako Iitani, Shinobu Shimizu, Hideki Hida, Takashi Temma, Shigeyoshi Saito, Hidehiro Iida, Masaaki Mizuno, Yoshiyuki Takahashi, Mari Dezawa, Cesar V Borlongan and Masahiro Hayakawa in Journal of Cerebral Blood Flow & Metabolism

Objective: Changes of obesity on renal perfusion and metabolism are poorly understood. Our aims were to evaluate whether obesity increases renal regional hemodynamics and metabolism in vivo, and to determine the effects of weight loss. Methods: 23 morbidly obese and 15 age- and sex-matched nonobese controls were recruited. Renal perfusion and fatty acid uptake (FAU) were measured using PET-CT scanning and [15O]- H2O and [18F]fluoro-6-thia-heptadecanoic acid ([18F]THA), respectively. Kidney volumes and radiodensity were measured by CT and cardiac output by MRI. Intraglomerular pressure (Pglo) was estimated by Gomez formula. Obese subjects were re-studied six months after bariatric surgery. Results: As compared to controls, obese subjects had larger renal volume (340[118] vs. 256[63] ml, median[interquartile range]) and lower renal radiodensity (15.3[13.1] vs. 31.5[9.8] units, p≤0.05 for both), suggesting accumulation of water and/or lipid. Both cardiac output and glomerular filtration rate (eGFR) were increased by ∼25% in the obese. While there were no differences in total renal perfusion between the two groups, Pglo was higher in the obese (61±5 mmHg vs. 55±3 of controls, p Conclusions: In obesity, renal hemodynamics are indicative of an incomplete protection against hyperperfusion and renal fatty acid uptake is increased, driven by higher substrate availability. Surgically-induced major weight loss reverses the hemodynamic but not the metabolic changes. Disclosure E. Rebelos: None. P. Dadson: None. V. Oikonen: None. H. Iida: None. J.C. Hannukainen: None. P. Iozzo: None. E. Ferrannini: None. P. Nuutila: Research Support; Self; AstraZeneca. Funding Academy of Finland; University of Turku; Turku University Hospital

Objective A direct causal relationship of cerebrovascular risk factors/stroke to amyloid β (Aβ) deposition has yet to be shown. We conducted [11 C] Pittsburgh compound B (PiB)-positron emission tomography (PET) analysis on subacute ischemic stroke patients and healthy controls. We hypothesized that subacute ischemic stroke patients would show focal Aβ accumulation in cortical regions, which would increase and extend over time during the chronic phase after stroke onset. Methods Patients were recruited 14 to 28 days after acute subcortical ischemic stroke and examined with [11 C]PiB-PET scans. Regional time-activity data were analyzed with the Logan graphical method. Whole brain voxel-based analysis was conducted to compare stroke patients with healthy controls. We also performed longitudinal comparison of patients with successive [11 C]PiB-PET scans 1 year after stroke. Results Voxel-based analysis revealed a significant increase of [11 C]PiB-BPND of the precuneus/posterior cingulate cortex (PCu/PCC) in stroke patients at the subacute stage. Based on stepwise multiple regression analysis of [11 C]PiB-BP changes during follow-up as the dependent variable, years of education was the best independent correlate. There was a significant negative relationship between changes in [11 C]PiB-BP and years of education. Conclusions Our results suggest that processes before and after the onset of ischemic stroke may trigger Aβ deposition in the PCu/PCC, whereby amyloid deposition begins at an early stage of Alzheimer's disease (AD). Our findings support the existence of a cooperative association between vascular risk factors/stroke and AD progression. Further, educational achievement had a protective effect against the increase in Aβ accumulation.

Positron emission tomography (PET) remains the gold standard for quantitative imaging of the cerebral metabolic rate of oxygen (CMRO2); however, it is an invasive and complex procedure that requires accounting for recirculating [15O]H2O (RW) and the cerebral blood volume (CBV). This study presents a non-invasive reference-based technique for imaging CMRO2 that was developed for PET/magnetic resonance imaging (MRI) with the goal of simplifying the PET procedure while maintaining its ability to quantify metabolism. The approach is to use whole-brain (WB) measurements of oxygen extraction fraction (OEF) and cerebral blood flow (CBF) to calibrate [15O]O2-PET data, thereby avoiding the need for invasive arterial sampling. Here we present the theoretical framework, along with error analyses, sensitivity to PET noise and inaccuracies in input parameters, and initial assessment on PET data acquired from healthy participants. Simulations showed that neglecting RW and CBV corrections caused errors in CMRO2 of less than ±10% for changes in regional OEF of ±25%. These predictions were supported by applying the reference-based approach to PET data, which resulted in remarkably similar CMRO2 images to those generated by analyzing the same data using a modeling approach that incorporated the arterial input functions and corrected for CBV contributions. Significant correlations were observed between regional CMRO2 values from the two techniques (slope = 1.00 ± 0.04, R 2 > 0.98) with no significant differences found for integration times of 3 and 5 min. In summary, results demonstrate the feasibility of producing quantitative CMRO2 images by PET/MRI without the need for invasive blood sampling.

Objective We hypothesized that cerebral amyloid accumulation is reflected in the periphery in the pre-dementia stage and used flow cytometry to investigate the peripheral lymphocytes as an easily accessible biomarker to observe neuro-inflammation. We aimed to determine whether peripheral lymphocytes are related to the cortical amyloid burden or vice versa in cognitively normal older subjects. Methods We applied [11C] Pittsburgh compound B (PiB)-positron emission tomography to 36 cognitively normal older individuals, and Aβ deposition was quantified by cortical binding potential (PiB-BPND). Blood samples were obtained, and lymphocyte subsets were evaluated. We examined differences between low and high PiB-BPND groups in the percentage of B cells, T cells, helper T cells, cytotoxic T cells, regulatory T cells, and natural killer cells. Results Subjects with high PiB-BPND showed significantly higher percentage of cytotoxic T cells (%CD3+). Correlation analysis revealed a significant relationship between the percentage of cytotoxic T cells and global cortical mean PiB-BPND. Hierarchical regression analyses showed that cytotoxic T cells were significantly related to the value of global cortical mean PiB-BPND and vice versa. Conclusions Our results indicated that a specific peripheral immune response, reflected in the increased ratio of cytotoxic T cells, could be regarded as a preclinical sign of AD and could be attributed to the Aβ neuropathological mechanism. Copyright © 2017 John Wiley & Sons, Ltd.

The ratio of signal intensity in T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) was recently proposed to enhance the sensitivity of detecting changes in disease-related signal intensity. The objective of this study was to test the effectiveness of T1w/T2w image ratios as an easily accessible biomarker for amyloid beta (Aβ) accumulation. We performed the T1w/T2w analysis in cognitively normal elderly individuals. We applied [11C] Pittsburgh Compound B (PiB)-PET to the same individuals, and Aβ deposition was quantified by its binding potential (PiB-BPND). The subjects were divided into low and high PiB-BPND groups, and group differences in regional T1w/T2w values were evaluated. In the regions where we found a significant group difference, we conducted a correlation analysis between regional T1w/T2w values and PiB-BPND. Subjects with high global cortical PiB-BPND showed a significantly higher regional T1w/T2w ratio in the frontal cortex and anterior cingulate cortex. We found a significant positive relationship between the regional T1w/T2w ratio and Aβ accumulation. Moreover, with a T1w/T2w ratio of 0.55 in the medial frontal regions, we correctly discriminated subjects with high PiB-BPND from the entire subject population with a sensitivity of 84.6% and specificity of 80.0%. Our results indicate that early Aβ-induced pathological changes can be detected using the T1w/T2w ratio on MRI. We believe that the T1w/T2w ratio is a prospective stable biological marker of early Aβ accumulation in cognitively normal individuals. The availability of such an accessible marker would improve the efficiency of clinical trials focusing on the initial disease stages by reducing the number of subjects who require screening by Aβ-PET scan or lumbar puncture., Graphical abstract Image 1, Highlights • We examined the T1w/T2w ratio of MR images in cognitively normal elderly subjects. • Aβ deposition was quantified by [11C] PiB-PET binding potential (PiB-BPND). • The T1w/T2w ratios were positively correlated with PiB-BPND values. • We correctly discriminated subjects with high PIB-BPND using the T1w/T2w ratio. • The T1w/T2w ratio from MRI is a potential biological marker of early Aβ deposition.

BackgroundA significantly lower fractional anisotropy (FA) value has been shown in anterior parts of the corpus callosum in patients with bipolar disorder.AimsWe investigated the association between abnormal corpus callosum integrity and interhemispheric functional connectivity (IFC) in patients with bipolar disorder.MethodsWe examined the association between FA values in the corpus callosum (CC-FA) and the IFC between homotopic regions in the anterior cortical structures of bipolar disorder (n=16) and major depressive disorder (n=22) patients with depressed or euthymic states.ResultsWe found a positive correlation between the CC-FA and IFC values between homotopic regions of the ventral prefrontal cortex and insula cortex, and significantly lower IFC between these regions in bipolar disorder patients.ConclusionsThe abnormal corpus callosum integrity in bipolar disorder patients is relevant to the IFC between homotopic regions, possibly disturbing the exchange of emotional information between the cerebral hemispheres resulting in emotional dysregulation.

Biotubes, i.e., in vivo tissue-engineered connective tubular tissues, are known to be effective as vascular replacement grafts with a diameter greater than several millimeters. However, the performance of biotubes with smaller diameters is less clear. In this study, MicroBiotubes with diameters 1 mm were prepared, and their patency was evaluated noninvasively by optical coherence tomography (OCT) and magnetic resonance angiography (MRA). MicroBiotube molds, containing seven stainless wires (diameter 0.5 mm) covered with silicone tubes (outer diameter 0.6 mm) per mold, were embedded into the dorsal subcutaneous pouches of rats. After 2 months, the molds were harvested with the surrounding capsular tissues to obtain seven MicroBiotubes (internal diameter 0.59 ± 0.015 mm, burst pressure 4190 ± 1117 mmHg). Ten-mm-long MicroBiotubes were allogenically implanted into the femoral arteries of rats by end-to-end anastomosis. Cross-sectional OCT imaging demonstrated the patency of the MicroBiotubes immediately after implantation. In a 1-month follow-up MRA, high patency (83.3 %, n = 6) was observed without stenosis, aneurysmal dilation, or elongation. Native-like vascular structure was reconstructed with completely endothelialized luminal surfaces, mesh-like elastin fiber networks, regular circumferential orientation of collagen fibers, and α-SMA-positive cells. Although the long-term patency of MicroBiotubes still needs to be confirmed, they may be useful as an alternative ultra-small-caliber vascular substitute.