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In the diagnosis of atherosclerosis, detailed evaluation of biomarkers related to its lesion formation is desired for estimation of its progression rate. In our previous proteomic studies of atherosclerosis mice, the protein level of thrombospondin-4 (TSP4) in the aorta, but not in plasma, elevated relatively with atherosclerotic plaque formation. Therefore, we supposed that TSP4 would be a potential biomarker for diagnostic imaging of atherosclerotic progression. Immunoglobulin G (IgG) has been widely used as a basic molecule of imaging probes providing images specific to their target biomolecules, owing to the antigen-antibody reaction. Therefore, we first developed anti-TSP4 monoclonal IgG radiolabeled with Tc (Tc-TSP4-mAb). Tc-TSP4-mAb showed higher accumulation in atherosclerotic aortas of apoE mice (atherosclerotic model mice); however, we found that the non-targeted monoclonal IgG radiolabeled with Tc also showed similar distribution in atherosclerotic aortas of apoE mice. IgG has also known to accumulate nonspecifically in the immunological disease such as inflammatory arthritis. However, the accumulation mechanism of IgG has still been unclear in detail. In this chapter, we would like to introduce recent topics on atherosclerotic imaging, focused on our work exploring the accumulation mechanisms of IgG in atherosclerotic lesions, and elucidating the usefulness of radiolabeled IgG images in the diagnosis of atherosclerosis.

Nuclear cardiology imaging with SPECT or PET is used widely in North America for the diagnosis and management of patients with coronary artery disease. Conventional myocardial perfusion imaging (MPI) can identify areas of reversible ischemia as suitable targets for coronary artery revascularization by angioplasty or bypass surgery. However, the accuracy of this technique is limited in patients with advanced disease in multiple coronary arteries, where there is no normal reference territory against which to assess the “relative” perfusion defects. We have developed methods for the routine quantification of absolute myocardial blood flow (MBF mL/min/g) and coronary flow reserve (stress/rest MBF) using rubidium-82 dynamic PET imaging. The incremental diagnostic and prognostic value of absolute flow quantification over conventional MPI has been demonstrated in several recent studies. Clinical use of this added information for patient management to direct optimal therapy and the potential to improve cardiac outcomes remains unclear, but may be informed by recent progress and widespread clinical adoption of invasive fractional flow reserve(FFR)-directed revascularization. This paper presents recent progress in this field, toward noninvasive CFR image-guided therapy with cardiac PET and SPECT.

Heart failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood [1]. Approximately 5 million patients in the USA and 15 million patients in Europe have HF. It is the leading cause of hospitalization in elderly people. Despite treatment advances, the mortality rate of HF has increased steadily. More patients are surviving myocardial infarction (MI) due to better standards of care, and consequently this may increase numbers of patients who subsequently develop HF. HF places a significant burden on patients, carers, and healthcare systems.

Limited progress has been made in identifying evidence-based, effective treatments for HF over the last decades. Potential contributors include an incomplete understanding of pathophysiology and poor matching of therapeutic mechanisms.

Positron emission tomography (PET), as a molecular imaging technique, with various tracers allows noninvasive evaluation of contractile function, myocardial perfusion, metabolism, and innervation. Molecular imaging approaches using PET could be further used to evaluate inflammation, angiogenesis, cell death, and ventricular remodeling. It could provide new insights on the chemotherapy-related cardiotoxicity and the roles of stem cell monitoring in living bodies for cell-based therapy from preclinical studies to clinical trials. In conclusion, cardiac PET is a promising tool to understand the physiologic consequences of HF, resulting in early detection of patients with HF at risk, improvement of risk stratification, and therapeutic strategy planning and treatment response monitoring. Therefore, in order to give the readers a brief and concise overview, we will mainly review the latest advances in cardiac PET studies in heart failure.

In response to concerns about overuse and increasing radiation exposure of myocardial perfusion imaging, nuclear medicine societies have declared statements aimed at lowering its radiation dose and costs. Simultaneously, two vendors have launched novel SPECT scanners with solid-state semiconductor detectors. Discovery NM 530c and D-SPECT utilize the same cadmium zinc telluride (CZT) detectors with a different combination of high-sensitivity multi-pinhole or parallel-hole collimator which focuses on the heart. The physical performance of those is dramatically higher than that of conventional Anger cameras; however, 2 CZT cameras are inherently different.

Although Tc-labeled myocardial perfusion tracers might not be ideal agents, estimation of absolute myocardial blood flow or myocardial flow reserve (MFR) using dynamic CZT SPECT is a challenging subject and attracts a great deal of interest in the field. Thus, novel software which allows automatic calculation of MFR index with dynamic CZT SPECT is currently under development and validated in our institution. This technology will hold promise if the several issues can be solved through future studies.

: Elevated pulmonary arterial pressure may increase right ventricular (RV) oxidative metabolism in patients with pulmonary hypertension (PH) and heart failure (HF). C- acetate positron emission tomography (PET) can be used to measure RV oxidative metabolism noninvasively. The combination of RV oxidative metabolism and cardiac work, as estimated by cardiac magnetic resonance imaging (CMR), indicates RV efficiency and can provide new insights. However, the clinical importance of these markers has not been fully studied. The purpose of this study was to investigate the possible impacts of these markers in patients with PH through C-acetate PET.

: Ventricular function was assessed using magnetic resonance imaging (MRI). Dynamic C-acetate PET was used to simultaneously measure RV and left ventricular (LV) oxidative metabolism (k). The RV myocardial work per oxygen consumption index was calculated as follows: [RV stroke volume index (SVI)/RV k]. PH patients who had additional or increased doses of PH-specific vasodilator(s), based on the joint guidelines of the European Society of Cardiology (ESC) and European Respiratory Society (ERS) for the diagnosis and management of PH, were compared with five PH patients who had no treatment modification (control group).

: PH patients showed higher RV k than did controls ( < 0.05). RV oxidative metabolism was correlated with the mean pulmonary arterial pressure (mPAP) ( = 0.44,  = 0.021), pulmonary vascular resistance (PVR) ( = 0.56,  = 0.002), and brain natriuretic peptide (BNP) ( = 0.42,  = 0.029). Members of the PH therapy group had reduced RV oxidative metabolism ( = 0.002) and improved RV work/oxygen consumption index ( < 0.001).

: RV oxidative metabolism increased as the correlation between mPAP and PVR increased. PH-specific treatments reduced RV oxidative metabolism. Therefore, RV metabolism and its efficiency can provide new pathophysiological insights and will be a new therapeutic marker in patients with PH.

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. The number of patients with cardiac involvement is considered to be limited, but cardiac sarcoidosis is a very serious and unpredictable aspect of sarcoidosis resulting in conduction-system abnormalities and heart failure. The severity of cardiac involvement depends on the extent and location of the granulomatous lesions.

When establishing a diagnosis, F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) is a useful tool to detect active inflammatory lesions associated with sarcoidosis. The heart uses different energy sources including free fatty acids (FFA), glucose, and others. The F-FDG is an analog of glucose, and for the precise evaluation of the extent and severity of cardiac involvement, recent studies have focused on reducing physiological myocardial F-FDG uptake. Long fasting and dietary modification, such as observing a low-carbohydrate or high-fat diet, are the recommended regimens for preparations to make a precise evaluation. The FFA level before the PET scan could be a predictor of the success to the suppression of the physiological F-FDG accumulation.

With F-FDG PET therapy monitoring or risk stratification based on quantitative F-FDG accumulation becomes possible. The quantification of the volume and intensity of F-FDG uptake could assist in predicting the clinical outcomes and in evaluating the efficiency of steroid treatments.

This report provides a summary of the usefulness of F-FDG PET in its current status as a diagnostic modality for cardiac sarcoidosis.

A good understanding of the in vivo pharmacokinetics of radioligands is important for accurate PET quantification in molecular brain imaging. For many reversibly binding radioligands for which there exists a brain region devoid of molecular target binding sites called “reference tissue,” data analysis methods that do not require blood data including the standardized uptake value ratio of target-to-reference tissue at a “fixed time point” (SUVR) and reference tissue model to estimate binding potential () are commonly used, the latter being directly proportional to the binding site density (). Theoretically, is the tissue ratio minus 1 at equilibrium. It is generally believed that radioligands should not ideally produce radiometabolites that can enter the brain because they might complicate accurate quantification of specific binding of the parent radioligand. However, the tissue ratio that contains the contribution of radiometabolite can also be theoretically a valid parameter that reflects the target binding site density. This article describes the validation of the tissue ratio concept using, as an example of our recent PET data analysis approach for a novel radioligand, C-PBB3, to quantify pathological tau accumulations in the brain of Alzheimer’s disease patients in which the SUVR and reference tissue model methods using the cerebellar cortex as the reference tissue were validated by the dual-input graphical analysis model that uses the plasma parent and radiometabolite activity as input functions in order to take into account the contribution of the radiometabolite entering the brain.

Tumor hypoxia is an important object for imaging because hypoxia is associated with tumor aggressiveness and resistance to radiation therapy. Here, F-fluoromisonidazole (FMISO) has been used for many years as the most commonly employed hypoxia imaging tracer. Unlike F-18 fluorodeoxyglucose (FDG), FMISO does not accumulate in normal brain tissue making it able to provide images of hypoxic brain tumors with high contrast. Clinical evidence has suggested that FMISO PET can predict patient prognosis and treatment response. Among gliomas of various grades (WHO 2007), it has been known that grade IV glioblastoma resides under severe hypoxia and is a cause of development of necrosis in the tumor. For this study we tested whether FMISO can distinguish the oxygen condition of glioblastomas and lower-grade gliomas. Twenty-three glioma patients underwent FMISO PET for the study. All the glioblastoma patients ( = 14) showed high FMISO uptakes in the tumor, whereas none of the other patients (i.e., gliomas of grade III or lower,  = 9) did, demonstrated by both qualitative and quantitative assessments. The data suggest that FMISO PET may be a useful tool to distinguish glioblastomas from lower-grade gliomas. Our results, however, were slightly different from previous investigations reporting that some lower-grade gliomas (e.g., grade III) showed positive FMISO uptake. Many of these acquired the FMISO PET images 2 h after the FMISO injection, while for the study here we waited 4 h to be able to collect hypoxia-specific signals rather than perfusion signals as FMISO clearance from plasma is slow due to its lipophilic nature. No optimum uptake time for FMISO has been established, and we directly compared the 2-h vs. the 4-h images with the same patients ( = 17). At 2 h, the gray matter had significantly higher standardized uptake value (SUV) than the white matter, possibly due to different degrees of perfusion but not due to hypoxia. At 4 h, there were no differences between gray and white matter without any significant increase in the noise level measured by the coefficient of variation between the 2-h and the 4-h images. At 2 h, 6/8 (75 %) of glioblastoma patients showed higher uptakes in the tumor than in the surrounding brain tissue, whereas at 4 h this was the case for 8/8 (100 %). In addition, at 2 h, 3/4 (75 %) of patients with lower-grade gliomas showed moderate uptakes, while at 4 h none did (0/4 or 0 %). These data indicate that 4-h images are better than 2-h images for the purpose of glioma grading. In conclusion, we evaluated the diagnostic performance of FMISO PET for gliomas and suggest that FMISO PET may be able to assist in the diagnosis of glioblastomas when PET images are acquired at 4 h post injection.

Since cerebral infarction results from a reduction of cerebral blood flow (CBF) by the occlusion or stenosis of carotid or intracranial arteries, CBF is a primary parameter to predict of ischemic brain injury. Single-photon emission tomography (SPECT) and positron emission tomography (PET) contributed to evaluate loss of cerebral autoregulation, uncoupling state between CBF and brain metabolism, and ischemic penumbra. Measurement of CBF and oxygen metabolism by O PET revealed the process of infarct growth in hyperacute stage of cerebral infarction and areas with depressed oxygen metabolism, but normal water diffusion in magnetic resonance imaging (MRI) was termed as “metabolic penumbra.” Recently, some researchers shed light on the role of glial cells in the energy metabolism of the brain and C-acetate PET and demonstrated that astrocytic energy metabolism in TCA cycle was protective against ischemia. SPECT and PET studies for secondary reaction after ischemia (i.e., selective neuronal loss by I-iomazenil SPECT and C-flumazenil PET, tissue hypoxia by F-FMISO PET, and neuroinflammation by TSPO-PET) are expected as new biomarkers. Combining these imaging biomarkers with classical CBF measurement may contribute to develop innovative drugs for pharmacological neuroprotection in the therapy of cerebral infarction.

Now we confront a super aging society in Japan. In the situation, it is important to preserve our cognitive function for entire life by preventing us from pathological brain aging. To perform the aim, we have built a large brain magnetic resonance imaging (MRI) database from around 3,000 subjects aged from 5 to 80 in order to reveal how brain develops and ages. We have also collected several cognitive functions, lifestyle such as eating and sleeping habits, and genetic data. Using the database, we have revealed normal brain development and aging and also have revealed what factors affect brain development and aging. For example, sleep duration is significantly associated with the gray matter volume of the bilateral hippocampi. In addition, there were significant negative correlation between alcohol drinking and gray matter volume of the frontoparietal region and body mass index and gray matter volume of the hippocampus in cross-sectional analysis. In addition, having intellectual curiosity showed significant negative correlation with regional gray matter volume decline rate in the temporoparietal region. These findings help understanding the mechanism of brain development and aging as well as performing differential diagnosis or diagnosis at an early stage of several diseases/disorders such as autism and Alzheimer’s disease.