Metabolic imaging using SPECT

金沢大学医学部附属病院核医学診療科Introduction: In normal condition, the heart obtains more than two-thirds of its energy from the oxidative metabolism of long chain fatty acids, although a wide variety of substrates such as glucose, lactate, ketone bodies and amino acids are also utilised. In ischaemic myocardium, on the other hand, oxidative metabolism of free fatty acid is suppressed and anaerobic glucose metabolism plays a major role in residual oxidative metabolism. Therefore, metabolic imaging can be an important technique for the assessment of various cardiac diseases and conditions. Materials and methods: In SPECT, several iodinated fatty acid traces have been introduced and studied. Of these, 123I-labelled 15-(p-iodophenyl)3-R, S-methylpentadecanoic acid (BMIPP) has been the most commonly used tracer in clinical studies, especially in some of the European countries and Japan. Results and discussion: In this review article, several fatty acid tracers for SPECT are characterised, and the mechanism of uptake and clinical utility of BMIPP are discussed in detail. © 2007 Springer-Verlag

虚血後心筋リモデリングにおけるプログラム細胞死、アポトーシスの関与とその画像化

Tc-99m-Annexin V(Tc・AV)を用いてラット心筋虚血再灌流モデルにおけるアポトーシスに対する各種インターベンションの効果ならびに虚血2週間後におけるアポトーシスの状況と心筋ダメージの関連を検討した。対照群ラットにおいて左冠動脈(LCA)を20分間閉塞し、その後再灌流30、90分後にTc-AV(100-200MBq)を投与し(n=13)、1時間後に屠殺した。2核種オートラジオグラフィにてTc-AV(アポプトーシス)とTl(虚血範囲)の分布を画像化し解析した。インターベンションとしてはischemic preconditioning(Precon)としてLCAの5分閉塞、5分再還流を4回繰り返した後、対照群と同様に処置した(n=11)。Postconditioning(Poscon)群は20分虚血再還流時に10秒の再還流と10秒の閉塞を6回繰り返した(n=11)。薬剤によるアポトーシス抑制群としてはcaspase inhibitorであるQ-VD-OPhを投与した後対照群と同様に処置した(n=11)。対照群では再環流30,90分での正常部に対する虚血部のTc-AVの集積比はそれぞれ4.15±1.89,3.70±1.41であった。Precon群ではTc-AVの集積はそれぞれ1.17±0.29,1.33±0.74と有意に低下した。Poscon群でも2.09±0.56,1.88±0.69と有意に低下し、Q-VD-OPh投与群でも2.08±0.50,1.27±0.24と有意に低下した。再灌流14日後のTc-AVの集積を検討した結果、心筋に菲薄化を生じなかった群の虚血部での集積は視覚的にはっきりせず、集積比も1.01±0.29と有意の増加を示さなかった。心筋に菲薄化を生じ内腔が拡大し、リモデリングを生じたと考えられる群では菲薄化した部分に一致したTc-AVの集積を視覚的に認め、集積比は1.71±0.34と有意に増加していた。心筋壁厚が正常部の1/2程度となった群ではTc-AVの集積は心内膜側から中部において高く、心外膜側の集積は低かった。一方、虚血部の心筋壁厚が1/3以下となり菲薄化した部位では、菲薄化部全体に不均一な集積を示していた。以上より、虚血後のリモデリングにはアポトーシスの関与が示唆され、虚血後早期のアポトーシスはPrecon,Poscon,caspase inhibitorによるインターベンションにて抑制できことが判明した。またTc-AVによるイメージングはアポトーシスのモニタリングに有用であることが示された。To determine whether cardio-protective interventions such as ischemic preconditioning, postconditioning, and suppression of apoptosis by caspase inhibitor suppress myocardial apoptosis, Tc-99m-annexin V (Tc-AV) imaging was performed in a rat model of 20min ischemia and reperfusion. After 20min of coronary occlusion and reperfusion, Tc-AV was injected at 30min and 90min after reperfusion. One hour later the coronary artery was re-occluded and thallium-201 was injected to delineated area at risk and the rats were sacrificed 1 min later. Dual tracer autoradiography was performed to assess Tc-AV uptake and area at risk. In control rats, significant Tc-AV uptake was observed within ischemic area (Tc-AV uptake ratio (ischemic to normal area\u27s count density ratio) was 4.15±1.89, 3.70±1.41 at 30min and 90min after reperfusion, respectively). In rats with ischemic preconditioning the uptake ratio decreased significantly (1.17±0.29, 1.33±0.74, respectively). By postconditioning the Tc-AV uptake was also suppressed (2.09±0.56, 1.88±0.69, respectively). Caspase inhibitor treatment also reduced the uptake (2.08±0.50, 1.27±0.24, respectively). Two weeks after reperfusion, Tc-AV uptake was not observed in rats without myocardial thinning (1.01± 0.29), however, the significant Tc-AV uptake was observed in the area of wall thinning or remodeling (1.71± 0.34). In conclusion, myocardial remodeling after ischemia may be related to apoptosis. Apoptosis can be suppressed by the cardio-protective interventions and Tc-AV imaging may be a way to monitor myocardial injury and its response to novel therapeutic interventions including postconditioning, preconditioning and antiapoptotic therapy.研究課題/領域番号:17591253, 研究期間(年度):2005-2007出典：「虚血後心筋リモデリングにおけるプログラム細胞死、アポトーシスの関与とその画像化」研究成果報告書　課題番号17591253 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

虚血心筋におけるプログラム細胞死、アポトーシスの画像化に関する核医学的研究

Tc-99m-Annexin V(Tc-AV)を用いてラット心筋虚血再灌流モデルにおけるアポトーシスの経時的変化を検討した。ウイスターラットにおいて左冠動脈(LCA)を20分(n=28)、15分(n=23)、10分(n=23)、5分(n=12)の間閉塞し、その後再灌流30、90分、6、24時間後にTc-Av(100-200MBq)を投与した。1時間後屠殺した。2核種オートラジオグラフィにてTc-AV(アポプトーシス)とT1(虚血範囲)の分布を画像化し解析した。5分閉塞群を除きTc-AVは不均一に再環流30、90分にて虚血部のmid myocardiumに集積し、6時間で心外膜、内膜側に拡大する傾向を示した。正常部に対する虚血部のTc-AVの集積はすべての再灌流時間において20分虚血で最も強く、15,10分では順次低下した。再環流30分での集積比は20,15 10,5分虚血群でそれぞれ7.36±2.95,4.46±3.16,2.02±0.47,0.97±0.08であった。再環流90分での集積比は20,15,10,5分虚血群でそれぞれ6.34±2.24,3.49±1.78,1.47±0.11,0.87±0.06であった。再環流6時間での集積比は20,15,10分虚血群でそれぞれ4.65±1.93,1.60±0.43,1.34±0.23であった。再環流24時間での集積比は20,15,10分虚血群でそれぞれ3.27±0.92,1.50±0.33,1.28±0.33であった。20分虚血再環流3,14日での集積比はそれぞれ1.84±0.55,1.65±0.31であった。20分虚血では明かな梗塞巣を認めたが、15分虚血では1%以下の梗塞病巣のみであり、10分以下の虚血では梗塞はなかった。以上より、アポトーシスは虚血再還流直後より生じ時間経過とともに低下してゆくことが示された。またそれは虚血の強度に依存して生じ、梗塞を起こさない虚血でもアポトーシスが生じていることが示唆された。To determine the time course, location and extent of this process in various severity of ischemia we studied ^Tc-annexin-V uptake in groups of rats following various intervals of coronary occlusion (20, 15, 10, 5 min) and reperfusion time (0.5, 1.5, 6, 24 hr, 3 day, 14 day). After reperfusion ^Tc-annexin-V was injected and 1 h later the rats were sacrificed. Dual tracer autoradiography was performed to assess ^Tc-annexin-V uptake and area at risk. In all 5-min occlusion and reperfusion models, no significant ^Tc-annexin V uptake was observed in the area at risk. In 10-min, 15-min, and 20-min ischemia and reperfusion models, significant ^Tc-annexin V uptake was observed depending on the severity of ischemia and reperfusion time. In each group of rats with the same reperfusion time, ^Tc-annexin V uptake depended on the severity of ischemia ; higher uptake in longer occlusion time. In each group of rats with the same ischemic time, ^Tc-annexin V uptake was highest in 0.5 h reperfusion model and the uptake decreased time dependently. In 20-min ischemia, a certain level of histological evidence of infarction was observed. In 15, 10, 5-min ischemia, there was no significant histological change was observed in 10-min and 5-min ischemia group. These data indicate that annexin binding depends on the severity of ischemia which results in the wide spectrum of histological change ; that is from infarction to no significant histological change. ^Tc-annexin V imaging may be feasible in the assessment of acute myocardial ischemia without infarction as well as infarction.研究課題/領域番号:14570842, 研究期間(年度):2002-2004出典：「虚血心筋におけるプログラム細胞死、アポトーシスの画像化に関する核医学的研究」研究成果報告書　課題番号14570842 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

虚血心筋における代謝、交感神経機能と心筋生存性の核医学的評価に関する研究

まず正常ラットにおける血流、脂肪酸代謝、交感神経機能評価を試みた。血流はTI-201とTc-99m-tetrofosmin(TF)を、脂肪酸代謝はI-125-15-(p-iodophenyl)-3-R,S-metylpentadecanoic acid(BMIPP)を、交感神経イメージングはI-125-metaiodobenzylguanidine(MIBG)を用い、尾静脈より投与し、屠殺後に各心筋部分のトレーサ集積を測定した。心筋虚血に関しては虚血左前下降枝を結紮することにより急性虚血モデルを作成し、病変部の血流、脂肪酸代謝の変化を評価した。血流はTIおよび、TFを、脂肪酸イメージングはBMIPPを用い評価した。急性虚血モデルを作成後に血流製剤とBMIPPを同時に尾静脈より投与し、20分後に屠殺しトレーサ分布を測定した。正常ラットでは、心筋内TIとTFの分布は各心筋部位、すなわち前壁、側壁、中隔、下壁、さらに心外膜、心内膜側でほぼ均一な分布を示した。一方、MIBGの分布は前壁、側壁、中隔、下壁各部では同等であったが、心内膜と心外膜での集積を比較すると心内膜側で低く投与180分後にはその比は0.8であった。BMIPPの分布は均一で静注15分後の心内膜、外膜比も0.98とほぼ1に近い値を示した。5分間の急性虚血においては、虚血中心部では血流が正常部の0.36±0.08に対してBMIPPの集積は0.34±0.07と同等の低下を示した。一方虚血辺縁部では血流低下が0.39±0.11に対してBMIPPの低下は0.63±0.08であり血流低下に対して有意に脂肪酸集積の相対的高値を示した。20分の虚血においても血流低下程度は高度であるものの5分虚血と同様に血流低下に対して有意に脂肪酸集積の相対的高値を示した。以上より急性虚血においては血流低下に比較し心筋の脂肪酸利用は相対的に高く、心筋脂質プールの増加の関与が示唆された。以上より心筋血流、代謝製剤を使った画像評価法は心筋虚血病態解明に有用であると考えられた。To assess the cardiac perfusion, metabolism and sympathetic function in normal and ischemic rats\u27 heart were imaged using perfusion tracers (Tl-201 and Tc-99m tetrofosmin), I-125-(-15-(p-iodophenyl)-3-R,S-metyl pentadecanoic acid (BMIPP), and I-125-metaiodobenzylguanidine (MIBG).In normal rats, both perfusion tracers distributed homogeneously among anterior, septal, lateral, inferior walls and endmyocardial and epicardial layers at 15 minutes after tracer injection. I-125-BMIPP also distributed homogeneously at 15 minutes after tracer injection and showed end to epicardial uptake ratio to be 0.98±0.23. I-125-MIBG distribute homogeneously among all segments but end to epicaldial uptake ratio was 0.95±0.01 at 15 minutes after injection and decreased to 0.80±0.04 at 3 hours after injection.In acute ischemic model, left anterior descending coronary artery was occluded and 5 and 20 minutes later, tetrofosmin and BMIPP were injected. In 5 minutes ischemia perfusion tracer uptake decreased to 0.36±0.08 of non-ischemic myocardium accompanied with similar reduction of BMIPP uptake of 0.34±0.07 of normal area in the center of the ischemic area. However, in peripheral zone of ischemia, BMIPP uptake reduction (0.63±0.08) was relatively mild compared with perfusion abnormality (0.39±0.11), suggesting perfusion metabolic mismatch. In 20 minutes ischemia, similar results were observed.These results suggested that 20 minutes after acute ischemia, myocardial fatty acid uptake was relatively preserved compared with perfusion abnormality, indicating that combined perfusion and metabolic imaging is useful for the evaluation of pathophysiologic diagnosis of acute myocardial ischemia.研究課題/領域番号:10670835, 研究期間(年度):1998-1999出典：「虚血心筋における代謝、交感神経機能と心筋生存性の核医学的評価に関する研究」研究成果報告書　課題番号10670835 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

Counterfactual Explanation of Brain Activity Classifiers Using Image-To-Image Transfer by Generative Adversarial Network

Deep neural networks (DNNs) can accurately decode task-related information from brain activations. However, because of the non-linearity of DNNs, it is generally difficult to explain how and why they assign certain behavioral tasks to given brain activations, either correctly or incorrectly. One of the promising approaches for explaining such a black-box system is counterfactual explanation. In this framework, the behavior of a black-box system is explained by comparing real data and realistic synthetic data that are specifically generated such that the black-box system outputs an unreal outcome. The explanation of the system's decision can be explained by directly comparing the real and synthetic data. Recently, by taking advantage of advances in DNN-based image-to-image translation, several studies successfully applied counterfactual explanation to image domains. In principle, the same approach could be used in functional magnetic resonance imaging (fMRI) data. Because fMRI datasets often contain multiple classes (e.g., multiple behavioral tasks), the image-to-image transformation applicable to counterfactual explanation needs to learn mapping among multiple classes simultaneously. Recently, a new generative neural network (StarGAN) that enables image-to-image transformation among multiple classes has been developed. By adapting StarGAN with some modifications, here, we introduce a novel generative DNN (counterfactual activation generator, CAG) that can provide counterfactual explanations for DNN-based classifiers of brain activations. Importantly, CAG can simultaneously handle image transformation among all the seven classes in a publicly available fMRI dataset. Thus, CAG could provide a counterfactual explanation of DNN-based multiclass classifiers of brain activations. Furthermore, iterative applications of CAG were able to enhance and extract subtle spatial brain activity patterns that affected the classifier's decisions. Together, these results demonstrate that the counterfactual explanation based on image-to-image transformation would be a promising approach to understand and extend the current application of DNNs in fMRI analyses

Tc-99m human serum albumin lymphoscintigraphy with SPECT/CT in chylothorax.

A 45-year-old man who had refractory right chylothorax after esophagectomy for esophageal cancer, underwent lymphoscintigraphy with Tc-99m human serum albumin. Focal abnormal uptake was seen in the mid-abdomen on planar image 30 minutes after the tracer injection. SPECT/CT delineated the extent of the accumulation between the anastomotic site and the right pleural effusion area. SPECT/CT effectively detected the site of lymphatic leakage

Comparison of diagnostic value of I-123 MIBG and high-dose I-131 MIBG scintigraphy including incremental value of SPECT/CT over planar image in patients with malignant pheochromocytoma/paraganglioma and neuroblastoma

金沢大学附属病院核医学診療科Purpose: To compare lesion detectability of I-123 MIBG scintigraphy with that of high-dose I-131 MIBG and to evaluate incremental benefit of SPECT/CT over planar image for the detection and localization of the lesions in patients with I-131 MIBG therapy for malignant pheochromocytoma/paraganglioma and neuroblastoma. Materials and Methods: We retrospectively investigated 16 patients with malignant pheochromocytoma/paraganglioma and neuroblastoma, who were referred for I-131 MIBG therapy. We investigated the lesion detectability in 10 pairs of I-123 and high-dose I-131 MIBG studies of the same patient, obtained within 2 weeks. In 31 studies of I-123 MIBG scintigraphy in 16 patients and 17 studies of high-dose I-131 MIBG scintigraphy in 12 patients, we compared planar and SPECT/CT images for the lesion detectability and localization. Results: The number of lesions detected by I-123 MIBG planer image and SPECT/CT and high-dose planer I-131 MIBG and SPECT/CT were 3.0 and 3.7, 7.3 and 7.7 per study, respectively. SPECT/CT images provided additional diagnostic information over planar images in 25 studies (81%) of 12 patients (75%) in I-123 MIBG scintigraphy and in 9 studies (53%) of 9 patients (75%) in high-dose I-131 MIBG scintigraphy. CONCLUSION: Post-therapy high-dose I-131 MIBG scintigraphy is superior to I-123 MIBG scintigraphy in lesion detectability even in comparison with I-123 MIBG SPECT/CT images and high-dose I-131 MIBG planar images in patients with malignant neuroendocrine tumors. SPECT/CT images are helpful for accurate identification of anatomic localization compared with planar images. Copyright © Lippincott Williams & Wilkins