Kaoru Maruyama

Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography.

OBJECTIVE Noninvasive imaging by positron emission tomography (PET) of macrophages in inflamed joints of patients with rheumatoid arthritis (RA) may allow early detection of disease activity. We undertook this study to investigate whether rheumatoid synovitis can be visualized by PET using the tracer 11C-(R)-PK11195, which binds to peripheral benzodiazepine receptors (PBRs) on macrophages. METHODS Knee joints of 11 RA patients with active arthritis of at least 1 knee joint were imaged with 11C-(R)-PK11195 PET. Tissue uptake of 11C-(R)-PK11195 was quantified. PET was followed by arthroscopy of the most inflamed knee joint of each RA patient. Synovial tissue samples were subjected to immunohistochemical staining. RESULTS 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints than in joints with moderate or mild signs of inflammation. In addition, tracer uptake in contralateral uninflamed knee joints of RA patients was significantly higher than in uninflamed joints of control patients without inflammatory joint disease, suggesting the presence of subclinical disease activity. PET tracer uptake in joints correlated significantly with PBR staining in the sublining of synovial tissue. PBR staining correlated significantly with CD68 staining of macrophages. CONCLUSION 11C-(R)-PK11195 PET imaging allows noninvasive in vivo imaging of macrophages in rheumatoid synovitis and possibly even in subclinical synovitis. Noninvasive visualization of macrophages may be useful both for detecting early synovitis and for monitoring synovitis activity during treatment.

99mTc-Hynic-annexin V imaging to evaluate inflammation and apoptosis in rats with autoimmune myocarditis

Abstract. Inflammation and cell death are two important components of myocarditis. We evaluated the distribution of inflammation and apoptotic cell death in rats with autoimmune myocarditis using two radiotracers – technetium-99m Hynic-annexin V (99mTc-annexin) as a marker of apoptotic cell death and carbon-14 deoxyglucose (14C-DG) as a marker of inflammation – in comparison with histologic findings. Three, 7 and 14 weeks after immunization with porcine cardiac myosin (acute, subacute, and chronic phases, respectively) 99mTc-annexin and 14C-DG were injected. The uptake in the total heart was determined as the percentage of injected dose per gram (% ID/g) by tissue counting. Dual-tracer autoradiography with 99mTc-annexin and 14C-DG was performed. The distribution of each of these agents was compared with the results of hematoxylin and eosin staining to identify areas of inflammation, and TUNEL staining to identify areas of apoptosis. Total cardiac uptake of 99mTc-annexin in the acute phase of myocarditis was significantly higher than that in normal rats (1.28%±0.30% vs 0.46%±0.01%; P<0.0001); it then decreased in the subacute phase and reached normal levels (0.56%±0.08% vs 0.60%±0.08%; P=NS). Total cardiac uptake of 14C-DG in the acute phase of myocarditis was significantly higher than that in normal rats (2.78%±0.95% vs 1.02%±0.25%; P<0.0001); it then decreased in the subacute phase, but still remained higher than in controls (2.06%±0.52% vs 1.37%±0.46%; P<0.05). Using autoradiography and staining of tissue specimens, it was found that most histologic inflammatory foci corresponded to areas of high 14C-DG uptake; some also corresponded to areas of high 99mTc-annexin uptake in the acute phase of myocarditis. 99mTc-annexin localization was strongly correlated with the number of TUNEL-positive cells (P<0.0001, r=0.83), but the uptake of 14C-DG showed no relationship with it. There is a marked difference in the distribution of inflammation and apoptotic cell death in the myocardium of animals with immune myocarditis. These changes are mirrored by the localization of 14C-DG and 99mTc-annexin. Sites of inflammation and zones of apoptotic cell death change over the course of immune myocarditis.

Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis

PurposeRheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[11C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[11C]PK11195 binding in the knee joints of RA patients.MethodsData from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[11C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[11C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (Vd) and standardized uptake values (SUV) were evaluated.ResultsAIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between Vd obtained using different input functions (R2=0.80–1.00) and between Vd obtained with one- and two-tissue reversible compartment models (R2=0.75–0.94). A high correlation was observed between optimal Vd and SUV after injection (R2=0.73).Conclusion(R)-[11C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with Vd, SUV is a practical alternative for clinical use.

Myocardial viability assessment with gated SPECT TC-99m tetrofosmin % wall thickening: Comparison with F-18 FDG-PET

Object: This study was designed to assess the value of gated SPECT Tc-99m-tetrofosmin (TF) wall thickening (WT) in addition to TF exercise (Ex)/rest myocardial SPECT, in comparison with F-18 fluorodeoxyglucose (FDG)-PET.Methods: The study population consisted of 33 patients with old myocardial infarction (27 men and 6 women; mean age, 62±8 years old). All patients underwent Ex/rest TF SPECT and glucose loading FDG-PET. Polar map images of Ex/rest TF were generated exercise-rest perfusion scintigraphy. LV segments with less than 70% of the maximum TF activity on the exercise image were defined as stress-induced defects. Among these, the segments whose TF activity increased by 10% from exercise to rest images or exceeded 70% of the maximum uptake were defined as reversible (viable) defects. The remaining defects on the rest image were irreversible (non-viable) defect segments, and were considered for viability study on the basis of %WT. %WT was calculated according to the standard method: {(counts ES—counts ED)/counts ED}×100. A viable segment on gated SPECT was defined as a segment whose %WT exceeded the lower limit of the normal value (mean-SD). PET viability was defined as FDG uptake exceeding 50% of the maximum count.Results: Among the 792 segments evaluated in the 33 patients studied, there were 689 PET viable segments. Of the 689 segments analyzed, 198 (29%) were identified as having defects on Ex images. Among these defects, 55 (8%) were reversible or partially reversible, as evidenced by rest images, and 143 (21%) were irreversible. Of the irreversible segments on Ex/rest images, 106 (15%) demonstrated no apparent WT by gated TF SPECT, whereas 37 (6%) segments with irreversible defects did have apparent WT. Overall, the sensitivity of Ex/rest TF perfusion imaging was 79%. Sensitivity was improved from 79% to 85% by combining %WT and perfusion data, but specificity was reduced from 70% to 56%.Conclusion: %WT evaluated from gated TF imaging enhanced myocardial viability assessment in comparison with FDG-PET.

Left ventricular mass index measured by quantitative gated myocardial SPECT with99mTc-tetrofosmin: a comparison with echocardiography

Objective: Left ventricular mass is an important determinant of diagnosis and prognosis in patients with heart disease. The aim of the present study was to validate measurement of the left ventricular mass index (LVMI) by quantitative gated myocardial SPECT (QGS) with99mTc-tetrofosmin by comparing it with echocardiography.Methods: QGS and M-mode echocardiography (Echo) were performed within one month of each other in 179 patients. M-mode echocardiography was carried out according to Devereuxs method. QGS images were acquired one hour after injection of99mTc-tetrofosmin at rest. Myocardial volume was defined as the volume between the endocardial and epicardial surface in the end-diastolic phase. LVMI (g/m2) was defined as myocardial volume divided by myocardial specific density and corrected for body surface area. QGS LVMI measurements were performed twice by the same observer and independently by two different observers. Regional hypoperfusion in the group of patients with old myocardial infarction (n=26) was evaluated semiquantitatively on the basis of the total defect score on the resting99mTc-tetrofosmin SPECT images.Results: Among the patients as a whole QGS LVMI was significantly correlated with Echo LVMI (r=0.96, p<0.001). Intra-observer and inter-observer analyses showed significant reproducibility (r=0.99 and r=0.98, respectively, p<0.001). In the patients with old myocardial infarction, but QGS LVMI was significantly lower than Echo LVMI (p<0.001), and the magnitude of the underestimation was closely related to the severity of the perfusion defect on the resting SPECT images.Conclusions: Measurements of LVMI by99mTc-tetrofosmin QGS are reproducible and consistent with echocardiograpic estimates. Underestimation in patients with severe perfusion defects must be taken into consideration.

Clinical value of lung uptake of iodine-123 metaiodobenzylguanidine (MIBG), a myocardial sympathetic nerve imaging agent, in patients with chronic heart failure

This study investigated the clinical value of I-123 MIBG pulmonary accumulation and washout in patients with chronic heart failure (CHF). Nineteen patients with CHF and 15 normal volunteers (NL) were included. The uptake ratio of heart to mediastinum (H/M), that of lung fields to mediastinum (L/M), and washout rate (WR) of the heart and lung fields were calculated in anterior planar images and compared with results of echocardiography and cardiac catheterization. In the CHF group, the lung uptake in delayed images increased and lung WR was decreased suggesting pulmonary endothelial lesions. Furthermore, there was a negative correlation between right and left lung WR and pulmonary arterial diastolic pressure (PA(d)) and pulmonary arterial systolic pressure (PA(s)) in the CHF group. Since the WR of MIBG reflected PA, it may be used as an index of severity of cardiac dysfunction.

14C-deoxyglucose imaging overestimates myocardial viability in subacute infarction of rats

Clinical studies using 18F-fluorodeoxyglucose suggest that this tracer may overestimate myocardial viability. This study aimed to elucidate whether 2-deoxyglucose accurately indicates myocardial viability at the early phase of myocardial infarction. Autoradiography with 14C-deoxyglucose was performed in fasting rats whose left coronary artery was occluded for 60 min and then reperfused. 14C-deoxyglucose was injected 30 min after the reperfusion (acute; n = 10) or 1 week later (subacute; n = 9). Infarction and risk areas were identified by triphenyl tetrazolium chloride or haematoxylin-eosin staining and methylene blue, respectively. Immuno-histochemical staining using anti-glucose transporter 1 and 4 antibodies was performed. At the acute stage, the uptake of deoxyglucose was consistent with the grade of anti-glucose transporter 4 expression. At the subacute stage, the uptake of deoxyglucose in poorly viable myocardium (543.4±343.7%: normalized with the uptake at the right ventricle) as well as in the viable one (335.2±149.8%) in the risk area was significantly greater than that in the remote area (116.4±94.9%, P<0.01). Anti-glucose transporter 1 was expressed in the poorly viable area where inflammatory cells infiltrated. It is concluded that deoxyglucose uptake by inflammatory cells which express anti-glucose transporter 1 causes overestimation of myocardial viability at subacute stage.