Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium-pilocarpine rat model.

The ketogenic diet (KD) has been shown to be effective in refractory epilepsy after long-term administration. However, its interference with short-term brain metabolism and its involvement in the early process leading to epilepsy remain poorly understood. This study aimed to assess the effect of a short-term ketogenic diet on cerebral glucose metabolic changes, before and after status epilepticus (SE) in rats, by using [18F]-FDG PET. Thirty-nine rats were subjected to a one-week KD (KD-rats, n = 24) or to a standard diet (SD-rats, n = 15) before the induction of a status epilepticus (SE) by lithium-pilocarpine administrations. Brain [18F]-FDG PET scans were performed before and 4 h after this induction. Morphological MRIs were acquired and used to spatially normalize the PET images which were then analyzed voxel-wisely using a statistical parametric-based method. Twenty-six rats were analyzed (KD-rats, n = 15; SD-rats, n = 11). The 7 days of the KD were associated with significant increases in the plasma ß-hydroxybutyrate level, but with an unchanged glycemia. The PET images, recorded after the KD and before SE induction, showed an increased metabolism within sites involved in the appetitive behaviors: hypothalamic areas and periaqueductal gray, whereas no area of decreased metabolism was observed. At the 4th hour following the SE induction, large metabolism increases were observed in the KD- and SD-rats in areas known to be involved in the epileptogenesis process late-i.e., the hippocampus, parahippocampic, thalamic and hypothalamic areas, the periaqueductal gray, and the limbic structures (and in the motor cortex for the KD-rats only). However, no statistically significant difference was observed when comparing SD and KD groups at the 4th hour following the SE induction. A one-week ketogenic diet does not prevent the status epilepticus (SE) and associated metabolic brain abnormalities in the lithium-pilocarpine rat model. Further explorations are needed to determine whether a significant prevention could be achieved by more prolonged ketogenic diets and by testing this diet in less severe experimental models, and moreover, to analyze the diet effects on the later and chronic stages leading to epileptogenesis.

A 1-week extension of a ketogenic diet provides a further decrease in myocardial 18F-FDG uptake and a high detectability of myocarditis with FDG-PET.

BACKGROUND: Short periods of fasting and/or low-carbohydrate diet have been proven beneficial for decreasing the myocardial uptake of 18F-fluorodeoxyglucose (18F-FDG) and enhancing the detection of inflammatory heart diseases by 18F-FDG positron emission tomography (PET). This study aimed at determining whether this benefit is increased when a low-carbohydrate ketogenic diet is prolonged up to 7 days. METHODS: Wistar rats underwent serial 18F-FDG-PET imaging after an 18-hour fasting period and after 2, 4 and 7 days of a ketogenic diet (3% carbohydrate) and they were compared to rats submitted to the same protocol but with normal diet (44% carbohydrate). The 18F-FDG-PET/ketogenic protocol was also applied in rats with immune myocarditis (injection of porcine cardiac myosin). RESULTS: The 7-day ketogenic diet was associated with (1) a sustained increase in circulating ketone bodies at an equivalent level to that reached after 18-hour fasting, (2) a gradual decrease in 18F-FDG uptake within normal myocardium reaching a lower level compared to fasting at the 7th day (myocardium-to-blood ratios: 1.68 ± 1.02 vs 3.25 ± 1.40, P < .05) and (3) a high 18F-FDG-PET detectability of myocarditis areas. CONCLUSION: One-week extension of a ketogenic diet provides a further decrease in the 18F-FDG uptake of normal myocardium and a high detectability of inflammatory areas.

Assessment of Myocardial CZT SPECT Recording in a Forward-Leaning Bikerlike Position.

This prospective randomized study assessed myocardial perfusion imaging with the high-sensitivity D.SPECT cadmium-zinc-telluride camera in a forward-leaning bikerlike position, which may potentially lower diaphragmatic attenuation and reduce breathing-related cardiac motion, in a manner comparable to the prone position proposed with other SPECT cameras. Methods: Patients referred for a stress-rest 99mTc-sestamibi protocol and positioned in the biker position, with the chest leaning forward on the D.SPECT camera-head at 35° from vertical, had an additional resting D.SPECT recording in the supine position (n = 40) or in the sitting position with the back rearward at 30° from vertical (n = 40). Segments with attenuation artifacts were defined as those with less than 65% uptake but with strictly normal contractility at gated SPECT and no defect reversibility from stress images. Results: The biker position was associated with lower heart-to-detector distances than the supine or sitting positions (both P < 0.001); lower cardiac motion amplitudes, assessed on panograms, than the supine position (P < 0.001); and fewer segments with attenuation artifacts than the supine position (on average, 1.10 ± 1.01 vs. 1.90 ± 1.74, P = 0.010) or the sitting position (0.75 ± 0.93 vs. 1.38 ± 1.60, P = 0.011). Conclusion: Myocardial perfusion images from D.SPECT are enhanced for patients positioned in a forward-leaning bikerlike position comparatively to sitting or supine positions, with a notably lower rate of attenuation artifacts.

Routine evaluation of left ventricular function using CZT-SPECT, with low injected activities and limited recording times.

PURPOSE: Gamma-cameras, with Cadmium-Zinc-Telluride (CZT) detectors, allow to perform myocardial perfusion imaging (MPI) with limited injected activities and recorded times. This study aimed at determining whether the routine assessment of left ventricular (LV) function with such limited counts protocols compares well with reference values from cardiac MRI. METHODS: The study included patients who have undergone cardiac MRI and an MPI routinely planned on a CZT camera with a low-dose protocol (120 MBq of Sestamibi for stress and 360 MBq at rest for 75 kg body weight), while targeting the recording of only 500 myocardial kcounts in order to limit the recording times (<10 minutes for stress, <4 minutes for rest). SPECT images were reconstructed with a method maintaining rather high spatial (8 mm) and temporal (16 frames/cycle) resolutions. RESULTS: Seventy-six patients were included, and mean effective dose was 3.5 ± 1.7 mSv for the total MPI protocol. Correlations between CZT-SPECT and MRI were good to excellent for ejection fraction (r 2 = 0.77), end-diastolic (r 2 = 0.88) and end-systolic (r 2 = 0.93) volumes, and the analysis of segmental contractility correlated well between the two techniques (kappa score = 0.72 ± 0.02). CONCLUSION: LV function, assessed on a CZT camera with low injected activities and limited recording times, correlates well with the reference assessment from cardiac MRI.

Low-dose dual-isotope procedure planed for myocardial perfusion CZT-SPECT and assessed through a head-to-head comparison with a conventional single-isotope protocol.

PURPOSE OF THE REPORT: This study aimed at assessing an original low-dose dual-isotope procedure in which the abnormal stress Tc-99m Sestamibi SPECT is followed by rest Tl-201 SPECT, along with a head-to-head comparison with a single-isotope procedure. METHODS AND RESULTS: One hundred two patients, referred for a low-dose stress-SPECT with Sestamibi (123 ± 20 MBq) on a CZT camera and for whom a rest Sestamibi SPECT was warranted, had an additional Tl-201 rest-SPECT (52 ± 5 MBq) between stress and rest Sestamibi SPECT recordings. Tl-201 images were processed for spill-over and scatter corrections, and uptake differences with stress Sestamibi SPECT were analyzed: (1) for rest acquisitions from Tl-201 (dual-isotope procedure) and from Sestamibi (single-isotope procedure) and (2) in segments for which a diagnosis of ischemia, infarct, or normal perfusion was achieved. Mean effective dose was 8.3 mSv for dual-isotope but would decrease to 5.7 mSv for an expected rate of 37% of patients for whom rest-SPECT is not warranted. After a further background correction of Tl-201 images, the rest-stress difference in myocardial uptake was equivalent between dual- and single-procedures for identifying ischemic segments (respective areas-under-curves: 0.83 ± 0.03 and 0.81 ± 0.03). CONCLUSION: This original dual-isotope procedure provides acceptable radiation doses and consistent results, as compared with conventional single-isotope.

Quantitative SPM Analysis Involving an Adaptive Template May Be Easily Applied to [18F]FDG PET Images of the Rat Brain.

PURPOSE: The Statistical Parametric Mapping (SPM) software is frequently used for the quantitative analysis of patients' brain images obtained from 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG PET). However, its adaptation to small animals is difficult, particularly for the initial step of spatial normalization which requires a specific brain anatomical template. This study was aimed at determining whether SPM analysis can be applied to rat, and more specifically to the lithium-pilocarpine model of epilepsy, by using an adaptive template. This template developed for PET clinical imaging is constructed from a block matching algorithm. PROCEDURES: SPM analysis of brain [18F]FDG PET images from Sprague-Dawley rats was used with the block matching (BM) adaptive template for the detection of brain abnormalities (1) artificially inserted within the initially normal brain images of 10 rats (50 % decrease in signal intensity within 40 spheres of 0.5 to 1.0 mm in diameter) and (2) occurring at 4 h (n = 16), 48 h (n = 15), and 8 days (n = 13) after lithium-pilocarpine treatment. RESULTS: Concordant positive clusters were documented for all inserted abnormalities, whereas no aberrant clusters were documented in remote brain areas. Positive clusters were also detected on sites known to be involved in the epileptogenesis process of the lithium-pilocarpine model (piriform and entorhinal cortex, hippocampus), with the expected time-specific changes involving an early hypermetabolism followed by a severe hypometabolism and a subsequent partial recovery. CONCLUSION: A quantitative SPM analysis of brain [18F]FDG PET images may be applied to the monitoring of rat brain function when using an adaptive BM template.

Stress-first protocol for myocardial perfusion SPECT imaging with semiconductor cameras: high diagnostic performances with significant reduction in patient radiation doses.

PURPOSE: Effective doses of 14 mSv or higher are currently being attained in patients having stress and rest myocardial perfusion imaging (MPI) single photon emission computed tomography (SPECT) performed on the same day with conventional protocols. This study aimed to assess the actual reduction in effective doses as well as diagnostic performances for MPI routinely planned with: (1) high-sensitivity cadmium zinc telluride (CZT) cameras, (2) very low injected activities and (3) a stress-first protocol where the normality of stress images may lead to avoiding rest imaging. METHODS: During a 1-year period, 2,845 patients had MPI on a CZT camera, a single-day stress-first protocol and low injected activities (120 MBq of (99m)Tc-sestamibi at stress for 75 kg body weight and threefold higher at rest). The ability to detect > 50% coronary stenosis was assessed in a subgroup of 149 patients who also had coronary angiography, while the normalcy rate was assessed in a subgroup of 128 patients with a low pretest likelihood of coronary artery disease (<10%). RESULTS: Overall, 33% of patients had abnormal MPI of which 34% were women and 34% were obese. The mean effective doses and the percentage of exams involving only stress images were: (1) 3.53 ± 2.10 mSv and 37% in the overall population, (2) 4.83 ± 1.56 mSv and 5% in the subgroup with angiography and (3) 1.96 ± 1.52 mSv and 71 % in the low-probability subgroup. Sensitivity and global accuracy for identifying the 106 patients with coronary stenosis were 88 and 80%, respectively, while the normalcy rate was 97 %. CONCLUSION: When planned with a low-dose stress-first protocol on a CZT camera, MPI provides high diagnostic performances and a dramatic reduction in patient radiation doses. This reduction is even greater in low-risk subgroups with high rates of normal stress images, thus allowing the mean radiation dose to be balanced against cardiac risk in targeted populations.

Assessment of the early stage of cardiac remodeling of spontaneously hypertensive heart failure rats using the quantitative 3-dimensional analysis provided by acipimox-enhanced FDG-PET.

Spontaneously hypertensive heart failure rats (SHHF) appear to constitute an original model for analyzing the evolution of the metabolic syndrome towards heart failure. This study aimed to characterize early cardiac dysfunction and remodeling in SHHF rats: (1) as compared with spontaneously hypertensive rats (SHR) and with a control group of Kyoto rats (WKY), and (2) by using the 3-dimensional quantitative analysis provided by acipimox-enhanced positron emission tomography (PET) with (18)F-fluorodesoxyglucose (FDG). Left ventricular (LV) ejection fraction (EF) and volume were quantified by automatic software on the FDG-PET images recorded in SHR (n = 20), SHHF (n = 18) and WKY-rats (n = 19) at ages 3 or 10 months old. Arterial blood pressure was determined by cardiac catheterization and cardiac fibrosis was quantified after sacrifice. Blood pressure was similarly elevated in SHR and SHHF rats (respective systolic blood pressures at 10-months: 199 ± 39 vs. 205 ± 2 mmHg), but SHHF rats had higher body mass than SHR rats (at 10-months, 630 ± 36 vs. 413 ± 27 g, p < 0.05) and higher blood levels of cholesterol and of triglycerides. At 3 months, cardiac parameters did not show significant differences between groups but at 10-months, SHHF and SHR rats exhibited an enhancement in myocardial mass and fibrosis associated with a clear decline in LV-EF (SHHF: 46 ± 6 %; SHR: 47 ± 5 %) as compared with WKY (56 ± 6 %, p < 0.01 for both comparisons). Cardiac remodeling of SHHF rats was clearly observable by FDG-PET from the age of 10-months, but in a similar way to that observed for SHR rats, suggesting a predominant role of hypertension.

Cardioprotective effects of adenosine within the border and remote areas of myocardial infarction.

BACKGROUND: Adenosine may have beneficial effects on left ventricular function after myocardial infarction (MI), but the magnitude of this effect on remote and MI areas is controversial. We assessed the long-term effects of adenosine after MI using electrocardiogram-triggered 18 F-fluorodeoxyglucose positron emission tomography. METHODS: Wistar rats were subjected to coronary ligation and randomized into three groups treated daily for 2 months by NaCl (control; n = 7), 2-chloroadenosine (CADO; n = 8) or CADO with 8-sulfophenyltheophilline, an antagonist of adenosine receptors (8-SPT; n = 8). RESULTS: After 2 months, control rats exhibited left ventricular remodelling, with increased end-diastolic volume and decreased ejection fraction. Left ventricular remodelling was not significantly inhibited by CADO. Segmental contractility, as assessed by the change in myocardial thickening after 2 months, was improved in CADO rats compared to control rats (+1.6% ± 0.8% vs. -2.3% ± 0.8%, p < 0.001). This improvement was significant in border (+5.6% ± 0.8% vs. +1.5% ± 0.8%, p < 0.001) and remote (-4.0% ± 1.0% vs. -10.4% ± 1.3%, p < 0.001) segments, but absent in MI segments. Histological analyses revealed that CADO reduced fibrosis, cardiomyocyte hypertrophy and apoptosis. Protective effects of CADO were blunted by 8-SPT. CONCLUSION: Long-term administration of adenosine protects the left ventricle from contractile dysfunction following MI.

Acipimox-enhanced ¹8F-fluorodeoxyglucose positron emission tomography for characterizing and predicting early remodeling in the rat infarct model.

The rat myocardial infarction (MI) model is widely used to study left ventricular (LV) remodeling. In this study, acipimox-enhanced (18)F-Fluorodeoxyglucose (FDG) gated-positron emission tomography (PET) was assessed for characterizing and predicting early remodeling in the rat infarct model. Nineteen Wistar rats had surgical occlusion of the left anterior descending coronary artery and 7 were sham-operated. PET was scheduled 48 h and 2 weeks later for quantifying MI area and LV function. Segments with <50% of FDG uptake had histological evidence of MI (74 ± 9% decrease in parietal thickness, fibrosis development). At 48 h, MI area was large (>35% of LV) in 6 rats, moderate (15-35% of LV) in 8 rats, limited (<15% of LV) in 5 rats and absent in the 7 sham rats. LV remodeling, assessed through the 2 weeks increase in end-diastolic volume, increased between rats with limited, moderate and large MI (+72 ± 25, +109 ± 56, +190 ± 69 µl, respectively, P = 0.007). This 3-groups classification allowed predicting 44% of the 2 weeks increase in end-diastolic volume, and additional 34% were predicted by heart rate at 48 h. The acipimox-enhanced FDG gated-PET technique provides efficient characterization and prediction of early remodeling in the rat infarct model.

ECG-triggered 18F-fluorodeoxyglucose positron emission tomography imaging of the rat heart is dramatically enhanced by acipimox.

PURPOSE: 18F-Fluorodeoxyglucose (FDG) imaging, provided by current positron emission tomography (PET) systems dedicated to small animals,might provide a precise functional assessment of the left ventricle (LV) in rats, although conventional metabolic conditioning by hyperinsulinaemic glucose clamping is not well adapted to this setting. This study was aimed at assessing cardiac FDG PET in rats premedicated with acipimox, a potent nicotinic acid derivative yielding comparable image quality to clamping in man. METHODS: Metabolic conditioning was compared in Wistar rats between a conventional oral glucose loading (1.5 mg/kg) and acipimox, which was given at high but well tolerated doses subcutaneously (25 mg/kg) or orally (50 mg/kg). Myocardial to blood (M/B) activity ratio and myocardial signal to noise (S/N) ratio were analysed on gated FDG PET images. RESULTS: The S/N ratio of the gated cardiac images evolved in parallel with the M/B activity ratio and these two ratios were independently enhanced by glucose loading and acipimox. However, these enhancements were: (1) dramatic for acipimox, especially for the high oral dose of 50 mg/kg (from 2.85 +/- 0.57 to 10.73 +/- 0.54 for the M/B ratio of rats with or without glucose loading; p<0.0001) and (2) much more limited for glucose loading (from 6.61 +/- 0.49 to 7.89 +/- 0.41 for the M/B ratio of rats with or without acipimox administration; p=0.049). With the high oral dose of acipimox, the gated cardiac FDG PET images had very high S/N ratios, at least equivalent to those currently documented in man. CONCLUSION: Metabolic conditioning by oral doses of acipimox is highly efficient for experimental studies planned with cardiac FDG PET in rats.

Initial infarct size predicts subsequent cardiac remodeling in the rat infarct model: an in vivo serial pinhole gated SPECT study.

UNLABELLED: The rat infarct model is widely used to study left ventricular (LV) remodeling, a main cause of heart failure characterized by progressive LV dilatation. Using pinhole collimators and advances in data processing, gated SPECT was recently adapted to image the rat heart. The aim of this study was to assess this new imaging technique for predicting and quantifying variable LV remodeling from the rat infarct model. METHODS: Pinhole 99mTc-sestamibi gated SPECT was validated for determining LV volume and identifying the necrotic and nonviable LV segments (<50% of 99mTc-sestamibi uptake) in rats, and it was applied to monitor rat LV function from 48 h to 12 wk after occlusion of the left anterior descending coronary artery (LAD) (n = 20) or sham operation (n = 9). RESULTS: In LAD-occluded rats, 48-h SPECT necrosis was large (> or =30% LV) in 6, limited (<30% LV) in 6, and undetectable in 8. End-diastolic volume of LAD-occluded rats was equivalent to that of sham-operated rats at 48 h (320 +/- 84 microL vs. 293 +/- 48 microL; not significant) but became higher at 12 wk (501 +/- 191 microL vs. 343 +/- 46 microL; P = 0.01). The follow-up increase in end-diastolic volume, which reflects the remodeling process, was closely related to the initial extent of necrosis revealed by the SPECT images (P < 0.001; R2= 0.85). This increase was limited in sham-operated rats (50 +/- 15 microL) and in the LAD-occluded rats with undetectable necrosis (55 +/- 35 microL) but it was around 3- and 7-fold higher in the LAD-occluded rats with limited (165 +/- 57 microL) and large (366 +/- 113 microL) necrosis, respectively. CONCLUSION: The variable LV remodeling documented after coronary occlusion in rats closely relates to the variable extent of necrosis provided by this model. Pinhole gated SPECT allows this remodeling to be predicted and quantified and, hence, constitutes an original tool for the experiments scheduled on the rat infarct model.

OSEM reconstruction, associated with temporal fourier and depth-dependant resolution recovery filtering, enhances results from sestamibi and 201Tl 16-interval gated SPECT.

UNLABELLED: Gated SPECT recorded with 16 intervals determines left ventricular (LV) ejection fraction more accurately than does gated SPECT recorded with 8 intervals but produces higher image noise. This study aimed to assess the results from sestamibi and (201)Tl 16-interval gated SPECT when both signal-to-noise ratio and spatial resolution were enhanced with an original method of reconstruction. METHODS: Forty patients with coronary artery disease underwent (201)Tl and sestamibi 16-interval gated SPECT and, to be used as a reference, cardiac MRI. Assessments of global and regional LV function provided by ordered-subsets expectation maximization (OSEM) with depth-dependant resolution recovery and temporal Fourier filtering were compared with those from conventional filtered backprojection (FBP) previously optimized by screening various filter frequencies and various temporal smoothing levels. RESULTS: For both tracers, LV ejection fraction was determined best when the association of OSEM with depth-dependant resolution recovery was used alone, with temporal Fourier filtering, or with a slight 2-frame temporal smoothing: Mean absolute values of relative errors ranged from 3.2% to 3.6% (4.0%-7.9% for FBP), and coefficient correlation ranged from 0.91 to 0.93 (0.70-0.91 for FBP). Among these 3 reconstruction methods, the association of OSEM with depth-dependant resolution recovery with temporal Fourier filtering provided the highest signal-to-noise ratio, with mean increases of 54% for sestamibi and 80% for (201)Tl when compared with FBP, and the best analysis of segmental contractility, with exact agreement rates with MRI being 73% for (201)Tl and 79% for sestamibi. CONCLUSION: OSEM associated with temporal Fourier filtering and depth-dependant resolution recovery filtering enhances the LV function assessment provided by sestamibi and (201)Tl 16-interval gated SPECT and dramatically reduces image noise, a property that enhances and facilitates image interpretation.