Monte Carlo simulations of clinical PET and SPECT scans: impact of the input data on the simulated images.

Monte Carlo simulations of emission tomography have proven useful to assist detector design and optimize acquisition and processing protocols. The more realistic the simulations, the more straightforward the extrapolation of conclusions to clinical situations. In emission tomography, accurate numerical models of tomographs have been described and well validated under specific operating conditions (collimator, radionuclide, acquisition parameters, count rates, etc). When using these models under these operating conditions, the realism of simulations mostly depends on the activity distribution used as an input for the simulations. It has been proposed to derive the input activity distribution directly from reconstructed clinical images, so as to properly model the heterogeneity of the activity distribution between and within organs. However, reconstructed patient images include noise and have limited spatial resolution. In this study, we analyse the properties of the simulated images as a function of the properties of the reconstructed images used to define the input activity distributions in (18)F-FDG PET and (131)I SPECT simulations. The propagation through the simulation/reconstruction process of the noise and spatial resolution in the input activity distribution was studied using simulations. We found that the noise properties of the images reconstructed from the simulated data were almost independent of the noise in the input activity distribution. The spatial resolution in the images reconstructed from the simulations was slightly poorer than that in the input activity distribution. However, using high-noise but high-resolution patient images as an input activity distribution yielded reconstructed images that could not be distinguished from clinical images. These findings were confirmed by simulated highly realistic (131)I SPECT and (18)F-FDG PET images from patient data. In conclusion, we demonstrated that (131)I SPECT and (18)F-FDG PET images indistinguishable from real scans can be simulated using activity maps with spatial resolution higher than that used in routine clinical applications.

Functional compensation in incipient Alzheimer's disease.

Aim of this study was to investigate the functional compensation mechanism in incipient Alzheimer's disease (AD). Seventeen elderly healthy subjects and nine amnestic MCI patients with incipient AD underwent brain MR scan and 99mTc ECD SPECT. We processed all images with SPM2, we created t maps, showing the wholebrain GM atrophy and functional changes, and we properly masked them with each other in order to assess relatively preserved perfusion or depression. Incipient AD showed GM atrophy in the medial temporal and temporoparietal lobes, in the insula and in the retrosplenial cortex, and GM hypoperfusion in the medial temporal and temporoparietal lobes. Relatively preserved perfusion, we could hypothesize to be compensatory in the setting of neuronal loss, was found in the posterior cingulate, in the head of the hippocampus, in the amigdala, and in the insula bilaterally, while functional depression occurred in bilateral parahippocampal gyri. In AD, a perfusional compensatory mechanism takes place in the neocortex, while perfusional depression occurs in the medial temporal lobe. These results help understand the reactive phenomena induced by the brain to try and counteract the pathological changes of AD.

Cerebral perfusion correlates of conversion to Alzheimer's disease in amnestic mild cognitive impairment.

OBJECTIVE: Aim of this study was to find cerebral perfusion correlates of conversion to dementia in patients with amnestic MCI. METHODS: 17 healthy subjects (age = 69 +/- 3, 9 females), and 23 amnestic MCI patients (age = 70 +/- 6, 10 females) underwent brain MR scan and (99m)Tc ECD SPECT. Conversion to AD was ascertained on average 19 +/- 10 months after baseline: 9 had converted (age = 69 +/- 3, 4 females), and 14 had not (age = 71 +/- 8, 6 females). We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing amnestic MCI patients converted to AD and non-converted to dementia vs controls. We assessed the effect of gray matter atrophy on the above results with SPM2 using an optimized Voxel-Based Morphometry (VBM) protocol. We compared significant hypoperfusion with significant atrophy on a voxel-byvoxel basis. RESULTS: In comparison with normal controls, amnestic MCI patients who converted to AD showed hypoperfusion in the right parahippocampal gyrus and left inferior temporal and fusiform gyri,whereas those who did not convert showed hypoperfusion in the retrosplenial cortex, precuneus and occipital gyri, mainly on the left side. We found no overlap between significant atrophy and significant hypoperfusion regions. CONCLUSIONS: Parahippocampal and inferior temporal hypoperfusion in amnestic MCI patients appears as a correlate of conversion to AD; hypoperfusion in the retrosplenial cortex is involved in memory impairment but does not seem the key prognostic indicator of conversion to dementia.

Reduced posterior cingulate binding of I-123 iodo-dexetimide to muscarinic receptors in mild Alzheimer's disease.

Early detection of Alzheimer's disease (AD) allows timely pharmacological and social interventions. Alteration in muscarinic receptor binding was evaluated with I-123 iodo-dexetimide (IDEX) in early clinical stage AD. We studied 11 mild AD patients (Folstein Minimental State Examination Score 24-27, Clinical Dementia Rating 0.5-1.0) and 10 age- and sex-matched normal subjects with SPECT brain imaging after injection of 185 MBq of IDEX and 750 MBq of 99mTc-HMPAO. Using a voxel based approach (Statistical Parametric Mapping (SPM99) software), a deficit in IDEX binding was found in the posterior cingulate cortex in the mild AD group with p (corrected)=0.06 for the most significant voxel and p=0.0003 for the voxel cluster. Region of interest (ROI) analysis confirmed the SPM99 results. SPM99 found no deficit in the HMPAO scans, suggesting that neither atrophy nor hypoperfusion were major factors in the reduced IDEX binding. This study provides further evidence of the involvement of the posterior cingulate region and of muscarinic receptors in early Alzheimer's disease and suggests that this change may precede an alteration in blood flow.

Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami.

OBJECTIVE: To determine whether regional cerebral blood flow (rCBF) is abnormal in any cerebral structure of women with fibromyalgia (FM), following a report that rCBF is reduced in the thalami and heads of caudate nuclei in FM. METHODS: Seventeen women with FM and 22 healthy women had a resting single-photon-emission computed tomography (SPECT) brain scan to assess rCBF and a T1-weighted magnetic resonance imaging (MRI) scan to enable precise anatomic localization. Additionally, all participants underwent 2 manual tender point examinations and completed a set of questionnaires evaluating clinical features. SPECT scans were analyzed for differences in rCBF between groups using statistical parametric mapping (SPM) and regions of interest (ROIs) manually drawn on coregistered MRI. RESULTS: Compared with control subjects, the rCBF in FM patients was significantly reduced in the right thalamus (P = 0.006), but not in the left thalamus or head of either caudate nucleus. SPM analysis indicated a statistically significant reduction in rCBF in the inferior pontine tegmentum (corrected P = 0.006 at the cluster level and corrected P = 0.023 for voxel of maximal significance), with consistent findings from ROI analysis (P = 0.003). SPM also detected a reduction in rCBF on the perimeter of the right lentiform nucleus. No correlations were found with clinical features or indices of pain threshold. CONCLUSION: Our finding of a reduction in thalamic rCBF is consistent with findings of functional brain imaging studies of other chronic clinical pain syndromes, while our finding of reduced pontine tegmental rCBF is new. The pathophysiologic significance of these changes in FM remains to be elucidated.

Validation of fully automatic brain SPET to MR co-registration.

Fully automatic co-registration of functional to anatomical brain images using information intrinsic to the scans has been validated in a clinical setting for positron emission tomography (PET), but not for single-photon emission tomography (SPET). In this paper we evaluate technetium-99m hexamethylpropylene amine oxime to magnetic resonance (MR) co-registration for five fully automatic methods. We attached six small fiducial markers, visible in both SPET and MR, to the skin of 13 subjects. No increase in the radius of SPET acquisition was necessary. Distortion of the fiducial marker distribution observed in the SPET and MR studies was characterised by a measure independent of registration and three subjects were excluded on the basis of excessive distortion. The location of each fiducial marker was determined in each modality to sub-pixel precision and the inter-modality distance was averaged over all markers to give a fiducial registration error (FRE). The component of FRE excluding the variability inherent in the validation method was estimated by computing the error transformation between the arrays of MR marker locations and registered SPET marker locations. When applied to the fiducial marker locations this yielded the surface registration error (SRE), and when applied to a representative set of locations within the brain it yielded the intrinsic registration error (IRE). For the best method, mean IRE was 1.2 mm, SRE 1.5 mm and FRE 2.4 mm (with corresponding maxima of 3.3, 4.3 and 5.0 mm). All methods yielded a mean IRE <3 mm. The accuracy of the most accurate fully automatic SPET to MR co-registration was comparable with that published for PET to MR. With high standards of calibration and instrumentation, intra-subject cerebral SPET to MR registration accuracy of <2 mm is attainable.

Simultaneous emission transmission tomography using technetium-99m for both emission and transmission.

This phantom study investigates whether attenuation maps from transmission data degraded by increased noise from subtraction of emission counts can still provide useful attenuation correction in the regular and obese chest. Technetium-99m was used for both emission and transmission on a triple head simultaneous emission transmission tomography (Tc-Tc SETT) system. Fanbeam transmission counts were computed by subtracting emission counts estimated from the two parallel collimator heads. Radioactive decay was used to simulate organ counts from injections of 900 and 400 MBq sestamibi for regular and obese chest sizes. Line source activity was 350 MBq. Control attenuation maps were obtained with no emission activity. Noise control included catering for negative and zero transmission counts, pre-filtering and segmentation of mu maps. Pre-filtering was tried before and after subtraction and before and after setting negative pixels to zero. Mean+/-SD count/pixel at the heart in anterior transmission projections was typically 33+/-18 for the regular and 1+/-7 for the obese chest. For the obese chest, pre-filtering before resetting negative counts best preserved mean mu in soft tissue and lung. Tc-Tc SETT mu mean+/-SD for the regular chest were 0.144+/-0.012 and 0.058+/-0.004 for soft tissue and lung and for the obese chest, 0.152+/-0.075 and 0.059+/-0.017. The accuracy of the Tc-Tc SETT bullseye plots for the regular chest was the same as with control map attenuation correction and 3 times better than with no correction. For the obese chest it was as good as with control map correction only if mu map segmentation was applied. Tc-Tc SETT soft tissue and lung mu in 28 patient studies indicated that segmentation is practical for a wide range of chest sizes. Tc-Tc SETT on a triple-head system offers an accurate, inexpensive method of attenuation correction for the majority of chest sizes.

Localization of temporal lobe epileptic foci with iodine-123 iododexetimide cholinergic neuroreceptor single-photon emission computed tomography.

There is evidence suggesting that muscarinic cholinergic neuroreceptors (mChR) are reduced at seizure foci. Iodine-123 (I-123) iododexetimide (IDEX) single-photon emission computed tomography (SPECT) permits in vivo imaging of mChR. We assessed 23 patients with temporal lobe epilepsy (TLE) undergoing preoperative assessment. Regions of interest were placed over the amygdala, hippocampus, and lateral temporal cortex on IDEX SPECT images. Eighteen patients had unilateral TLE. In these, IDEX binding in the ipsilateral hippocampal region was reduced by 19.1 +/- 12%. This was significantly greater than blood flow asymmetry (p < 0.02 by Wilcoxon's signed-rank test). Changes were less marked in the amygdala (11.3 +/- 6.4%) and lateral cortex (7.6 +/- 12.1%). Blinded visual analysis gave correct localization in 14 (78%) patients, and hexamethylpropylenamine oxide (HMPAO) SPECT gave correct localization in 50%. MRI revealed hippocampal sclerosis in 13 (72%) patients and was normal in 5 patients. Of the latter group, four were correctly localized by IDEX. This study confirms that mChR receptors are altered in medial temporal lobe structures in TLE. IDEX SPECT appears to be superior to interictal HMPAO SPECT and complimentary to MRI for seizure focus localization.

Human dosimetry and biodistribution of iodine-123-iododexetimide: a SPECT imaging agent for cholinergic muscarinic neuroreceptors.

UNLABELLED: Iodine-123-iododexetimide (IDEX) has recently been used for SPECT imaging of muscarinic cholinergic neuroreceptors (mAChR) in humans. We report the human radiation dosimetry, whole-body and normal cerebral distribution of IDEX. METHODS: Serial whole-body planar and brain SPECT scans were performed over 24 hr in four normal subjects. Organ activity was calculated from attenuation-corrected geometric mean counts from ROIs drawn over visible organs. Thigh activity was used for background subtraction. Organ absorbed doses and effective dose were calculated using the MIRD schema. Brain SPECT was performed 6 hr postinjection in ten normal subjects. ROIs placed over cortical and subcortical structures were used to determine brain distribution. RESULTS: The effective dose was 24.7 microSv/MBq. An average of 54% of IDEX remained in the body background. Decay-corrected brain uptake was 6.9% of injected dose at 1 hr, 8.6% at 6 hr and 8.1% at 24 hr. Regional brain distribution showed high uptake in striatum and cortex with low activity in thalamus and cerebellum. At 6 hr, activity relative to striatum was 70% for frontal and parietal cortex, 102% for occipital cortex, 54% for thalamus and 11% for cerebellum. CONCLUSION: Iodine-123-IDEX produced high quality SPECT images with activity at 6 hr reflecting the known distribution of mAChR receptors. The favorable dosimetry of IDEX and high synthetic yield (50%-70%) suggest it to be a suitable agent for clinical studies.

Dietary fat modulation of left ventricular ejection fraction in the marmoset due to enhanced filling.

OBJECTIVE: The aim was to investigate the influence of long term dietary fish oil consumption on cardiac function in a non-human primate, to elucidate further the basis of the apparently reduced cardiovascular disease mortality associated with its consumption in man. METHODS: Adult male marmoset monkeys (Callithrix jacchus) were fed diets supplemented with polyunsaturated fatty acids (PUFA) of marine (tuna fish oil) or plant (sunflower seed oil) origin, saturated animal fat (sheep perirenal fat), or a low fat reference diet for 24 months. Cardiac function was assessed using radionuclide angiography under pentobarbitone anaesthesia with a counts based adaptation for ventricular volume estimations. Measures were made at rest and during infusion of adrenaline. RESULTS: The mean left ventricular ejection fraction was greater in the tuna fish oil group [55.0(SEM 1.1)% n = 7] and the sunflower seed oil group [58.1(2.4)% n = 8] than in the reference group [48.5(1.4)% n = 9] and the sheep fat group [47.6(1.8)% n = 8]. This was associated with a more than 25% greater end diastolic volume and 40-70% increases in stroke volume in tuna fish or sunflower seed oil fed animals. There was no evidence of cardiac hypertrophy. In contrast, adrenaline increased stroke volume and ejection fraction by increasing emptying, thus reducing residual end systolic. Tuna fish oil fed animals had a low resting heart rate. When this was raised to comparable levels by adrenaline, lower pressure-rate indices and greater cardiac minute work suggested higher myocardial energy efficiency in PUFA fed animals compared with the reference and sheep fat groups. CONCLUSIONS: Dietary fish oil and sunflower seed oil increased the left ventricular ejection fraction in the marmoset monkey by enhancing ventricular filling, thus providing an energy sparing promotion of diastolic relaxation.

Radionuclide angiographic study of the influence of dietary lipid supplements on cardiac function in the marmoset (Callithrix jacchus).

Radionuclide angiography was used to examine the influence of dietary fat on cardiac function in the common marmoset monkey (Callithrix jacchus jacchus) under barbiturate anaesthesia. Animals were fed for 6-8 months with a low fat (4.5%) reference diet or the same diet supplemented (12%) with sunflower seed oil or sheep fat. Although there was a tendency towards increased heart rate, left ventricular ejection fraction, peak ejection rate, and peak filling rate in both fat supplemented groups, significant increases in heart rate (+50%), peak ejection rate (+71%), and peak filling rate (+84%) were found with sheep fat supplementation, whereas only the vegetable oil supplement produced a significant improvement in left ventricular ejection fraction (+23%). There were no differences in resting blood pressure, and the main consequence of dietary fat supplementation was a major increase in apparent cardiac oxygen consumption (+58%) with the sheet fat diet, as determined by the pressure-rate index. Infusion of isoprenaline hydrochloride (0.2 microgram.kg-1.min-1) increased all indices of cardiac function towards common maxima. There were no differences in either the depth or duration of anaesthesia between dietary groups. It therefore is unlikely that this contributed to any of the observed dietary induced differences in cardiac function. It is suggested that dietary saturated animal fat increased cardiac work and oxygen consumption at rest to the extent that functional reserve to respond to stress was significantly diminished. Feeding a linoleic acid rich polyunsaturated vegetable oil supplement was, however, accompanied by evidence of some improvement in left ventricular ejection fraction.

Gated blood-pool studies of cardiac function in the rat and marmoset.

To develop a sensitive, relatively noninvasive method for monitoring cardiac function in small laboratory animals, equilibrium gated blood-pool imaging (with Tc-99m RBC) was adapted for use in an inbred strain of laboratory rats of 400-470 g body weight and in marmosets of 320-400 g body weight. A 2-mm pinhole collimator was fitted to the gamma camera to produce a distinct image of the left ventricle following intravenous injection of 5 mCi of pertechnetate. Reproducible and consistent data for heart rate, left-ventricular ejection fraction, and peak ejection rate were obtained from studies on 13 male rats and five marmosets maintained on constant diets. An intravenous injection of 0.4 microgram of isoprenaline led to predictable increases in heart rate, left-ventricular ejection fraction, and peak ejection rate, and provided evidence of the sensitivity of the method in monitoring heart function in small laboratory animals.

Effect of renal transplantation on left ventricular function in hemodialysis patients.

The effect of renal transplantation on left ventricular function was evaluated in 14 patients with end-stage renal disease requiring maintenance hemodialysis. They had no apparent clinical evidence of heart disease. Ischemic heart disease was excluded by history, electrocardiography and radionuclide ventriculography. Echocardiography and radionuclide ventriculography were recorded in the interdialytic periods. Sixty-four per cent of the patients had abnormal left ventricular function despite adequate hemodialysis. Left ventricular function was reassessed within the first two months after successful renal transplantation. All parameters improved shortly after the transplantation. Cardiac index increased by an average of 0.76 +/- 0.11/min/m2 (P less than 0.001), stroke volume by 23.9 +/- 0.5 ml (P less than 0.001), ejection fraction by 9.7 +/- 1.9% (P less than 0.001), mean normalized posterior wall velocity by 0.17 +/- 0.06 second-1 (P less than 0.01), mean velocity of circumferential fiber shortening by 0.28 +/- 0.02 circle/second (P less than 0.001), and mitral valve diastolic closure rate by 17.2 +/- 2.3 mm/second (P less than 0.01). Our findings support the existence of a specific uremic cardiomyopathy which is a functional defect probably related to poorly dialyzed uremic toxins.