High-resolution Single-photon Emission Tomography Research Articles

Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery.

The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI. Using simultaneous dual-isotope imaging, we demonstrate that the regional CNS tissue exposure of molecules with varying chemical properties is affected by IT space anatomy, cerebrospinal fluid (CSF) dynamics, CSF clearance routes, and the location and volume of the injected bolus. These imaging approaches can be used across species to optimize the safety and efficacy of IT drug therapy for neurological disorders.

Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease.

Reductions in regional cerebral perfusion, particularly in the posterior temporo-parietal lobes, are well recognized in Alzheimer's disease. We set out to correlate perfusion changes, using (99m)Tc-HMPAO single photon emission tomography (SPET), with the pathological stage of Alzheimer's disease. The 'Braak stage' of the distribution of neurofibrillary pathology in post-mortem brains was used to classify SPET scans taken in life from a mixed (dementia and control) elderly population into the entorhinal stage (n = 23 subjects), limbic stage (n = 30 subjects) and neocortical stage (n = 36 subjects) Alzheimer's disease pathology. The SPET scans were then registered to a common, standard Talaraich space, and single template scans produced for each pathological stage. Comparison of these templates revealed an evolution in the pattern of reduction in regional perfusion. Additional comparisons were performed using earlier SPET scans obtained 5 years before death. For comparisons between templates, a threshold of 10% perfusion change was chosen so as to be clinically relevant as well as statistically significant. Reduced perfusion appears between the entorhinal and limbic stages in the anterior medial temporal lobe, subcallosal area, posterior cingulate cortex, precuneus and possibly the supero-anterior aspects of the cerebellar hemispheres. Large posterior temporo-parietal perfusion defects then appear between the limbic and neocortical stages, before finally large frontal lobe perfusion defects. The time course of these perfusion defects appears relatively long, suggesting that perfusion changes may have scope to be a diagnostic aid in staging Alzheimer's disease in life. The reduction in anterior medial temporal lobe perfusion may have future relevance on modern high resolution SPET and PET systems and also perfusion-type MRI sequences.

Differential alteration of the nigrostriatal dopaminergic system in Wilson's disease investigated with [123I]ss-CIT and high-resolution SPET.

Wilson's disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2ss-carbomethoxy-3ss-(4[123I]iodophenyl)tropane ([123I]ss-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [123I]ss-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [123I]ss-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [123I]ss-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4+/-3.0 vs 11.7+/-2.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [123I]ss-CIT binding ratios from pseudo-sclerosis CD (9.4+/-2.3), through pseudo-parkinsonian CD (9.1+/-2.1) to arrhythmic-hyperkinetic CD (8.5+/-1.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30+/-0.19 vs 1.11+/-0.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [123I]ss-CIT binding ratios (r=-0.49 to -0.57). For degree of liver alteration, significant correlations were obtained with the putaminal binding ratio (r=-0.37) and the CA/PU ratio (r=0.44). From these results is concluded that in WD the nigrostriatal dopaminergic function is compromised to varying extents. The degree of this presynaptic alteration of dopaminergic neurotransmission depends on the clinical course and severity of this copper deposition brain disorder and also varies in the different striatal substructures.

Specific binding and laterality of human extrastriatal dopamine D 2/D 3 receptors in late onset type 1 alcoholic patients

Late onset type 1 alcoholism has been suggested to be associated with decreased dopaminergic transmission. Our hypothesis was that late onset type 1 alcoholics have also abnormal extrastriatal dopamine D 2/D 3 receptor distribution. We performed binding, heterogeneity and laterality analysis of extrastriatal and striatal dopamine D 2/D 3 receptors in nine late onset male alcoholics and in 12 age-matched healthy males. A radioligand, [ 123I]epidepride was used in high resolution single-photon emission tomography (SPET). Specific binding of epidepride in the left temporal pole was significantly ( P<0.05) lower in type 1 alcoholics (0.74±0.14 ml/ml) than in controls (0.89±0.14 ml/ml). In alcoholics, there was no normal left-to-right asymmetry of the temporal cortical heterogeneity of epidepride distribution observed in control males (0.89±0.19 vs. 1.10±0.19; P<0.05). The results suggest that the specific binding of dopamine D 2/D 3 receptors in late type 1 alcoholics is decreased and its laterality in the temporal brain is altered from normal.

Rapid renal single-photon emission tomography by continuous infusion of iridium-191m.

Continuous infusion of iridium-191m (t1/2 = 5 s), produced with an 191Os/191mIr generator, was used to obtain rapid high-resolution single-photon emission tomography (SPET) of renal blood flow in the rabbit. SPET scans of the abdomen were obtained with a triple-detector SPET system (MS3, Siemens Gammasonics). The generator was eluted at a flow rate of 3 ml/min, which delivered a steady-state dose of 170 MBq (4.5 mCi) of 191mIr. The total 191Os breakthrough was 850 kBq (23 microCi). A 5-min SPET acquisition recorded a total of 2.8 million counts, resulting in images of high technical quality. Volume-rendered images clearly showed the abdominal aorta, splenic artery, spleen, renal arteries, kidneys and splanchnic vasculature. Tomographic slices through the kidneys revealed tracer primarily within the renal cortices without visualization of the collecting system. The estimated effective dose equivalent for a 5 min infusion of 191mIr at a steady-state dose of 170 MBq is 0.74 mSv compared with 2.7 mSv from a 170 MBq dose of 99mTc-DMSA. This study demonstrates the feasibility of high-resolution SPET of regional renal perfusion in the rabbit by continuous intravenous infusion of 191mIr. The renal distribution of continuously infused 191mIr is largely within the cortices, with minimal or no detectable activity in the region of the renal pelvicalyceal system. Using this technique, cortical renal SPET can be completed much more rapidly (< 5 min) than with conventional renal cortical imaging agents, which suggests that this technique could be applied to the observation of rapid changes in renal perfusion such as those resulting from pharmacologic intervention, obviating the need for the patient to return for additional visits. Additional studies are required to (a) validate the methodology in larger animals prior to considering the potential for use in human beings, (b) optimize the generator design for continuous infusion, and (c) evaluate the changes in the distribution of 191mIr that occur in animal models of altered renal perfusion.

Regional cerebral blood flow single-photon emission tomography with 99mTc-HMPAO and the acetazolamide test in the evaluation of vascular and Alzheimer's dementia.

The diagnostic potential of technetium-99m hexamethylpropylene amine oxime (HMPAO) following systemic administration of the cerebral vasodilator acetazolamide (acetazolamide test) was evaluated by regional cerebral blood flow (rCBF) single-photon emission tomography (SPET) in patients with Alzheimer's disease (AD) or vascular dementia (VD). An initial, high-resolution SPET study was performed with 99mTc-HMPAO, and after 2 days the patients were re-evaluated with 99mTc-HMPAO following systemic administration of acetazolamide. Reconstructed SPET slices were evaluated visually and semiquantitatively by a semi-automatic rCBF map method. When 99mTc-HMPAO alone was used, bilateral hypoperfusion was found in the temporal and/or parietal regions in 33% (6/18) of the VD patients and in 70% (23/33) of the AD patients. The corresponding data obtained by quantitative evaluation were 41% (7/17) and 71% (15/21), respectively. The vascular reserve capacity, as determined with the acetazolamide test, was preserved visually in 22% (4/18) and quantitatively in 29% (5/17) of the VD patients, but in 73% (24/33) and 76% (16/21) of the AD patients. The differences in the perfusion patterns between the VD and AD patients were statistically significant (P<0.01, Fischer's exact test). Of the VD patients with hypoperfusion (bilateral temporal and/or parietal), 4/6 (67%, visual evaluation) and 4/7 (57%, quantitative evaluation) had a decreased vascular reserve capacity as determined with the acetazolamide test. In the AD group of patients the corresponding results were 3/23 (13%) and 4/15 (27%). It is concluded that the acetazolamide test is promising in rCBF SPET to differentiate VD from AD.

Fractal analysis of striatal dopamine re-uptake sites.

Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT). The mean fractal dimension was 1.15+/-0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19+/-0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions.

Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]epidepride single-photon emission tomography.

The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2 receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91+/-0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [123I]epidepride can be used for imaging striatal and extrastriatal dopamine D2 receptor sites in the living human brain.

Initial human studies with single-photon emission tomography using iodine-123 labelled 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)- 7-iodo-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine (NNC 13-8241).

The iodine-123 labelled ligand 3-(5-cyclopropyl-1,2, 4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1, 5-a][1,4]-benzodiazepine ([123I]NNC 13-8241) was evaluated as a probe for in vivo imaging of benzodiazepine receptor sites in the human brain. Four healthy volunteers were imaged with a high-resolution single-photon emission tomography (SPET) scanner. The metabolism of [123I]NNC 13-8241 in plasma was slow. The total brain uptake was about 1.5-fold higher than that of [123I]iomazenil. The specific binding in the cortical areas was high and less intense in the thalamus. The most intense uptake was seen in the occipital cortex. The peak cortical uptake of [123I]NNC 13-8241 was observed 6-10 h after the injection of tracer. The radiation burden to the patient was moderate, being 2.5 middle dot10(-2 )mSv/MBq (effective dose equivalent). A slow metabolism together with favourable kinetics indicates that [123I]NNC 13-8241 is a specific and promising SPET ligand for imaging benzodiazepine receptor sites in the living human brain.

Myocardial infarction in rats: high-resolution single-photon emission tomographic imaging with a pinhole collimator.

The purpose of this study was to evaluate the accuracy of myocardial imaging by means of high-resolution single-photon emission tomography (SPET) with a pinhole collimator in rats with experimental infarction. Myocardial infarctions were induced in male Wistar rats by ligation of the left coronary artery for 30 min, followed by reperfusion. Two days after the reperfusion, pinhole SPET was performed after the intravenous administration of 111 MBq of thallium-201 chloride, using a rotating gamma camera equipped with a pinhole insert (2.0-mm aperture) in a low-energy pinhole collimator. SPET projection data were collected at 6 degrees increments over 360 degrees using a 4-cm radius of rotation to reconstruct the short- and long-axis images. Projection data were acquired in 15 or 30 s, the SPET imaging being accomplished within 40 min after the injection of 201Tl. After SPET, the rats were sacrificed to remove the hearts for autoradiography (ARG) and nitroblue tetrazolium (NBT) staining as a visual correlative study. Quantitative correlative studies between pinhole SPET and ARG were performed with linear regression analysis for infarct size and distribution properties (relative counts on SPET images and relative density on autoradiographs) on the short-axis sections. All infarcts (4 mm in minimum diameter) in seven rats were detected by pinhole SPET. The SPET images in rats with or without myocardial infarction were consistent with the findings of ARG and NBT staining. There were significant correlations between pinhole SPET and ARG with respect to the infarct size (r=0.933, P <0.001; n=15) and the relative radiotracer distribution (r=0.931, P <0.001; n=68). This study therefore confirmed the accuracy of myocardial pinhole SPET imaging in rats with myocardial infarction. This method may partially substitute for ARG and prove useful for assessing new myocardial imaging agents in vivo in small laboratory animals.

Three-phase bone scintigraphy of hydroxyapatite ocular implants.

Hydroxyapatite ocular implants are replicas of lamellar bone tissue derived from the exoskeleton of a reef-building coral by a hydrothermal chemical exchange reaction. Attached to the eye muscles, they act as a passive framework for fibrovascular ingrowth and can be drilled to hold the visible part of the artificial eye and allow synchronous eye movement. Fibrovascular ingrowth has to be confirmed by bone scintigraphy before the drilling procedure. This study monitored the vascular ingrowth into the implant in ten patients over 12 months to establish a clinically feasible imaging protocol. Tracer accumulation was monitored visually and quantitatively in dynamic and single-photon emission tomography (SPET) scans after the intravenous administration of 600 MBq of 99mTc-DPD. The implants showed no tracer accumulation in the arterial or blood pool phase. Accordingly, dynamic scintigraphy can be omitted from the imaging protocol. Delayed tracer accumulation appeared no earlier than 2 and no later than 6 months after surgery. Planar scintigraphy is not recommended as high-resolution SPET is necessary to separate the implant from the surrounding bone. We conclude that imaging can be confined to high-resolution SPET 3 h after tracer injection, no earlier than 3 months after surgery. The vascularized hydroxyapatite orbital implant is an important in vivo model for bone-seeking agents to study their uptake kinetics independently of any soft tissue and bone disease. Our results provide evidence that in normal bones the chemical absorption of 99mTc-DPD into the crystalline structure of hydroxyapatite is the only quantitatively relevant uptake mechanism.

Initial experience with single-photon emission tomography using iodine-123-labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane in human brain.

The iodinated cocaine analogue 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), a new dopamine transporter, was preliminary tested in human brain. Two normal volunteers and two patients with Parkinson's disease were imaged with a high-resolution single-photon emission tomography scanner. The specific binding of [123I]beta-CIT in the basal ganglia and thalamus was high in normal volunteers. In addition, there was relatively intense uptake in the medial prefrontal area. Patients with Parkinson's disease who were older than controls showed significantly lower specific binding in the basal ganglia and thalamus and no uptake in the medial prefrontal cortex. This decrease in the dopamine transporter may be age related.