Impact of Region-of-Interest Delineation Methods, Reconstruction Algorithms, and Intra- and Inter-Operator Variability on Internal Dosimetry Estimates Using PET.

PURPOSE: Human dosimetry studies play a central role in radioligand development for positron emission tomography (PET). Drawing regions of interest (ROIs) on the PET images is used to measure the dose in each organ. In the study aspects related to ROI delineation methods were evaluated for two radioligands of different biodistribution (intestinal vs urinary). PROCEDURES: PET images were simulated from a human voxel-based phantom. Several ROI delineation methods were tested: antero-posterior projections (AP), 3D sub-samples of the organs (S), and a 3D volume covering the whole-organ (W). Inter- and intra-operator variability ROI drawing was evaluated by using human data. RESULTS: The effective dose estimates using S and W methods were comparable to the true values. AP methods overestimated (49 %) the dose for the radioligand with intestinal biodistribution. Moreover, the AP method showed the highest inter-operator variability: 11 ± 1 %. CONCLUSIONS: The sub-sampled organ method showed the best balance between quantitative accuracy and inter- and intra-operator variability.

Molecular imaging PET and SPECT approaches for improving productivity of antipsychotic drug discovery and development.

The need for innovation in research is leading to an increased use of imaging biomarkers, which have shown to reduce timings and increase productivity, thus saving costs. PET and SPECT neurotransmission imaging has shown usefulness in the discovery and development of drugs for the central nervous system, providing unique information on drug-target interactions in the living human brain. Among the different therapeutic areas, antipsychotic drugs pioneered the application of these technologies in early phases of development. PET and SPECT radioligands for the most commonly targeted neurotransmission systems in the development of these drugs, such as the dopaminergic and serotoninergic systems are available, thus fostering the inclusion of PET and SPECT studies in the antipsychotic drug development plans. Radioligands for other neurotransmission systems more recently implicated in the pathophysiology of schizophrenia, such as the glutamatergic system, are being currently investigated. This review focuses on neurotransmission PET and SPECT aiming to serve as guidance for procedure requirements and methodology choices to be applied in antipsychotic drug development, through specific examples. Cutting-edge study designs and quantification approaches will be reviewed. Finally, some clues to get the most out of the PET and SPECT studies in the development of antipsychotic drugs will be provided.

Impact of scatter correction on D2 receptor occupancy measurements using 123I-IBZM SPECT: comparison to 11C-Raclopride PET.

Reported values of D(2) receptor occupancy (RO) achieved by antipsychotic drugs tend to be lower when measured with (123)I-IBZM SPECT than with (11)C-Raclopride PET. Image degrading factors such as attenuation, distance-dependent collimator response and scatter could account for this difference. While attenuation correction is routinely applied to SPECT images, the other degradations are not usually accounted for. The aim of this work was to assess the impact of scatter correction on D(2) RO quantification with (123)I-IBZM SPECT, and to compare the results of both corrected and un-corrected SPECT values with (11)C-Raclopride PET measurements. Phantom experiments as well as within-subject human data from a previous study were used for this purpose. SPECT images were reconstructed using filtered back-projection including attenuation correction (FBP(A)), ordered subsets expectation maximization including attenuation and point spread function corrections (OSEM(A+PSF)) and ordered subsets expectation maximization including attenuation, point spread function and scatter corrections (OSEM(A+PSF+SCT)). PET images were reconstructed using the FBP algorithm and corrected for attenuation, scatter, random coincidences and dead time. Quantification of receptor availability was performed using the tissue ratio at pseudoequilibrium for SPECT, and the simplified reference tissue model (SRTM) for PET. Analysis was performed using both occipital cortex (occ) and cerebellum (cer) as reference regions for both modalities. When images were reconstructed using FBP(A), SPECT D(2) RO values were significantly lower as compared with PET leading to a D(2) RO difference of -20% (CI(95%): -13, -27%) (occ) and -23% (CI(95%): -14, -31%) (cer). When images were reconstructed using OSEM(A+PSF), SPECT D(2) RO values were also lower as compared with PET leading to a D(2) RO difference of -21% (CI(95%): -14, -27%) (occ) and -24% (CI(95%): -18, -30%) (cer). When images were reconstructed using OSEM(A+PSF+SCT), the D(2) RO bias was reduced to -6% (CI(95%): 0, -13%) (occ) and -11% (CI(95%): -4, -18%) (cer). These data suggest that the scatter correction plays a major role in explaining the differences between D(2) RO measurements using (123)I-IBZM SPECT and (11)C-Raclopride PET.

Neurotransmission SPECT and MR registration combining mutual and gradient information.

PURPOSE: Image registration is important in functional image analysis. In neurotransmission single photon emission tomography (nSPECT), specific uptake sites can be accurately localized by superimposing the SPECT study onto a high-resolution structural image such as a magnetic resonance (MR) of the subject. Mutual-information (MI)-based algorithms are usually employed for this purpose. Nevertheless, nSPECT/MR registration using MI is often limited by the low count rates present in nSPECT. Several works have proposed extensions of the MI measures to include gradient information (GI) from the images but their performance has not been evaluated in SPECT studies. METHODS: In this work, the accuracy of the MI including gradient information (MIG) was compared with the standard MI using data from healthy volunteers and data simulating a specific uptake reduction using three different radioligands: 123I-IBZM, 123I-ADAM, 123I-R91150. RESULTS: The results showed that MIG-based registration yielded better accuracy than MI. The MIG-based similarity measures were less sensitive to sparse sampling and diminished computational time without a substantial decrease in registration accuracy. CONCLUSIONS: Accuracy of nSPECT/MR registration is improved when gradient information is included in the MI-based algorithm, which makes MIG-based registration potentially useful for clinical applications.

Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients.

The (123)I-IBZM SPECT measured D(2) receptor occupancy (D(2)RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D(2) receptor occupancy (D( 2)RO) and plasma concentration (C(P)) in stabilized schizophrenic patients on clinically relevant doses using (123)I-IBZM SPECT; 2) To investigate the time course of AP-induced D(2)RO and corresponding C(P). Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D( 2)RO and C(P) were measured over time following a sparse-sampling experimental design, and individual PK and D(2)RO-time profiles were estimated using a population approach. Observed striatal D(2)RO and C(P) ranges were 28-75% and 9.4-60.5 ng/mL for risperidone, 22-84% and 8.6-89.5 ng/mL for olanzapine, 5-53% and 41.6-818.2 ng/mL for clozapine and 0-64% and 37.9-719.6 ng/mL for quetiapine. A PK-D(2)RO relationship was found for the four APs. D(2)RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D(2)RO and C(P) at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D(2)RO below 65%. D(2)RO patterns over time differ between AP. These results should be considered for accurate interpretation of D(2)RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

Cerebral perfusion and haemodynamics measured by SPET in symptom-free patients with transient ischaemic attack: clinical implications.

Transient ischaemic attacks (TIAs) are heterogeneous from the clinical, physiopathological, aetiological and prognostic points of view. Single-photon emission tomography (SPET) may influence patient management by helping to define the vascular topography and by suggesting the probable mechanism (embolic or haemodynamic). However, the variables predicting focal regional cerebral blood flow (rCBF) and cerebrovascular reserve (CVR) abnormalities on SPET and their clinical correlation are poorly known. Our objective in this study was to assess the value of rCBF and CVR measured by SPET in a prospective series of 42 patients with recent (within the preceding 30 days) first-ever TIA Two SPET examinations [baseline and post-acetazolamide (ACZ)] were consecutively performed, and region/reference ratios were obtained using an irregular region of interest (ROI) method. Percentages of interhemispheric asymmetry between homologous brain regions were used to identify abnormalities on baseline SPET, and the percentage changes in asymmetry between the baseline and post-ACZ SPET studies were used to identify abnormal responses to the vasodilator stimulus. Mean baseline and test-retest values previously obtained in normals were used as a reference. The relationship of SPET findings with clinical data and results of complementary examinations was assessed. Most patients (98%) had abnormal findings on either baseline (43%), post-ACZ (19%) or both SPET studies (36%). Thus, 33 patients had hypoperfusion on baseline SPET (78.5%, symptom related in 45%). In 23 patients, a poor response to ACZ was found (55%, symptom related in 21.5%). No predictors for rCBF or CVR impairment were found. Most patients with a first-ever TIA episode present focal hypoperfusion on SPET, either with or without correlation with TIA symptoms. Post-ACZ SPET increases the probability of finding cerebrovascular abnormalities, and orients attention towards an haemodynamic compromise. Focal hypoperfusion on SPET should not be viewed as clinically insignificant because it probably reflects previous or ongoing clinical and/or subclinical episodes of cerebral ischaemia.

Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint.

The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.

Concordance between rest MIBG and exercise tetrofosmin defects: possible use of rest MIBG imaging as a marker of reversible ischaemia.

Perfusion imaging combined with pharmacological stress is the study of choice in patients with ischaemic heart disease who are incapable of exercising. Some medical conditions, however, can preclude the use of pharmacological stress. In these particular situations, availability of a diagnostic test which allows for the assessment of ischaemic territory at rest would be desirable. With the purpose of providing a marker of reversible ischaemia, we evaluated myocardial iodine-123 metaiodobenzylguanidine (MIBG) uptake in regions with fixed and reversible defects defined by exercise/rest perfusion study. Fifty-four male patients with ischaemic heart disease and previous myocardial infarction were studied by means of exercise/rest tetrofosmin and MIBG single-photon emission tomography (SPET). Regional tracer uptake was quantified and expressed as a percentage of maximum peak activity. Areas with denervated but perfused myocardium and areas with ischaemic myocardium were calculated. Regions with<75% of peak activity in the exercise perfusion study were divided into two groups according to whether the increase in peak activity in the respective rest study was >10% (reversible regional defect) or <10% (fixed regional defect). These percentages were compared with the percentages of the innervation study. The area of the innervation defect was significantly larger when the perfusion defect was reversible than when it was fixed. In regions with reversible perfusion defects, the size of the area of denervated but perfused myocardium was similar to the size of the area of ischaemic myocardium. In regions with reversible defects, the percentage of myocardial MIBG uptake was not significantly different from the percentage of tetrofosmin uptake at exercise, while it was significantly lower than the percentage of tetrofosmin uptake at rest. In regions with fixed defects, the percentage of myocardial MIBG uptake was significantly lower than the percentage of tetrofosmin uptake at exercise and at rest. In patients who developed angina during exercise test, the area of denervated but perfused myocardium was significantly larger than in patients without angina (4.1+/-2.4 vs 3.4+/-2.5, P=0.02). The same trend was observed with regard to the size of the innervation defect (8.6+/-2.4 vs 5.7+/-2.2, P=0.02). It is concluded that when the use of pharmacological stress is not possible in patients incapable of exercising, rest studies with MIBG combined with rest myocardial perfusion studies may be useful as a marker of reversible ischaemia.

SPECT mapping of cerebral activity changes induced by repetitive transcranial magnetic stimulation in depressed patients. A pilot study.

Repetitive transcranial magnetic stimulation (rTMS) is being investigated as an alternative treatment for depression. However, little is known about the clinical role and the neurophysiological mechanisms of the action of rTMS in these patients. In this study, 99mTc-HMPAO single photon emission computed tomography (SPECT) was used to map the effects of left dorsolateral prefrontal rTMS on prefrontal activity in seven patients who met DSM-IV criteria for major depression resistant to pharmacological treatment. rTMS consisted of 30 trains of 2-s duration stimuli (20 Hz, 90% of motor threshold), separated by 30-s pauses. Each patient underwent three SPECTs: at baseline; during the first rTMS; and 1 week after 10 daily sessions of rTMS. Regional cerebral blood flow (rCBF) of each cerebral region was normalized to the rCBF value in the cerebellum and relative changes in normalized rCBF were addressed using a region-of-interest analysis. The Hamilton Depression Rating Scale (HDRS) was used for clinical evaluation before and after rTMS. A significant rCBF increase after the 10 sessions of rTMS was found in the left prefrontal region (MANOVA F=5.29, d.f.=2,10, P=0.027), but no significant rCBF changes were found during the first rTMS session. The remaining cerebral regions showed no significant rCBF changes at any time. Only two patients showed a clinical improvement after rTMS, with 50% reduction of the initial HDRS score. The study was repeated under placebo conditions (identical design but addressing coil discharges to the air) in these two patients, who failed to show any rCBF increase during sham-rTMS. No relationship was found between the percentage of left prefrontal rCBF change and the clinical findings. In conclusion, rTMS of the left prefrontal cortex induces a significant rCBF increase in this region, despite the limited clinical effect in our sample of depressed patients. Cerebral perfusion SPECT is a useful tool to map cerebral activity changes induced by rTMS.

Brain SPECT in clinical practice. Part I: perfusion.

Brain perfusion SPECT is a functional neuroimaging technique that allows noninvasive study of physiologic and physiopathologic events in the human brain. With the appropriate technique and careful interpretation of the information provided, brain perfusion SPECT has proven potential for patient management. SPECT has clinical value in the diagnosis, therapeutic management, and follow-up of patients. The diversity of central nervous system diseases and the still incomplete knowledge of the mechanisms that underlie them have contributed to the success of brain perfusion SPECT as a research tool in neurosciences. This article provides fundamental knowledge on how and when to perform brain perfusion SPECT in clinical practice. A general overview of the clinical value of this technique is followed by relevant information on cerebral physiology for proper understanding of brain SPECT images. Practical considerations on quantification and interventional studies are also offered. Finally, step-by-step recommendations for interpreting and reporting brain perfusion SPECT images are provided to obtain the maximum clinical benefit from this technique.