Search

Purpose This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes. Methods Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [18F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking. Conclusion All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.

Quantitative assessment of dopamine transporter imaging can aid in diagnosing Parkinson disease (PD) and assessing disease progression in the context of therapeutic trials. Previously, the software program SBRquant was applied to 123I-ioflupane SPECT images acquired on healthy controls and subjects with PD. Earlier work on optimization of the parameters for differentiating between controls and subjects with dopaminergic deficits is extended here for maximizing change measurements associated with disease progression on longitudinally acquired scans. Methods: Serial 123I-ioflupane SPECT imaging for 51 subjects with PD (conducted approximately 1 y apart) were downloaded from the Parkinson Progression Markers Initiative database. The software program SBRquant calculates the striatal binding ratio (SBR) separately for the left and right caudates and putamen regions of interest (ROIs). Parameters were varied to evaluate the number of summed transverse slices and the positioning of the striatal ROIs for determining the signal-to-noise ratio associated with their annual rate of change in SBR. The parameters yielding the largest change in the lowest putamen's SBR from scan 1 to scan 2 were determined. Results: From scan 1 to scan 2 in the 51 subjects, the largest annual change was observed when the putamen ROI was placed 3 pixels away from the caudate and by summing 5 central striatal slices. This resulted in an 11.2% ± 4.3% annual decrease in the lowest putamen SBR for the group. Conclusion: Quantitative assessment of dopamine transporter imaging for assessing progression of PD requires specific, optimal parameters different from those for diagnostic accuracy.

For the 2011 FDA approved Parkinson’s Disease (PD) SPECT imaging agent I-123 labeled DaTscan, the volume of interest (VOI) is the interior portion of the brain. However imaging of the occipital lobe is also required with PD for calculation of the striatal binding ratio (SBR), a parameter of significance in early diagnosis, differentiation of PD from other disorders with similar clinical presentations, and monitoring progression. Thus we propose the usage of a combination of a multi-pinhole (MPH) collimator on one head of the SPECT system and a fan-beam on the other. The MPH would be designed to provide high resolution and sensitivity for imaging of the interior portion of the brain. The fan-beam collimator would provide lower resolution but complete sampling of the brain addressing data sufficiency and allowing a volume-of-interest to be defined over the occipital lobe for calculation of SBR’s. Herein we focus on the design of the MPH component of the combined system. Combined reconstruction will be addressed in a subsequent publication. An analysis of 46 clinical DaTscan studies was performed to provide information to define the VOI, and design of a MPH collimator to image this VOI. The system spatial resolution for the MPH was set to 4.7 mm, which is comparable to that of clinical PET systems, and significantly smaller than that of fan-beam collimators employed in SPECT. With this set, we compared system sensitivities for three aperture array designs, and selected the $3 \times 3$ array due to it being the highest of the three. The combined sensitivity of the apertures for it was similar to that of an ultra-high resolution fan-beam (LEUHRF) collimator, but smaller than that of a high-resolution fan-beam collimator (LEHRF). On the basis of these results we propose the further exploration of this design through simulations, and the development of combined MPH and fan-beam reconstruction.

Quantitative assessment of dopamine transporter imaging can aid in diagnosing Parkinson disease (PD) and assessing disease progression in the context of therapeutic trials. Previously, the software program SBRquant was applied to

Dopamine transporter (DaT) imaging is an adjunct diagnostic tool in parkinsonian disorders. Interpretation of DaT scans is based on visual reads. SBRquant is an automated method that measures the striatal binding ratio (SBR) in DaT scans, but has yet to be optimized. We aimed to (1) optimize SBRquant parameters to distinguish between patients with Parkinson disease (PD) and healthy controls using the Parkinson's Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort.For optimization, 336 DaT scans (215 PD patients and 121 healthy controls) from the PPMI database were used. Striatal binding ratio was calculated varying the number of summed transverse slices (N) and positions of the striatal regions of interest (d). The resulting SBRs were evaluated using area under the receiver operating characteristic curve. The optimized parameters were then applied to 77 test patients (35 PD and 42 non-PD patients). Striatal binding ratios were also correlated with clinical measures in the PPMI-PD group.The optimal parameters discriminated the training groups in the PPMI cohort with 95.8% sensitivity and 98.3% specificity (lowest putamen SBR threshold, 1.037). The same parameters discriminated the groups in the test cohort with 97.1% sensitivity and 100% specificity (lowest putamen SBR threshold, 0.875). A significant negative correlation (r = -0.24, P = 0.0004) was found between putamen SBRs and motor severity in the PPMI-PD group.SBRquant discriminates DaT scans with high sensitivity and specificity. It has a high potential for use as a quantitative diagnostic aid in clinical and research settings.

Most brain SPECT imaging procedures are currently being performed using general-purpose systems which are unable to fully take advantage of the use of clinically available agents. We are designing a novel multi-detector, multi-pinhole modular dedicated brain SPECT imaging system called AdaptiSPECT-C to improve sensitivity and resolution, and address the static and dynamic imaging needs. The aim of this study was to evaluate the axial and angular sampling sufficiency of a preliminary design of the system using simulation of the XCAT and a customized Defrise phantom. The simulator as well as image reconstruction projector is based on analytical modeling. The results provided an insight into the axial and angular sampling of the region-ofinterest of the AdaptiSPECT-C system and possible approaches to enhance the image quality in this regard showing that the application of approaches for increasing axial and angular samples including multipinhole shattering concept can enhance the quality of the reconstructed images.

A next-generation, adaptive, brain-imaging, single photon emission computed tomography system is currently under development at the Universities of Arizona and Massachusetts. The proposed multi-pinhole based modular gamma camera configuration enables the acquisition of “quasi-vertex” views i.e., views close to the vertex. This study is concerned with understanding how activity inferior to the brain will influence these views and ultimately, the reconstruction of the volume of interest. Analytical models can provide some measure of the detected primary gamma radiation originating in an organ or tissue outside the region of interest. Scattered gamma radiation will be detected as well but given the difficulty in modeling such phenomena, Monte Carlo simulations are used to quantify its effect. Using computer generated phantoms, the influence of activity from organs and tissues in the thorax, neck and lower head as compared to that from brain structures in the quasivertex views, will be detected, identified and quantified. The simulation consists of two components: detectors and sources. The detectors were simulated gamma camera modules consisting of a tungsten pinhole collimator, an air gap, and a NaI(Tl) scintillator surrounded by lead shielding. The sources were phantoms with activity (I-123, primary gamma photons at 159 keV) set in the liver, lungs, striatum, salivary glands and the thyroid.

Herein we report on the mathematical modeling of the simulated point spread functions (PSFs) of pinhole apertures for clinical I-123 DaTscan imaging on a dual-head SPECT system consisting of fan and multi-pinhole (MPH) collimators on separate heads. The PSFs can be measured sparsely by translating a point source within the volume of interest (VOI). These PSFs were generated using GATE Monte Carlo simulation software and were then modeled using standard 2D Gaussian having 6 parameters, and three other models using higher order polynomial terms as well as cross terms in the exponential. The goal is to efficiently store the parameters of the modeled PSF, measured across the VOI and then interpolate them on the fly during reconstruction. It has been shown that MPH reconstruction can be improved with accurate modeling of the PSF. However, for our application it has been determined that improved accuracy in PSF modeling (reduced NRMSE) can be obtained by incorporating more polynomial terms in the exponential than employed by the standard 2D Gaussian, especially with increased pinhole angulations. In this paper we introduce higher order polynomial terms (degree 3 and 4) as an extension to the Gaussian model and observe that these added terms could significantly reduce the NRMSE.

We are designing a modular SPECT camera for specialized imaging applications. We proposed to use NaI(Tl) as our scintillation crystal whose shape is hexagonal with $\sim$ 100 mm side lengths and > 5 mm thickness. Our target average spatial resolution is $\sim$ 1.5 mm (FWHM) which corresponds to a$\sigma$ (RMSE) of 0.45 mm. We propose putting SiPMs on the edges to help improve the spatial resolution. Our preliminary simulation result shows that with 8 mm crystal thickness, 6 mm light guide, and 37 close-packed photomultiplier tubes (1.0’’ diameter), the root mean squared error (RMSE) across the detector plane is 2.84 mm, due to the very high bias and variance in regions close to the edges; By attaching 4 SiPMs on each edge, the RMSE is improved to 1.34 mm; If the SiPMs’ window material and coupling medium’s refractive index is increased to 1.82, the RMSE is improved to 1.00 mm. We are still optimizing the detector design by tuning the parameters such as thickness of crystal, thickness of light guide, positions of SiPMs on the edges and number of PMTs to achieve the target spatial resolution without a significant trade-off on the detection sensitivity.

An automated objective striatal analysis (OSA) software program was applied to dopamine transporter 123I-ioflupane images acquired on subjects with varying severities of parkinsonism. The striatal binding ratios (SBR) of the left and right putamina (relative to the occipital lobe) were computed, and the laterality of that measure was compared with clinical symptoms and visual reads. The objective over-read of OSA was evaluated as an aid in confirming the laterality of disease onset. Methods: One hundred one 123I-ioflupane scans were acquired on clinically referred subjects. SPECT images were analyzed using the OSA software, which locates the slices containing the striatal and background (occipital) structures, positions regions over the left and right caudate nuclei and putamina, and calculates the background-subtracted SBR. Seven images were uninterpretable because of patient motion or lack of visualization of the striatum. The remaining 94 scans were analyzed with OSA. Differences between left and right putaminal SBR ranged from 0% to 36.6%, with a mean of 11.4%. When the difference between the SBR of the left and right putamina was greater than 6%, the lower side was taken as the side of onset. Left-to-right differences less than 6% were considered to be nonlateralizing (symmetric). The 94 scans were reviewed independently by 3 masked expert readers. By majority consensus, abnormal findings were seen on 67 of the 94 scans, of which 46 had available clinical findings. Results: Clinically, 34 subjects presented with lateralized tremors and 12 with symmetric or no tremors. Of the 34 cases of clinically lateralized tremors, 26 (76%) were concordant with the OSA findings, 5 were disparate with OSA (15%), and in 3 the OSA results were symmetric (9%). For the same 34 patients, the visual reads were concurrent with clinical tremor findings in 24 cases (71%), 1 was disparate (3%), and 9 visual reads were symmetric (26%). Of the 9 scans deemed symmetric by readers, 4 were correctly lateralized by OSA, and of the 3 symmetric OSA results, 2 were correctly lateralized visually. Conclusion: The OSA program may be a helpful aid in the interpretation of 123I-ioflupane SPECT images for determining laterality representing the asymmetric loss of dopamine transporters in the striata. OSA offers an objective, reproducible over-read evaluation for the laterality of onset in Parkinson disease.

A fully automated objective striatal analysis (OSA) program that quantitates dopamine transporter uptake in subjects with suspected Parkinson’s disease was applied to images from clinical 123I-ioflupane studies. The striatal binding ratios or alternatively the specific binding ratio (SBR) of the lowest putamen uptake was computed, and receiver-operating-characteristic (ROC) analysis was applied to 94 subjects to determine the best discriminator using this quantitative method. Methods: Ninety-four 123I-ioflupane SPECT scans were analyzed from patients referred to our clinical imaging department and were reconstructed using the manufacturer-supplied reconstruction and filtering parameters for the radiotracer. Three trained readers conducted independent visual interpretations and reported each case as either normal or showing dopaminergic deficit (abnormal). The same images were analyzed using the OSA software, which locates the striatal and occipital structures and places regions of interest on the caudate and putamen. Additionally, the OSA places a region of interest on the occipital region that is used to calculate the background-subtracted SBR. The lower SBR of the 2 putamen regions was taken as the quantitative report. The 33 normal (bilateral comma-shaped striata) and 61 abnormal (unilateral or bilateral dopaminergic deficit) studies were analyzed to generate ROC curves. Results: Twenty-nine of the scans were interpreted as normal and 59 as abnormal by all 3 readers. For 12 scans, the 3 readers did not unanimously agree in their interpretations (discordant). The ROC analysis, which used the visual-majority-consensus interpretation from the readers as the gold standard, yielded an area under the curve of 0.958 when using 1.08 as the threshold SBR for the lowest putamen. The sensitivity and specificity of the automated quantitative analysis were 95% and 89%, respectively. Conclusion: The OSA program delivers SBR quantitative values that have a high sensitivity and specificity, compared with visual interpretations by trained nuclear medicine readers. Such a program could be a helpful aid for readers not yet experienced with 123I-ioflupane SPECT images and if further adapted and validated may be useful to assess disease progression during pharmaceutical testing of therapies.

We proposed an inexpensive method to improve the performance of the conventional dual-camera SPECT systems for I-123 dopamine transporter (DAT) imaging for Parkinson Disease. In this method, one of the collimators is replaced with a specifically designed multi-pinhole (MPH) collimator, thus performing combined MPH/Fanbeam acquisition. The MPH consists of 9 pinholes focusing to the central brain and covering a cylindrical field of view (diameter: 12cm and height: 8cm), which includes the striatum. We present here our Monte Carlo simulation work investigating the optimal aperture size for the striatal binding ratio (SBR) and caudate/putamen ratio (C/P). Projections of the XCAT brain phantom were obtained for a range of aperture sizes (radius:1–5 mm, with increments of 1mm). Multiple noise realizations were simulated for each aperture size at realistic count levels. Reconstructions from MPH, Fanbeam and combined MPH/Fanbeam systems were obtained for various numbers of iterations. For SBR and C/P calculations activities within the striatum were estimated for a range of region of interests. Normalized root mean square errors (NRMSE) of the SBR and C/P measurements were obtained for the Fanbeam and combined MPH/Fanbeam reconstructions at different iterations and VOIs, using custom made and clinically employed quantitative analysis software. Our preliminary results suggest that an aperture radius of 2-3 mm for the MPH component yields both visually and quantitatively better estimations for the MPH/Fanbeam reconstructions.

Diseases of ectopic calcification of the vascular wall range from lethal orphan diseases such as generalized arterial calcification of infancy (GACI), to common diseases such as hardening of the arteries associated with aging and calciphylaxis of chronic kidney disease (CKD). GACI is a lethal orphan disease in which infants calcify the internal elastic lamina of their medium and large arteries and expire of cardiac failure as neonates, while calciphylaxis of CKD is a ubiquitous vascular calcification in patients with renal failure. Both disorders are characterized by vascular Mönckeburg's sclerosis accompanied by decreased concentrations of plasma inorganic pyrophosphate (PPi). Here we demonstrate that subcutaneous administration of an ENPP1-Fc fusion protein prevents the mortality, vascular calcifications and sequela of disease in animal models of GACI, and is accompanied by a complete clinical and biomarker response. Our findings have implications for the treatment of rare and common diseases of ectopic vascular calcification., Generalized arterial calcification of infancy (GACI) is a terminal disease caused by the ENPP1 enzyme deficiency. Here, Albrigh et al. show that ENPP1 enzyme replacement therapy prevents the ectopic calcifications and mortality in mice with GACI, suggesting a novel treatment for vascular calcification in humans.

Current therapeutic approaches for Alzheimer's disease (AD) have evolved to target specific molecular biological, metabolic and neuropathologic hallmarks of the disease. Since these approaches are hypothesized to be most effective at the earliest stages of the degenerative process, the ability to accurately detect and monitor progression of AD pathology and metabolic changes in vivo may accelerate the discovery and development of disease-modifying drugs. The use of molecular imaging biomarkers can not only enhance diagnostic accuracy and facilitate patient selection/stratification, but can also serve as key outcomes for clinical trials. In this review, we discuss emerging trends in the use of PET in AD drug development and provide a roadmap for harnessing its promise in multicenter clinical trials.

Summary: Purpose: Regions of seizure onset and propagation in human generalized tonic–clonic seizures are not well understood. Cerebral blood flow (CBF) measurements with single photon emission computed tomography (SPECT) during electroconvulsive therapy (ECT)-induced seizures provide a unique opportunity to investigate seizure onset and propagation under controlled conditions. Methods: ECT stimulation induces a typical generalized tonic–clonic seizure, resembling spontaneous generalized seizures in both clinical and electroencephalogram (EEG) manifestations. Patients were divided into two groups based on timing of ictal (during seizure) SPECT tracer injections: 0 s after ECT stimulation (early group), and 30 s after ECT (late group). Statistical parametric mapping (SPM) was used to determine regions of significant CBF changes between ictal and interictal scans on a voxel-by-voxel basis. Results: In the early injection group, we saw increases near the regions of the bitemporal stimulating electrodes as well as some thalamic and basal ganglia activation. With late injections, we observed increases mainly in the parietal and occipital lobes, regions that were quiescent 30 s prior. Significant decreases occurred only at the later injection time, and these were localized to the bilateral cingulate gyrus and left dorsolateral frontal cortex. Conclusions: Activations in distinct regions at the two time points, as well as sparing of intermediary brain structures, suggest that ECT-induced seizures propagate from the site of initiation to other specific brain regions. Further work will be needed to determine if this propagation occurs through cortical–cortical or cortico-thalamo-cortical networks. A better understanding of seizure propagation mechanisms may lead to improved treatments aimed at preventing seizure generalization.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

The anatomical brain regions involved in the therapeutic and adverse actions of electroconvulsive therapy (ECT) are unknown. Previous studies suggest that bifrontal vs. bitemporal ECT differ in therapeutic efficacy and cognitive side effects. We therefore performed cerebral blood flow (CBF) imaging during bitemporal vs. bifrontal ECT-induced seizures to identify regions crucial for the differences between these treatments. Patients with major depression, undergoing bitemporal or bifrontal ECT, were studied. Ictal–interictal SPECT images were analyzed with statistical parametric mapping for bitemporal ( n =11 image pairs in 8 patients) and bifrontal ( n =4 image pairs in 2 patients) ECT-induced seizures to identify regions of ictal CBF changes. Bifrontal ECT was found to cause increases in CBF in prefrontal and anterior cingulate regions. Bitemporal ECT, however, caused CBF increases in the lateral frontal cortex and in the anterior temporal lobes. In bifrontal ECT, a greater increase in prefrontal activation, while sparing the temporal lobes, may result in a better therapeutic response and fewer adverse effects on memory than bitemporal ECT.

Changes in regional cerebral glucose metabolism were investigated for varying levels of tissue oxygenation using a dynamic positron autoradiography technique. While incubating fresh rat brain slices with [18F]FDG in an oxygenated solution, serial images of the tissue slices were obtained over a time period of up to 300 min and archived onto over 20 phosphorous imaging plate exposures. In order to properly create time activity curves of the uptake levels, images of the individual tissue samples were automatically located, digitally extracted, and registered with the later images of the same tissue samples. After applying image processing techniques for aligning tissue sample images, time activity curves were extracted for individual substructures in the rat brain and quantitative results were reported using Patlak plots. Since the levels of oxygenation can be controlled for these experiments, [18F]FDG uptakes can be reported representing states of hypoxia, pseudoischemia, and reoxygenation. The image processing techniques developed for this application have enabled more experiments and tissue samples to be acquired and analyzed than would otherwise be possible using manual ROI techniques. The objective spatial registration of tissue samples and automated extraction of data has increased the analysis accuracy and decreased the operator error associated with the interactive handling of the image data. This supports improved kinetic modeling of FDG uptake in animal studies, and can be used for more accurate dosimetry calculations in humans.

Summary: Purpose: Statistical parametric mapping (SPM) is an image-analysis tool that assesses the statistical significance of cerebral blood flow (CBF) changes on a voxel-by-voxel basis, thereby removing the subjectivity inherent in conventional region-of-interest (ROI) analysis. Our platform of single-photon emission computed tomography (SPECT) ictal–interictal difference imaging in clinical epilepsy has been validated for localizing seizure onset. We extend the tools of SPM by further applying statistical measures for the significance of perfusion changes in individual patients to localize epileptogenic foci in patients with defined temporal lobe epilepsy by using paired scans in this preliminary study. Methods: Twelve patients with pairs of periictal and interictal SPECT scans were analyzed in this comparison study between SPECT difference imaging and SPM difference analysis by using a reference database of paired normal healthy images. These 12 patients possessed seizure foci localized to the mesial temporal lobe as confirmed by surgical outcome and by hippocampal sclerosis on pathology. SPM was used to identify clusters of increased or decreased CBF in each patient in contrast to our control group. Results: The regions having the most significant increased or decreased CBF by SPM analysis were in agreement with regions identified by conventional difference imaging and visual analysis by viewers blinded to the results of the SPM analysis. Differentiated further by time of radiopharmaceutical injection, six of seven patients injected within 100 s of seizure onset displayed hyperperfusion changes localized to the corresponding epileptogenic temporal lobe by both techniques. Among patients receiving injections after 100 s, both techniques showed primarily regions of hypoperfusion, which again were similar between these two methods. Conclusions: The results provide strong evidence supporting SPM difference analysis in assessing regions of significant CBF change from baseline in concordance with our current clinically used technique of SPECT ictal–interictal difference imaging in epilepsy patients. Difference analysis using SPM could serve as a useful diagnostic tool in the evaluation of seizure focus in temporal lobe epilepsy.

Study goal: A Phase 1 evaluation of the kinetics, clearance and cerebral distribution of one novel peripheral benzodiazepine receptors(PBR)positron emission tomography (PET) imaging agent, 18F-PBR-111 following intravenous administration in healthy volunteers and Alzheimer's disease (AD) patients. Short title: Evaluation of PET imaging with PBR-111 in HV and AD subjects Proof of Mechanism. Primary Objective: To evaluate the cerebral distribution of PBR-111 positron emission tomography (PET) for detection/exclusion of microglial activation in patients with Alzheimer's disease subjects compared to healthy volunteers. Secondary objectives: - To assess the dynamic uptake and washout of [18F]PBR-111, a potential imaging bio-marker for inflammatory changes in brain, using positron emission tomography in subjects with Alzheimer's disease (AD) and healthy volunteers (HV). - To perform blood metabolite characterization of [18F]PBR-111 in subjects with AD and HV to determine the nature of metabolites in assessment of [18F]-PBR-111 as a PET brain imaging agent. Name of radioactive drug substance: PBR-111 Dose(s): The applied PBR-111 radioactive dose will be up to 5.0 mCi, diluted in a maximum of 10 ml of saline. The radioligand will be administered as a slow intravenous bolus injection (i.e., 6 sec/ml) into a large vein (e.g., antecubital vein). Route of administration: Intravenous injection Duration ofmore » treatment: Single administration of a diagnostic agent Indication: PBR-111 positron emission tomography (PET) imaging has the potential to detect microglial activation. In the presence of PBR-111 uptake (representative of microglial activation), inflammation in the brain can be detected. Diagnosis and main criteria for inclusion: Study participants will be HVs and patients diagnosed with probable AD. HVs must be 18 years of age (at least four subjects 50 years of age) and have no evidence of cognitive impairment or other neurologic disease by medical history. The lack of cognitive impairment will also be based on a Clinical Dementia Rating (CDR) of 0. Patients with probable AD must be 50 years of age and must fulfill the National Institute of Neurological and Communicative Disorders and Stroke, Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria for probable AD. The CDR score must be 1.0 and 2.0 and have a modified Hachinski of 4. All HVs and all patients with probable AD must be able to comply with all study procedures. Study design: This is a Phase 1, open-label, single-center, non-randomized single dose study to assess the kinetics, clearance and cerebral distribution of PBR-111 PET imaging in detecting microglial activation in the brain in patients with probable AD compared to HVs. All aspects related to image acquisition, processing, and visual as well as quantitative evaluation will be developed, optimized, and validated (where required). Each subject will be required to visit the study center during the screening phase and on the PBR-111 PET imaging day (baseline). A telephone follow-up visit will be performed 7 days (± 3 days) after PBR-111 PET administration. At the screening visit, each subject (or caregiver in the case of AD subjects) will be asked to provide written informed consent or assent. During the screening phase (maximum duration of 60 days) subject medical, neurological, and surgical history, clinical assessments, and a neuro-psychiatric evaluation will be performed on all eligible subjects. Subjects will be allowed to leave the center after all evaluations have been completed. During this period an MRI of the brain will be performed during the screening period. If an MRI of the brain has been performed within six months of the imaging visit using the methods described in the protocol, and there has been no medically significant events in the interim, the previous MRI may be used. During the PBR-111 PET imaging day, all subjects will receive a single intravenous injection of PBR-111 and scanning will be performed over a 3.5 hour period. Each subject will have a telephone follow-up 7 days (± 3 days) thereafter to assess for adverse events. Methodology: - Assessments to provide clinical characterization of the AD subjects will be performed. - After administration of PBR-111, images will be generated with state-of-the-art PET imaging. Images will be assessed quantitatively for the presence of microglial activation by a nuclear physician blinded to clinical data. - Total radioactivity and estimation of the fraction of radioactivity associated to the un-metabolized tracer will be determined. In addition, the metabolite patterns of PBR-111 are determined in venous plasma and arterial samples based on high-performance liquid chromatography (HPLC) analyses. - Arterial sampling will be acquired in the initial two AD and two HV subjects and modeling will be assessed to determine if additional arterial sampling is necessary.« less

Peri-ictal single-photon emission tomography (SPET) difference images co-registered to magnetic resonance imaging (MRI) visualize regional cerebral blood flow (rCBF) changes and help localize the epileptogenic area in medically refractory epilepsy. Few reports have examined the reproducibility of SPET difference image results. Epilepsy patients having two peri-ictal and at least one interictal SPET scan who later underwent surgical resection were studied. Localization accuracy of peri-ictal SPET difference images results, interictal electroencephalography (EEG), and ictal EEG from the first (seizure 1) and second (seizure 2) seizure, as well as MRI and positron emission tomography (PET) findings, were compared using surgical resection site as the standard. Thirteen patients underwent surgical resection (11 temporal lobe and 2 extratemporal). SPET results from seizure 1 were localized to the surgical site in 12/13 (92%) patients, while SPET results from seizure 2 were localized in 13/13 (100%) patients. All other modalities were less accurate than the SPET results [interictal EEG – seizure 1 6/13 (46%); ictal EEG – seizure 1 5/13 (38%); interictal intracranial EEG – seizure 2 4/9 (44%); ictal intracranial EEG – seizure 2 results 8/9 (89%); MRI 6/13 (46%); PET 9/13 (69%)].SPET results were reproducible in 12/13 (92%) patients.SPET difference images calculated from two independent peri-ictal scans appear to be reproducible and accurately localize the epileptogenic area. While SPET difference images visualize many areas of rCBF change, the quantification of these results along with consideration of injection time improves the diagnostic interpretation of the results.

Ictal single photon emission computed tomography (SPECT) is a sensitive means of seizure localization in partial epilepsy. The purpose of this study is to enhance the diagnostic yield of postictal SPECT for epilepsy and to overcome the difficulties in its conventional interpretation. We developed a method for coregistration, normalization, and subtraction of interictal from ictal SPECT to reveal positive difference images (and ictal from interictal to reveal negative difference images) of cerebral blood flow (CBF) during seizures. This method also allows quantification of regions of greatest percent increase and decrease, normalized to seizure duration. We studied 12 patients who had confirmed epileptogenic regions by surgery and pathology (seven temporal, five extratemporal). In all 12 patients, with either early (during ictus) or late injection (after seizure termination), the difference images showed increases or decreases respectively in blood flow consistent with the epileptogenic region. We highlight the localizing value of the negative difference change in perfusion (state of hypoperfusion) that persists for up to 100 seconds after seizure termination and corresponds to the epileptogenic region. Application of this technique for the quantification of perfusion changes during seizure or immediately after seizure cessation enhances the diagnostic yield of SPECT in both temporal and extratemporal epilepsy.

By appreciating the technical basis of Fourier representations and filtering, a better interpretation of SPECT images can be gained. The ramp filter has no selectable parameters and is the required filter used in tomography. The resulting noisy reconstructed image is smoothed by using a filter where the cut-off and order can be selected. By relating frequencies to sizes of structures in the image, reasonable values for the cut-off frequency for the smoothing filter can be selected. Most important, the realization that the ramp-filtered image (without the smoothing filter applied) is the most correct image means that subsequent smoothing can slightly degrade the numeric correctness of the reconstructed image. Smoothing filters make the image easier for clinical interpretation because noisy structures are difficult for the human eye to perceive. Selection of the smoothing filter to maximize noise reduction and image structure preservation is accomplished by matching the cut-off frequency to the image noise or camera resolution. This understanding should reduce the amount of time spent searching for a smoothing filter, which is used routinely in clinical imaging studies.

In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test–retest results, and dosimetry estimates of 123I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain. Methods: Nine healthy human subjects were enrolled in this study; 7 completed 123I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating 123I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test–retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. Results:123I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4–2.0 were determined. Binding potentials around 0.8–1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average test–retest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. Conclusion: The data indicate that 123I-MNI-420 is a useful SPECT radiotracer for imaging A2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of 123I-MNI-420 offers the possibility of investigating A2A activity in specific conditions and evaluating drug occupancy for A2A candidate therapeutics.

For the recently FDA approved Parkinson's Disease (PD) SPECT imaging agent I-123 labeled DaTscan the volume of interest (VOl) is the interior portion of the brain. However imaging of the occipital lobe is also required with PD for calculation of the striatal binding ratio (SBR), a parameter of significance in early diagnosis, differentiation of PD from other disorders with similar clinical presentations, and monitoring progression. Thus we propose the usage of a combination of a multi-pinhole (MPH) collimator on one head of the SPECT system and a fan-beam on the other. The MPH would be designed to provide high resolution and sensitivity imaging of the interior portion of the brain. The fan-beam collimator would provide lower resolution but complete sampling of the brain addressing data sufficiency and allowing a volume-of-interest to be defined over the occipital lobe for calculation of SBR's. Herein we analyze 20 clinical DaTscan studies to provide information on the VOl, and then design a MPH collimator to image this VOl. Using standard collimator equations we determine a system spatial resolution for the MPH of 4.4 mm which is comparable to that of clinical PET systems, and significantly smaller than that of fan-beam collimators employed in SPECT. The combined sensitivity of the apertures of the MPH was larger than that of an ultra-high resolution fan-beam (LEUHRF) collimator, but smaller than that of a high resolution fan-beam collimator (LEHRF). On the basis of these early results we propose the exploration of further improvements in design, and the development of combined MPH and fan-beam reconstruction.

Manual segmentation of 129 x-ray CT transverse slices of a living male human has been done and a computerized 3-dimensional volume array modeling all major internal structures of the body has been created. Each voxel of the volume contains a index number designating it as belonging to a given organ or internal structure. The original x-ray CT images were reconstructed in a 512 x 512 matrix with a resolution of 1 mm in the x,y plane. The z-axis resolution is 1 cm from neck to midthigh and 0.5 cm from neck to crown of the head. This volume array represents a high resolution model of the human anatomy and can serve as a voxel-based anthropomorphic phantom suitable for many computer-based modeling and simulation calculations.

Due to the availability of digitally stored human anatomy images, 3-dimensional surfaces of internal structures of the body can be stored in computer volume arrays. Such a volume based software phantom delineates internal human organs with millimeter resolution and lends itself to fully 3-dimensional Monte Carlo simulations. Our simulation models 45 internal human organs (each with an associated radioisotope concentration and attenuation coefficient), calculates gamma radiation histories through these structures, and accepts gamma events onto a collimated planar camera. Variance reduction techniques are applied to decrease the time required to compute a given number of events at the detector. Stratification and two implementations of forced detection variance reduction techniques are compared to ”brute force” calculations for their efficiency speed-ups in this heterogeneous geometry. Simulated clinical images of the liver are shown.

We have used SPECT (single photon emission computed tomography) imaging in non-human primates to examine the time course and pharmacological specificity of 123I-labeled Ro 16-0154 as an in vivo probe of the benzodiazepine receptor. Maximal brain uptake was reached approximately 70 min post i.v. administration of the radioligand and represented approximately 10% of the injected dose. The regional distribution of radioactive densities was consistent with the known distribution of benzodiazepine receptor in primate brain, with highest uptake localized over the occipital area. Washout of radioactivity was relatively slow with a rate of 3% per hour after the time of peak radioactivity. Injection of the benzodiazepine antagonist Ro 15-1788 (0.2–0.3 mg/kg i.v.) caused a rapid decrease of more than 90% of radioactivity from brain. In summary, [123I]Ro 16-0154 is a promising in vivo SPECT radioligand for the benzodiazepine receptor, with high brain uptake, a stable period of peak radioactivity, appropriate regional distribution, and ability to be displaced by other benzodiazepine receptor agents.

UNLABELLED Reliable quantitative dopamine transporter imaging is critical for early and accurate diagnosis of Parkinson's disease (PD). Image quantitation is made difficult by the variability introduced by manual interventions during the quantitative processing steps. A fully automated objective striatal analysis (OSA) program was applied to dopamine transporter images acquired from PD subjects with early symptoms of suspected parkinsonism and compared with manual analysis by a trained image-processing technologist. METHODS A total of 101 (123)I-beta-CIT SPECT scans were obtained of subjects recruited to participate in the Query-PD Study. Data were reconstructed and then analyzed according to a package of scripts (OSA) that reorients the SPECT brain volume to the standard geometry of an average scan, automatically locates the striata and occipital structures, locates the caudate and putamen, and calculates the background-subtracted striatal uptake ratio (V3''). The striatal uptake ratio calculated by OSA was compared with manual analysis by a trained image-processing technologist. Several parameters were varied in the automated analysis, including the number of summed transverse slices and the size and separation of the regions of interest applied to the caudate and putamen to determine the optimum OSA analysis. The parameters giving V3'' with the closest correlation to the manual analysis were accepted as optimal. RESULTS The optimal comparison between the V3'' obtained by the human analyst and that obtained by the automated OSA analysis yielded a correlation coefficient of 0.96. CONCLUSION Our optimized OSA delivers V3'' evaluations that closely correlate with a similar evaluation manually applied by a highly trained image-processing technologist.