George Zubal

SPECT imaging of the benzodiazepine receptor in non-human primate brain with [123I]Ro 16-0154

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 receptors 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.

Optimizing Compton camera geometries

Compton cameras promise to improve the characteristics of nuclear medicine imaging, wherein mechanical collimation is replaced with electronic collimation. This leads to huge gains in sensitivity and, consequently, a reduction in the radiation dosage that needs to be administered to the patient. Design modifications that improve the sensitivity invariably compromise resolution. The scope of the current project was to determine an optimal design and configuration of a Compton camera that strikes a balance between these two properties. Transport of the photon flux from the source to the detectors was simulated with the camera geometry serving as the parameter to be optimized. Two variations of the Boltzmann photon transport equation, with and without photon polarization, were employed to model the flux. Doppler broadening of the energy spectra was also included. The simulation was done in a Monte Carlo framework using GEANT4. Two clinically relevant energies, 140 keV and 511 keV, corresponding to 99mTc and 18F were simulated. The gain in the sensitivity for the Compton camera over the conventional camera was 100 fold. Neither Doppler broadening nor polarization had any significant effect on the sensitivity of the camera. However, the spatial resolution of the camera was affected by these processes. Doppler broadening had a deleterious effect on the spatial resolution, but polarization improved the resolution when accounted for in the reconstruction algorithm.

3-D Registration Of Intermodality Medical Images

We report a technique for registering functional and structural 3-D images of patient images (particularly applicable to the human brain). The registration is modeled as a solid rotation, translation and magnification of one image to fit the other. In increasing order of complexity, we developed a hierarchy of landmarks which consist of points, lines, curves, planes, surfaces and volumes. We allow for three different kinds of matches between landmarks: a complete match, a fragmented match, and a containment match. Our technique allows for explicit constraints on the possible rotation, translation and magnification obtained as a result of matching the landmarks. Finally, we show that the above can be cast as a linear programming problem and provide preliminary evidence that it leads to a fast and provably convergent algorithm for 3-D registration promising clinical registration accuracy on the order of one millimeter.

Receiver-operating-characteristic analysis of an automated program for analyzing striatal uptake of 123I-ioflupane SPECT images: calibration using visual reads.

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.

Semiquantitative Analysis of Dopamine Transporter Scans in Patients with Parkinson Disease

Purpose 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 Parkinsons Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort. Methods 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. Results 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. Conclusions 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.

Evaluation of an Objective Striatal Analysis Program for Determining Laterality in Uptake of 123I-Ioflupane SPECT Images: Comparison to Clinical Symptoms and to Visual Reads

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.

Optimization of Parameters for Quantitative Analysis of123I-ioflupane SPECT Images for Monitoring of Progression of Parkinson's Disease

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.

Quantitative evaluation of anthropomorphic brain phantoms for standardization of amyloid PET SUVrs in alzheimer's Multicenter Therapeutic Trials

We therefore wish to assess the impact on brain atrophy as measured by the boundary shift integral (BSI) of changing from non-accelerated to accelerated MRI acquisitions over a 12-month interval.Methods: Accelerated and non-accelerated scans of 55 early mild cognitive impairment subjects, acquired in the same scanning session, were downloaded from ADNI. Brain regions were automatically delineated by Multi-Atlas Propagation and Segmentation, visually checked andmanually edited if necessary. BSIswere calculated using both a non-accelerated baseline scan and non-accelerated repeat scans (i.e. consistent acquisition), and a non-accelerated baseline scan and an accelerated repeat scan (i.e. changed acquisition). Results: Mean BSI from changed acquisition was 0.12%/year (p1⁄40.02) lower than consistent acquisition (see Table 1 and Fig. 1). Fig. 1(a) shows that most of the differences are close to zero, and 10 BSIs have differences > 0.5%/ year, which consists of all the 3 BSIs from site 21 (marked in red). There was no evidence that the standard deviations were different (p1⁄40.7). Conclusions: We found a relatively small (w0.1% of brain volume) effect on brain volume change in BSI when changing from non-accelerated to accelerated MRI during follow-up. This difference isw1/5 of the annual atrophy rate in normal aging in elderly subjects (w0.5%/year). However there did appear to be site-specific differences; this may reflect greater differences in the accelerated acquisition on that scanner. Going from non-accelerated baseline to acceleratedMRI for follow-up may have surprisingly little effect

Objective SUVr Determination using MRI Segmentation Maps in Florbetaben Beta-amyloid Brain PET Improves Discrimination of Alzheimer's and Controls

Background: The robustness of a PET tracer for visualising b-amyloid in vivo can be assessed by the following metrics: 1) Sensitivity and Specificity of the visual interpretation with clinical diagnosis as the gold standard, 2) The extent to which a number of independent readers agree on the same interpretation of the images, 3) Reader self consistency and 4) The confidence in which readers are able to make their interpretation. The performance of [F]flutemetamol was assessed against these metrics within the primary objective of the ALZ201 phase-II clinical trial. Methods: Five independent readers were trained on phase I images and classified 72 [F]flutemetamol randomised PET images of the whole brain into the categories of normal or abnormal appearance where abnormal refers to the ability of a reader to identify tracer binding in the grey matter. Readers also rated their confidence in their assessment on a 5 point scale. The clinical classification of these subjects was 27 probable Alzheimer’s Disease (pAD), 25 healthy volunteers (HV) and 20 amnestic Mild Cognitive Impairment (aMCI). The classification based on visual assessment was done blinded to the clinical status of the subjects and also to any quantitative evaluation. In a separate read, the same assessments and metrics were obtained for 20 of the pADs and all of the aMCI subjects who were also images with [C]PiB, typically on the same day as [F]flutemetamol. Results: Classification based on the visual assessment of [F]flutemetamol images categorised 25 of 27 AD as abnormal, 24 of 25 HV as normal and 9 of 20 MCI as abnormal. For the pAD & HV cohort this provided a sensitivity of 92.6% and specificity of 96.0%. Interreader agreement was measured and the reader agreement was 98.7% or a Fleiss’ kappa score of k 1⁄4 0.96. All readers re-read 8 different images and the self consistency was 97.5%. The readers rated their classification as highest confidence in the vast majority of all reads. There was exact concordance between the readers results for the subjects’ [F]flutemetamol and [C]PiB images. Conclusions: Visual assessment of [F]flutemetamol images is highly robust and consistent.

Multicenter quantitative amyloid PET imaging in phase III alzheimer therapeutic trials: Strategies for achieving good imaging practices in the support of drug development

different sites were initially reconstructed using the sites’ routine methods. The methods used were FBP and OSEM. The co-registered PET data sets underwent VOI analysis to obtain putamen cavity to refernce ratios. The returned VOI capture ratios had a mean of 1.3 to 1 with a SD of 0.06 (less than 10% total difference). With optimisation of post reconstruction filtering, these differences reduce further. Conclusions: Partial volume effects reduce the measured uptake ratios as expected. However, on the cameras and reconstruction methods used there is good consistency between the ratios. The level of variation in uptake ratio introduced by measurements accross different cameras is small compared to the actual variation in uptake found in both amyloid negative and positive images. This supports the robustness of quantitative measurements via VOI analysis. Striatal phantom images and target/reference ratios.