Ing-Tsung Hsiao

Whole-body biodistribution and brain PET imaging with [18F]AV-45, a novel amyloid imaging agent - a pilot study

PURPOSE The compound (E)-4-(2-(6-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy) pyridin-3-yl)vinyl)-N-methylbenzenamine ([(18)F]AV-45) is a novel radiopharmaceutical capable of selectively binding to beta-amyloid (A beta) plaques. This pilot study reports the safety, biodistribution, and radiation dosimetry of [(18)F]AV-45 in human subjects. METHODS In vitro autoradiography and fluorescent staining of postmortem brain tissue from patients with Alzheimers disease (AD) and cognitively healthy subjects were performed to assess the specificity of the tracer. Biodistribution was assessed in three healthy elderly subjects (mean age: 60.0+/-5.2 years) who underwent 3-h whole-body positron emission tomography (PET)/computed tomographic (CT) scans after a bolus injection of 381.9+/-13.9 MBq of [(18)F]AV-45. Another six subjects (three AD patients and three healthy controls, mean age: 67.7+/-13.6 years) underwent brain PET studies. Source organs were delineated on PET/CT. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. RESULTS In vitro autoradiography revealed exquisitely high specific binding of [(18)F]AV-45 to postmortem AD brain sections, but not to the control sections. There were no serious adverse events throughout the study period. The peak uptake of the tracer in the brain was 5.12+/-0.41% of the injected dose. The highest absorbed organ dose was to the gallbladder wall (184.7+/-78.6 microGy/MBq, 4.8 h voiding interval). The effective dose equivalent and effective dose values for [(18)F]AV-45 were 33.8+/-3.4 microSv/MBq and 19.3+/-1.3 microSv/MBq, respectively. CONCLUSION [(18)F]AV-45 binds specifically to A beta in vitro, and is a safe PET tracer for studying A beta distribution in human brain. The dosimetry is suitable for clinical and research application.

A Bayesian Joint Mixture Framework for the Integration ofAnatomical Information in Functional Image Reconstruction

We present a Bayesian joint mixture framework for integrating anatomical image intensity and region segmentation information into emission tomographic reconstruction in medical imaging. The joint mixture framework is particularly well suited for this problem and allows us to integrate additional available information such as anatomical region segmentation information into the Bayesian model. Since this information is independently available as opposed to being estimated, it acts as a good constraint on the joint mixture model. After specifying the joint mixture model, we combine it with the standard emission tomographic likelihood. The Bayesian posterior is a combination of this likelihood and the joint mixture prior. Since well known EM algorithms separately exist for both the emission tomography (ET) likelihood and the joint mixture prior, we have designed a novel EM2 algorithm that comprises two EM algorithms—one for the likelihood and one for the prior. Despite being dove-tailed in this manner, the resulting EM2 algorithm is an alternating descent algorithm that is guaranteed to converge to a local minimum of the negative log Bayesian posterior. Results are shown on synthetic images with bias/variance plots used to gauge performance. The EM2 algorithm resulting from the joint mixture framework has the best bias/variance performance when compared with six other closely related algorithms that incorporate anatomical information to varying degrees.

Noise properties of low-dose CT projections and noise treatment by scale transformations

Projection data acquired for image reconstruction of low-dose computed tomography (CT) are degraded by many factors. These factors complicate noise analysis on the projection data and render a very challenging task for noise reduction. In this study, we first investigate the noise property of the projection data by analyzing a repeatedly acquired experimental phantom data set, in which the phantom was scanned 900 times at a fixed projection angle. The statistical analysis shows that the noise can be regarded as normally distributed with a nonlinear signal-dependent variance. Based on this observation, we then utilize scale transformations to modulate the projection data so that the data variance can be stabilized to be signal independent. By analyzing the relationship between the data standard deviation and the data mean level, we propose a segmented logarithmic transform for the stabilization of the non-stationary noise. After the scale transformations, the noise variance becomes approximately a constant. A two-dimensional Wiener filter is then designed for an analytical treatment of the noise. Experimental results show that the proposed method has a better noise reduction performance without circular artifacts, by visual judgment, as compared to conventional filters, such as the Harming filter.

The healing of critical-sized femoral segmental bone defects in rabbits using baculovirus-engineered mesenchymal stem cells

Management of massive segmental bone defects remains a challenging clinical problem and bone marrow-derived mesenchymal stem cells (BMSCs) hold promise for bone regeneration. To explore whether BMSCs engineered by baculovirus (an emerging gene delivery vector) can heal large bone defects, New Zealand White (NZW) rabbit BMSCs were transduced with the BMP2-expressing baculovirus or VEGF-expressing baculovirus, and co-implanted into critical-sized (10mm) femoral segmental defects in NZW rabbits. X-ray analysis revealed that the baculovirus-engineered BMSCs not only bridged the defects at as early as week 2, but also healed the defects in 100% of rabbits (13/13) at week 4. The osteogenic metabolism, as monitored by positron emission tomography (PET) also suggested the completion of bone healing at week 8. When compared with other control groups, the BMP2/VEGF-expressing BMSCs remarkably enhanced the segmental bone repair and mechanical properties, as evidenced by micro-computed tomography (microCT), histochemical staining and biomechanical testing. The ameliorated bone healing concurred with the augmented angiogenesis. These data demonstrated, that BMSCs engineered to express BMP2 and VEGF accelerate the repair of large femoral bone defects and improve the quality of the regenerated bone, which paves an avenue to utilizing baculovirus as a vector for BMSCs modification and regenerative medicine.

An accelerated convergent ordered subsets algorithm for emission tomography

We propose an algorithm, E-COSEM (enhanced complete-data ordered subsets expectation-maximization), for fast maximum likelihood (ML) reconstruction in emission tomography. E-COSEM is founded on an incremental EM approach. Unlike the familiar OSEM (ordered subsets EM) algorithm which is not convergent, we show that E-COSEM converges to the ML solution. Alternatives to the OSEM include RAMLA, and for the related maximum a posteriori (MAP) problem, the BSREM and OS-SPS algorithms. These are fast and convergent, but require ajudicious choice of a user-specified relaxation schedule. E-COSEM itself uses a sequence of iteration-dependent parameters (very roughly akin to relaxation parameters) to control a tradeoff between a greedy, fast but non-convergent update and a slower but convergent update. These parameters are computed automatically at each iteration and require no user specification. For the ML case, our simulations show that E-COSEM is nearly as fast as RAMLA.

Analytical noise treatment for low-dose CT projection data by penalized weighted least-square smoothing in the K-L domain

By analyzing the noise properties of calibrated low-dose Computed Tomography (CT) projection data, it is clearly seen that the data can be regarded as approximately Gaussian distributed with a nonlinear signal-dependent variance. Based on this observation, the penalized weighted least-square (PWLS) smoothing framework is a choice for an optimal solution. It utilizes the prior variance-mean relationship to construct the weight matrix and the two-dimensional (2D) spatial information as the penalty or regularization operator. Furthermore, a K-L transform is applied along the z (slice) axis to further consider the correlation among different sinograms, resulting in a PWLS smoothing in the K-L domain. As a tool for feature extraction and de-correlation, the K-L transform maximizes the data variance represented by each component and simplifies the task of 3D filtering into 2D spatial process slice by slice. Therefore, by selecting an appropriate number of neighboring slices, the K-L domain PWLS smoothing fully utilizes the prior statistical knowledge and 3D spatial information for an accurate restoration of the noisy low-dose CT projections in an analytical manner. Experimental results demonstrate that the proposed method with appropriate control parameters improves the noise reduction without the loss of resolution.

A new convex edge-preserving median prior with applications to tomography

In a Bayesian tomographic maximum a posteriori (MAP) reconstruction, an estimate of the object f is computed by iteratively minimizing an objective function that typically comprises the sum of a log-likelihood (data consistency) term and prior (or penalty) term. The prior can be used to stabilize the solution and to also impose spatial properties on the solution. One such property, preservation of edges and locally monotonic regions, is captured by the well-known median root prior (MRP), an empirical method that has been applied to emission and transmission tomography. We propose an entirely new class of convex priors that depends on f and also on m, an auxiliary field in register with f. We specialize this class to our median prior (MP). The approximate action of the median prior is to draw, at each iteration, an object voxel toward its own local median. This action is similar to that of MRP and results in solutions that impose the same sorts of object properties as does MRP. Our MAP method is not empirical, since the problem is stated completely as the minimization of a joint (on f and m) objective. We propose an alternating algorithm to compute the joint MAP solution and apply this to emission tomography, showing that the reconstructions are qualitatively similar to those obtained using MRP.

Correlation of Parkinson Disease Severity and 18F-DTBZ Positron Emission Tomography

IMPORTANCE Currently, diagnosis of Parkinson disease is mainly based on clinical criteria characterized by motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability. Reliable in vivo biomarkers to monitor disease severity and reflect the underlying dopaminergic degeneration are important for future disease-modifying therapy in Parkinson disease. OBJECTIVES To use [18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-DTBZ; [18F]AV-133) positron emission tomography (PET) to explore the characteristics of vesicular monoamine transporter type 2 imaging in patients with Parkinson disease (PD) with different severity levels as well as to investigate its capability in monitoring clinical severity. DESIGN, SETTING, AND PARTICIPANTS Regional uptakes for 18F-DTBZ PET of different disease stages were measured. Seventeen healthy control participants and 53 patients in 3 groups of mild, moderate, and advanced stages of PD were recruited for 18F-DTBZ PET scans from the Movement Disorders Clinic in the Chang Gung Memorial Hospital, Taiwan. MAIN OUTCOMES AND MEASURES The severity of disease in patients with PD was quantified by modified Hoehn-Yahr Scale, Unified Parkinson Disease Rating Scale total scores and subscores of posture instability and gait disturbance, tremor, akinesia, and rigidity while not taking medication. Both voxelwise- and volume of interest-based image analyses were performed. The specific uptake ratio (SUR) of each volume of interest and voxel was calculated as (target uptake - reference uptake) / reference uptake using the occipital reference region from magnetic resonance imaging-based spatially normalized 18F-DTBZ images for each participant. Average SUR images were displayed as 2-dimensional and 3-dimensional to illustrate the image patterns in each group. The nonparametric Kruskal-Wallis test on regional SUR was used for group comparison between healthy control participants and patients with PD at different stages. Quantitative parameters were correlated with severity of disease and disease duration by Spearman correlation. Voxelwise analysis for evaluating dopaminergic neuron decline of different PD stages was performed by SPM5. RESULTS The 2-dimensional and 3-dimensional 18F-DTBZ PET images demonstrated that the reduction of vesicular monoamine transporter type 2 availability was obviously correlated with the severity of disease in patients with PD. The mean reductions of vesicular monoamine transporter type 2 density for the caudate, putamen,and substantia nigra were 21.50%, 58.20%, and 21.10% for mild PD[Parkinson disease];60.75%, 79.49%,and 39.87%formoderate PD; and63.94%,83.20%, and 44.00% for advanced PD, respectively [corrected]. The SURs of bilateral striatal regions exhibited significantly exponential correlations to stage; disease duration; Unified Parkinson Disease Rating Scale motor score; posture instability and gait disturbance; and akinesia, rigidity, and tremor scores. CONCLUSIONS AND RELEVANCE In PD, 18F-DTBZ PET is a potential imaging biomarker for measuring dopaminergic degeneration in vivo and monitoring the severity of disease.

Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography.

PurposeThe literature suggests that a history of depression is associated with an increased risk of developing Alzheimer’s disease (AD). The aim of this study was to examine brain amyloid accumulation in patients with lifetime major depression using 18F-florbetapir (AV-45/Amyvid) PET imaging in comparison with that in nondepressed subjects.MethodsThe study groups comprised 25 depressed patients and 11 comparison subjects who did not meet the diagnostic criteria for AD or amnestic mild cognitive impairment. Vascular risk factors, homocysteine and apolipoprotein E (ApoE) genotype were also examined. The standard uptake value ratio (SUVR) of each volume of interest was analysed using whole the cerebellum as the reference region.ResultsPatients with a lifetime history of major depression had higher 18F-florbetapir SUVRs in the precuneus (1.06 ± 0.08 vs. 1.00 ± 0.06, p = 0.045) and parietal region (1.05 ± 0.08 vs. 0.98 ± 0.07, p = 0.038) than the comparison subjects. Voxel-wise analysis revealed a significantly increased SUVR in depressed patients in the frontal, parietal, temporal and occipital areas (p < 0.01). There were no significant associations between global 18F-florbetapir SUVRs and prior depression episodes, age at onset of depression, or time since onset of first depression.ConclusionIncreased 18F-florbetapir binding values were found in patients with late-life major depression relative to comparison subjects in specific brain regions, despite no differences in age, sex, education, Mini Mental Status Examination score, vascular risk factor score, homocysteine and ApoE ε4 genotype between the two groups. A longitudinal follow-up study with a large sample size would be worthwhile.

Whole-Body Biodistribution and Radiation Dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A Novel Vesicular Monoamine Transporter 2 Imaging Agent

Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-18F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (18F-FP-(+)-dihydrotetrabenazine [DTBZ] or 18F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use. Methods: Nine healthy human subjects (mean age ± SD, 58.6 ± 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 ± 22.9 MBq of 18F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs. Results: The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% ± 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 ± 23.8 μGy/MBq, was the pancreas. The effective dose equivalent and effective dose for 18F-AV-133 were 36.5 ± 2.8 and 27.8 ± 2.5 μSv/MBq, respectively. These values are comparable to those reported for any other 18F-labeled radiopharmaceutical. Conclusion: 18F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.