S.C. Huang

Current and future uses of neuroimaging for cognitively impaired patients

Technological advances have led to greater use of both structural and functional brain imaging to assist with the diagnosis of dementia for the increasing numbers of people with cognitive decline as they age. In current clinical practice, structural imaging (CT or MRI) is used to identify space-occupying lesions and stroke. Functional methods, such as PET scanning of glucose metabolism, could be used to differentiate Alzheimers disease from frontotemporal dementia, which helps to guide clinicians in symptomatic treatment strategies. New neuroimaging methods that are currently being developed can measure specific neurotransmitter systems, amyloid plaque and tau tangle concentrations, and neuronal integrity and connectivity. Successful co-development of neuroimaging surrogate markers and preventive treatments might eventually lead to so-called brain-check scans for determining risk of cognitive decline, so that physicians can administer disease-modifying medications, vaccines, or other interventions to avoid future cognitive losses and to delay onset of disease.

Brain structural mapping using a novel hybrid implicit/explicit framework based on the level-set method

This paper presents a novel approach to feature-based brain image warping, by using a hybrid implicit/explicit framework, which unifies many prior approaches in a common framework. In the first step, we develop links between image warping and the level-set method, and we formulate the fundamental mathematics required for this hybrid implicit/explicit approach. In the second step, we incorporate the large-deformation models into these formulations, leading to a complete and elegant treatment of anatomical structure matching. In this latest approach, exact matching of anatomy is achieved by comparing the target to the warped source structure under the forward mapping and the source to the warped target structure under the backward mapping. Because anatomy is represented nonparametrically, a path is constructed linking the source to the target structure without prior knowledge of their point correspondence. The final point correspondence is constructed based on the linking path with the minimal energy. Intensity-similarity measures can be naturally incorporated in the same framework as landmark constraints by combining them in the gradient descent body forces. We illustrate the approach with two applications: (1) tensor-based morphometry of the corpus callosum in autistic children; and (2) matching cortical surfaces to measure the profile of cortical anatomic variation. In summary, the new mathematical techniques introduced here contribute fundamentally to the mapping of brain structure and its variation and provide a framework that unites feature and intensity-based image registration techniques.

Novel observations with FDOPA‐PET imaging after early nigrostriatal damage

Striatal 6‐[18F]fluoro‐L‐DOPA (FDOPA) kinetic rate constants were measured by positron emission tomography (PET) in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated squirrel monkeys. After scanning, stereological counts of dopaminergic neurons were done in substantia nigra, and dopamine (DA) and metabolite concentrations were determined in the caudate, putamen, and substantia nigra. Graded doses of MPTP produced animals with mild to moderate reductions (10–35%) in dopaminergic neurons, where the percent of cell loss was proportional to the amount of MPTP given. Striatal DA and metabolite concentrations were relatively unchanged in animals given 1.0 and 1.5 mg/kg of MPTP, but were significantly reduced after 2.0 mg/kg of MPTP. All animals injected with a single dose of MPTP showed no overt signs of parkinsonism. In contrast, DA and metabolite concentrations in the substantia nigra were significantly reduced for all MPTP‐treated animals. Reduction of dopaminergic indices in the substantia nigra did not parallel reductions in the striatum, indicating differential sensitivity of the nigrostriatal pathway to the neurotoxic effects of MPTP. The percent change in FDOPA uptake (Ki) and decarboyxlation (k3) after MPTP showed significant positive correlations to striatal DA levels, but not to the number of dopaminergic neurons. This suggests that FDOPA is a good index of striatal DA levels.

A modeling-based factor extraction method for determining spatial heterogeneity of Ga-68 EDTA kinetics in brain tumors

The ROI method used in a Ga-68 EDTA PET dynamic study for quantitative determination of brain tumor (blood brain barrier) BBB permeability assumes that the tumor is homogeneous in terms of Ga-68 EDTA kinetics, even though it is known to be highly heterogeneous. It is desirable to examine regions of different kinetics separately. In this study, we have developed an efficient and effective method to separate tissue regions of different Ga-68 EDTA kinetics. The method uses a two-compartment model to extract three principal component factors (vascular component, fast and slow components) from whole-tumor kinetics by model fitting, then each pixel kinetics in the tumor was expressed in terms of these factors by least-square regression to provide factor images. The whole tumor was separated into two regions-one with mainly fast kinetics and one with slow kinetics. The two regions have markedly different uptake and clearance rates. This method has combined the advantage of statistical factor analysis and a modeling approach. The PET-to-MRI image registration program was employed in this study for registering Ga-68 EDTA PET images to MRI T1 weighted images.

Estimation of myocardial glucose utilisation with PET using the left ventricular time-activity curve as a non-invasive input function

The validation study is described of a new modelling method that has been developed, using tracer kinetic modelling with positron emission tomography (PET) to achieve non-invasive measurement of myocardial metabolic rate of glucose (MMRGlc). Eight data sets obtained from dynamic cardiac PET 2-[18F]fluoro-2-deoxy-D-glucose (FDG) studies on human subjects are employed, and the estimation of MMRGlc using both the new and traditional methods is compared. The results from all eight human FDG studies are consistent with those from previous computer simulations. With the new method, the estimated mean of K (a parameter directly proportional to MMRGlc) increases by about 8%, and that of k4 (the rate constant of FDG dephosphorylation) decreases by about 48%. The approach should be more suitable for use in dynamic cardiac PET studies when non-invasive means are used to obtain the plasma time-activity curve from left-ventricle PET images.

A Public Domain Dynamic Mouse FDG MicroPET Image Data Set for Evaluation and Validation of Input Function Derivation Methods

A set of over 20 dynamic mouse FDG microPET images has been collected experimentally at UCLA and is made available to the public on the Internet. Accompanying each dynamic image set also is the radioactivity measurements of multiple sequential blood samples taken during the study. The data are expected to be useful for investigators who want to know more about the characteristics of dynamic mouse FDG microPET images before doing their own experiments, and will be especially useful for those who are interested in developing image-based methods for deriving blood activity curves from dynamic mouse microPET images.

Optimal design in dynamic PET data acquisition: a new approach using simulated annealing and component-wise Metropolis updating

Dynamic positron emission tomography (PET) is a powerful tool of measuring biological activities in vivo. Due to the inherent high noise level, there are always concerns about how to increase the signal-to-noise ratio. One possible approach is to optimize the experimental design. In this paper, we propose a discretized representation of the experimental design and transform it to a combinatorial problem. This combinatorial optimization problem then can be solved using simulated annealing with component-wise Metropolis Monte Carlo simulation. We showed that using this novel approach one can design an optimal input function as well as an optimal sampling schedule efficiently. Our results show that the current dynamic scanning of approximately 20 frames does not give us much more information than an optimized four-frame schedule, and needlessly increases storage requirements. This is consistent with the conclusion given by Li et al. (1996). We also reproduced the optimal sampling schedule for the fluorodeoxy-glucose (FDG) study proposed. Moreover, we show that the single bolus injection is almost optimal in the sense of D-optimal design, as well as many other measures.

A nonlinear, image domain filtering method for PET images

An adaptive, nonlinear image domain filtering strategy is described which improves positron emission tomography (PET) images. The method was formulated to improve on the linear, low-pass filtering typically applied to each projection in the filtered back-projection (FBP) reconstruction algorithm. The algorithm is a potential alternative to linear smoothing which reduces noise but degrades resolution; this method uses the FBP algorithm for reconstruction, but aims to incorporate some of the statistical information and nonlinear smoothing utilized in iterative reconstruction algorithms. The approach uses sinogram segmentation to separate the sinogram elements with higher and lower signal-to-noise ratios, and then reconstruct each with FBP using a more appropriate choice of filter and cut-off frequency. Also, this algorithm addresses the radial streak artifacts introduced by FBP. The algorithm was evaluated using simulations as well as clinical data of cardiac PET studies on an ECAT 931 PET scanner. The initial results suggest that this technique has advantages over the current clinical protocol. Images processed with the method show generally improved visual image quality and reduced radial streaks without the introduction of artifacts. Also, by using a higher resolution filter for the high activity segment of the sinogram, increased contrast recovery and resolution are realized.

A hybrid attenuation correction technique to compensate for lung density in 3D total body PET

A hybrid attenuation correction technique (ACT) has been developed for /sup 18/F-FDG Total Body Positron Emission Tomography (PET). With a short transmission scan of the thorax, any time within a few days of the isotope injection, it can correct for attenuation in the entire body. Segmentation, registration, and active contour finding techniques are applied to both emission and short transmission images to locate and map the major attenuating structures in the body. This technique eliminates the need for patient to remain still from the start of the transmission scan to the end of the emission scan without the added noise of simultaneous or post transmission scan measurements. The results of volunteer studies are comparable to standard measured ACT, both visually and quantitatively. Efficient use of scanner and maximum comfort for patients make it a highly desirable technique for clinical imaging.<<ETX>>

Optimal design of a new kinetic strategy for extracting FDG transport and uptake information in microfluidic multi-chamber cell culture chip coupled with PSAPD camera

Information on the transport and phosphorylation rate constants (k1,k2,k3,k4,Ki) of a tracer reflects the biological state of cells. A microfluidic cell culture chip coupled with PSAPD camera (MF-PSAPD) has been developed to give continuous measurements of radioactivity in individual wells. However, constant infusion (CI) of PET tracers through the chambers would give high background activity due to the relatively large volume space of the infusing medium in the wells of cultured cells that compromise the ability of the setup to estimate the k values. New strategies of controlling the infusion and tracer level are needed to provide reliable estimates of the parameters. A switching strategy (SS) was conceived that consists of multiple medium-infusion cycles, each of which has a tracer incubation (TI) period followed by a background-removed (BR) period (tracer-free medium). In this paper, equally switching strategy (ESS) with 12 cycles of constant TI and BR periods (5 min each) was evaluated by computer simulation and by experiments on MF-PSAPD using the tracer fluorodeoxy-glucose (FDG) and the four parameter FDG model. The SS was further optimized by using a simulated annealing algorithm and D-optimal criterion to obtain optimal switching strategy (OSS). Simulations showed that the 12-cycle ESS did not perform as well (i.e., with larger estimated variability of the model parameters) as a 5-cycle OSS that also has multiple practical advantages. Patterns of OSS were found to be insensitive to the variation of cell number and k values, and all tended to have longer TI at the beginning but longer BR at later times. Estimated k values with SS have large reduction in %CV compared to those of CI, with the largest reduction for Ki--from 762% down to 26% under the same count rate conditions. The new optimized strategy of tracer incubation/measurement is able to provide reliable estimates of FDG ks in MF-PSAPD.