Richard Carson, PhD

Following administration of a positron-emitting radiopharmaceutical (tracer), PET permits the direct measurement of the four-dimensional radioactivity profile throughout a 3D object over time. Depending on the characteristics of the tracer, physiological parameters can be estimated, such as blood flow, metabolism, and receptor concentration. These measurements can be made with subjects in different states (e.g., stimulus or drug activation), used to compare patient groups to controls, or to assess the efficacy of drug treatment.

Tracer Kinetic Modeling

The goal of PET tracer kinetic modeling is to devise a biologically validated, quantitatively reliable, and logistically practical method for use in human PET studies. Animal studies are typically performed to characterize the tracers, followed by initially complex human studies, typically leading to the development of simplified methods, e.g., using continuous tracer infusion. These techniques are also applied on a pixel-by-pixel level to produce images of PET physiological and pharmacological parameters, such as blood flow and receptor binding. Mathematical methodology includes linear and non-linear differential equations, statistical estimation theory, methods to avoid the needs for arterial blood measurements (the input function) such as blind deconvolution, plus the development of novel rapid computational algorithms.

PET Physics and Reconstruction.

Proper characterization of the PET image data is essential for modeling studies. This requires accurate and carefully characterized corrections for the physics and electronics of coincident event acquisition. Studies of these effects are performed with phantom measurements made on the scanner.

A critical component in the application to real data is the correction for subject motion, particularly as the resolution of modern machines has improved (better than 3-mm in human brain machines). Both hardware and software approaches are employed to address these issues. To produce accurate images with minimum noise, a statistically-based iterative reconstruction algorithm is necessary. Developments in this area include the mathematical aspects of algorithm development, the computer science issues associated with a large cluster-based algorithm, the incorporation of the physics and motion correction, the use of prior information provided from MR images, and the tuning and characterization necessary for practical application for biological studies. The ultimate goal is the combination of the tracer kinetic modeling and image reconstruction to directly process a 4D dataset into parametric images of the physiological parameters of interest. When applied in the thorax, respiratory and cardiac motion must be included, raising the problem to 5D and 6D analysis.

These issue are now all being taken to the next level for the building and optimization of the NeuroEXPLORER (a.k.a. NX), which will have 10-fold higher sensitivity than the previous state-of-the-art HRRT. This system, scheduled to arrive at Yale early in 2023 will open new vista for brain PET investigations.

PET Applications

PET studies are performed in human subjects and preclinical models of a wide variety of diseases. Examples of interest include:

• Develop the highest resolution and sensitivity human brain PET system (U01EB029811)
• Synaptic density imaging in the living human brain (See Science Translational Medicine, 2016 and subsequent clinical and preclinical paper)
• Measuring beta cells in the pancreas for diabetes with novel tracers including ligands for the vesicular monoamine transporter
• Using PET to measure drug delivery in cancer
• Neuroreceptor studies have focused on determining changes in receptor concentration as a function of disease or measurement of receptor occupancy by drugs. Such changes have been successfully demonstrated in the dopaminergic, muscarinic, and serotonergic systems.
• Measurement of the relationship between dopamine receptors and impulsivity
• New methods for quantification of myocardial blood flow
• Hypoxia assessment in tumors before and after radiation treatment
• Differentiation of radiation necrosis vs. tumor recurrence

• 4D/5D Image reconstruction for PET
• Mathematical model development for novel radiopharmaceuticals
• Imaging of beta cells in the pancreas
• Neuroinflammation imaging in a wide variety of disorders
• Novel preclinical and clinical applications in oncology