Faculty Bibliography

PURPOSE/OBJECTIVE:To develop a flexible method for tracking respiratory and cardiac motions throughout MR and PET-MR body examinations that requires no additional hardware and minimal sequence modification. METHODS:The incorporation of a contrast-neutral rosette navigator module following the RF excitation allows for robust cardiorespiratory motion tracking with minimal impact on the host sequence. Spatial encoding gradients are applied to the FID signal and the desired motion signals are extracted with a blind source separation technique. This approach is validated with an anthropomorphic, PET-MR-compatible motion phantom as well as in 13 human subjects. RESULTS:Both respiratory and cardiac motions were reliably extracted from the proposed rosette navigator in phantom and patient studies. In the phantom study, the MR-derived motion signals were additionally validated against the ground truth measurement of diaphragm displacement and left ventricle model triggering pulse. CONCLUSION/CONCLUSIONS:The proposed method yields accurate respiratory and cardiac motion-state tracking, requiring only a short (1.76 ms) additional navigator module, which is self-refocusing and imposes minimal constraints on sequence design.

Objectives: There is an urgent need for the development of Parkinson's disease (PD) treatments that can slow disease progression. LRRK2 (leucine-rich repeat kinase 2) has recently been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with LRRK2 mutation G2019S linked to the most frequent familial form of PD. Several LRRK2 inhibitors have been developed and evaluated in vitro; however, in vivo target engagement has never been characterized. Despite research efforts invested to date, there is no radiotracer available for in vivo imaging of LRRK2 using PET. In our pilot studies, we synthesized and evaluated two tritium-labeled potent and selective kinase inhibitors, [³H]LRRK2-IN-1 (1^st generation) and [³H]GNE-9605 (second-generation LRRK2 inhibitors), via in vitro (IC50, Kd, Bmax) and in vivo/ex vivo methodologies (autoradiography, bio-distribution, and blocking experiments) in rodents and human striatum tissues. Comparative studies indicated that, although LRRK2-IN-1 has a lower DELTAG (lower free binding energy to the target enzyme determined via docking studies) than GNE-9605, GNE-9605 is more CNS permeable due to its higher lipophilicity than LRRK2-IN-1, suggesting more promising properties for ligands derived from second-generation LRRK2 inhibitors. We have, since then, identified candidates that are more potent and selective than current known LRRK2 inhibitors, based on in vitro assays. Radiolabeling and microPET evaluation studies are ongoing, preliminary results will be presented.
Method(s): We have prepared and evaluated several novel LRRK2 inhibitors and compared their in vitro properties (e.g., IC50 values,membrane permeability, and the P-glycoprotein liability) with those previously developed LRRK2 inhibitors, such as GNE compounds. We have also synthesized several corresponding precursors and carried out radiolabeling with either C-11 or F-18 to obtain the desired target molecules for further evaluation of their in vivo properties as PET ligands via microPET/CT studies, including in vivo/ex vivo bio-distribution and blocking studies.
Result(s): Several in vitro assays were conducted to compare IC50 values (for example, in HEK293 cells with transient overexpression of LRRK2 G2019S measuring decrease of phosphoserine 935 with an antibody in a robust Meso Scale Discovery assay) for LRRK2-a and LRRK2-b (novel inhibitors) vs. GNE-7915 and GNE-9605. The results are consistently indicated that LRRK2-b (10 nM) is more potent and selective than GNE-7915 (40 nM), and GNE-9605 (90 nM). The results of the low efflux ratio (<3) from the CNS permeability measurement via MDR assay in the absence or presence of a Pgp inhibitor suggested that LRRK2-b is a promising candidate as its BBB permeability may not be a concern and it is not a good Pgp substrate. Radiolabeling of LRRK2-a and LRRK2-b with F-18 has been accomplished via one-step fluoro-for-tosyl radiosynthesis. In vivo microPET/CT evaluation studies in mice are underway.
Conclusion(s): Potential in vivo imaging of LRRK2 with PET is an exciting, but at the same time uncharted research area, limited thus far by a lack of relevant information, resources and tools. Based on the in vitro and in vivo/ex vivo results, we have identified several candidates and will fine-tune the structure-activity relationship (SAR) to generate promising PET ligand candidates for in vivo imaging of brain LRRK2

Introduction: Breast cancer is a worldwide health issue with about 1 million new cases every year. Dysregulated cellular proliferation, a common feature to all human cancers, is a key player of aberrant proliferative signaling and is therefore considered as a "hallmark of cancer. In breast cancer, a lot of attention focuses on particular members of the cell cycle machinery, the D-type cyclins and their partner cyclin-D kinases 4 and 6 (CDK4/6). CDKs are serine/threonine kinases key in regulating cell cycle progression by associating with cyclins. Several studies have identified alterations of cell cycle regulators in human breast cancer and provide a strong rationale for a therapeutic role for CDK4/6 inhibition in this tumor type. Amplification of the cyclin-D1 occurs in about 20% of human breast cancers, while overexpression of the protein is above 60%. The subtype for which CDK4/6 inhibition has the strongest rationale is estrogen receptor (ER)-positive disease. These subtypes almost always retain Rb function, thereby CDK4 and CDK6 targeting agents can block pRb phosphorylation (in low nanomolar concentration) and induce G1 arrest in sensitive cell lines. It is often controversial whether CDK4/6 inhibitors are capable to prolong overall survival. Moreover, it is urgent to find a way to select which patients are most likely to benefit from these drugs and to monitor, non-invasively, the progress of the disease and the overall treatment response. To this aim, we developed a PET imaging agent ([¹⁸F]-CDKi) as an in vivo PET reporter of CDK4/6 status with the final aim to improve efficacy of breast cancer therapy. To generate our fluorine-18 inhibitor, we introduced an F-18 prosthetic group (¹⁸F-fluorobenzoic acid, [¹⁸F-FBA]), on the terminal piperazine and transformed palbociclib (Inbrance, Pfizer) into a different PET active functional molecule. The first in vitro experiment aiming to analyze pharmacokinetics (PK) and in vitro activity revealed that [¹⁸F]-CDKican be a successful PET agent with nearly ideal imaging characteristics. Moreover, we demonstrated that [¹⁸F]-CDKi is stable in vitro and in vivo (>98% at 4h post injection) and maintained a potent targeting affinity to CDK4/6. Cellular uptake experiments performed in MCF-7 breast cancer cell line (ER-positive/HER2-negative) demonstrated specific uptake. Similar significant uptake values were also observed in biodistributed MCF-7 bearing mouse models. The strong activation of CDK4/6 in cancer cells in concert with its low activation in untransformed healthy cells makes [¹⁸F]-CDKi a nearly ideal imaging agent for the early detection of malignant growth of the breast. Moreover, we also hypothesize it could be an excellent PET imaging agent for metastatic breast cancer due to their high proliferative rate. CDKi represents the first of a new generation of PET imaging agents critical to study how cancer cells escape the cell cycle arrest and develop resistance to conventional treatment

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

BACKGROUND AND PURPOSE/OBJECTIVE:Na) MR imaging. MATERIALS AND METHODS/METHODS:Na) MR imaging using a 3T scanner. Total sodium concentration was measured in the genu, body, and splenium of the corpus callosum with 5-mm ROIs; total sodium concentration of the genu-to-splenium ratio was calculated and compared between patients and controls. RESULTS:= .001). CONCLUSIONS:Complex differences are seen in callosal total sodium concentration in symptomatic patients with mild traumatic brain injury, supporting the notion of ionic dysfunction in the pathogenesis of mild traumatic brain injury. The total sodium concentration appears to be altered beyond the immediate postinjury phase, and further work is needed to understand the relationship to persistent symptoms and outcome.

Joint activity and attenuation reconstruction methods from time of flight (TOF) positron emission tomography (PET) data provide an effective solution to attenuation correction when no (or incomplete/inaccurate) information on the attenuation is available. One of the main barriers limiting their use in clinical practice is the lack of validation of these methods on a relatively large patient database. In this contribution, we aim at validating the activity reconstructions of the maximum likelihood activity reconstruction and attenuation registration (MLRR) algorithm on a whole-body patient data set. Furthermore, a partial validation (since the scale problem of the algorithm is avoided for now) of the maximum likelihood activity and attenuation reconstruction (MLAA) algorithm is also provided. We present a quantitative comparison of the joint reconstructions to the current clinical gold-standard maximum likelihood expectation maximization (MLEM) reconstruction with CT-based attenuation correction.Methods:The whole-body TOF-PET emission data of each patient data set is processed as a whole to reconstruct an activity volume covering all the acquired bed positions, which helps to reduce the problem of a scale per bed position in MLAA to a global scale for the entire activity volume. Three reconstruction algorithms are used: MLEM, MLRR and MLAA. A maximum likelihood (ML) scaling of the single scatter simulation (SSS) estimate to the emission data is used for scatter correction. The reconstruction results are then analyzed in different regions of interest.Results:The joint reconstructions of the whole-body patient data set provide better quantification in case of PET and CT misalignments caused by patient and organ motion. Our quantitative analysis shows a difference of -4.2% (±2.3%) and -7.5% (±4.6%) between the joint reconstructions of MLRR and MLAA compared to MLEM, averaged over all regions of interest, respectively.Conclusion:Joint activity and attenuation estimation methods provide a useful means to estimate the tracer distribution in cases where CT-based attenuation images are subject to misalignments or are not available. With an accurate estimate of the scatter contribution in the emission measurements, the joint TOF-PET reconstructions are within clinical acceptable accuracy.

A novel approach is presented for group statistical analysis of diffusion weighted MRI datasets through voxelwise Orientation Distribution Functions (ODF). Recent advances in MRI acquisition make it possible to use high quality diffusion weighted protocols (multi-shell, large number of gradient directions) for routine in vivo study of white matter architecture. The dimensionality of these data sets is however often reduced to simplify statistical analysis. While these approaches may detect large group differences, they do not fully capitalize on all acquired image volumes. Incorporation of all available diffusion information in the analysis however risks biasing the outcome by outliers. Here we propose a statistical analysis method operating on the ODF, either the diffusion ODF or fiber ODF. To avoid outlier bias and reliably detect voxelwise group differences and correlations with demographic or behavioral variables, we apply the Low-Rank plus Sparse (L+S) matrix decomposition on the voxelwise ODFs which separates the sparse individual variability in the sparse matrix S whilst recovering the essential ODF features in the low-rank matrix L. We demonstrate the performance of this ODF L+S approach by replicating the established negative association between global white matter integrity and physical obesity in the Human Connectome dataset. The volume of positive findings (p<0.01, 227 cm³) agrees with and expands on the volume found by TBSS (17 cm³), Connectivity based fixel enhancement (15 cm³) and Connectometry (212 cm³). In the same dataset we further localize the correlations of brain structure with neurocognitive measures such as fluid intelligence and episodic memory. The presented ODF L+S approach will aid in the full utilization of all acquired diffusion weightings leading to the detection of smaller group differences in clinically relevant settings as well as in neuroscience applications.

In this article, we evaluate Parallel Level Sets (PLS) and Bowsher's method as segmentation-free anatomical priors for regularized brain positron emission tomography (PET) reconstruction. We derive the proximity operators for two PLS priors and use the EM-TV algorithm in combination with the first order primal-dual algorithm by Chambolle and Pock to solve the non-smooth optimization problem for PET reconstruction with PLS regularization. In addition, we compare the performance of two PLS versions against the symmetric and asymmetric Bowsher priors with quadratic and relative difference penalty function. For this aim, we first evaluate reconstructions of 30 noise realizations of simulated PET data derived from a real hybrid positron emission tomography/magnetic resonance imaging (PET/MR) acquisition in terms of regional bias and noise. Second, we evaluate reconstructions of a real brain PET/MR data set acquired on a GE Signa time-of-flight PET/MR in a similar way. The reconstructions of simulated and real 3D PET/MR data show that all priors were superior to post-smoothed maximum likelihood expectation maximization with ordered subsets (OSEM) in terms of bias-noise characteristics in different regions of interest where the PET uptake follows anatomical boundaries. Our implementation of the asymmetric Bowsher prior showed slightly superior performance compared with the two versions of PLS and the symmetric Bowsher prior. At very high regularization weights, all investigated anatomical priors suffer from the transfer of non-shared gradients.