IU Indianapolis ScholarWorks :: Browsing by Author "Territo, Paul R."

Browsing by Author "Territo, Paul R."

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18F-NaF and 18F-FDG as molecular probes in the evaluation of atherosclerosis
(Springer Nature, 2018-11) McKenney-Drake, Mikaela L.; Moghbel, Mateen C.; Paydary, Koosha; Alloosh, Mouhamad; Houshmand, Sina; Moe, Sharon; Salavati, Ali; Sturek, Jeffrey M.; Territo, Paul R.; Weaver, Connie; Werner, Thomas J.; Høilund-Carlsen, Poul Flemming; Sturek, Michael; Alavi, Abass; Cellular and Integrative Physiology, School of Medicine
The early detection of atherosclerotic disease is vital to the effective prevention and management of life-threatening cardiovascular events such as myocardial infarctions and cerebrovascular accidents. Given the potential for positron emission tomography (PET) to visualize atherosclerosis earlier in the disease process than anatomic imaging modalities such as computed tomography (CT), this application of PET imaging has been the focus of intense scientific inquiry. Although 18F-FDG has historically been the most widely studied PET radiotracer in this domain, there is a growing body of evidence that 18F-NaF holds significant diagnostic and prognostic value as well. In this article, we review the existing literature on the application of 18F-FDG and 18F-NaF as PET probes in atherosclerosis and present the findings of original animal and human studies that have examined how well 18F-NaF uptake correlates with vascular calcification and cardiovascular risk.
70329 Automated Lungs Segmentation and Airways Skeletonization from CT Scans in Patients with Cystic Fibrosis
(Cambridge University Press, 2021) Chie, Juan A. Chong; Territo, Paul R.; Salama, Paul; Medicine, School of Medicine
ABSTRACT IMPACT: Improve healthcare of patients with Cystic Fibrosis by reducing the time needed to generate results. OBJECTIVES/GOALS: We developed an automated framework capable of segmenting the lungs, extract the airways, and create a skeletonize map of the airways from CT scans of Cystic Fibrosis patients. As future expansion, the framework will be expanded to measure the airways diameters, detect the abnormal airways, and count the number of visible airways generations. METHODS/STUDY POPULATION: For this study, 35 CT scans from CF patients with different levels of severity were used to test the developed framework. The lungs segmentation was performed using an algorithm based on Gaussian Mixture Models for mild cases, and for severe cases a technique that uses convex hull and the recurrent addition of ‘dots’ was implemented. The airways extraction was performed using a 26-points connected components algorithm in conjunction with a curve fitting technique over the histogram of voxel values. Medial axis transform was used to perform the skeletonization of the extracted airways, and airways diameters determined via ray-casting. RESULTS/ANTICIPATED RESULTS: The framework was able to correctly obtain the segmented lungs in all 35 sample volumes regardless of disease severity. In contrast, it tends to fail to skeletonize the airways for severe cases where the framework is unable to differentiate between abnormal lungs conditions and dilated airways. Fine tuning is required to achieve better results. The expected result of the future implemented sections of the framework are focused to characterize the extracted airways by: 1) measuring the airways diameters; 2) detect and count the number of abnormal airways sizes; and 3) count the number of visible airways branching which will permit determination of stage and grade of the lungs of CF patients. DISCUSSION/SIGNIFICANCE OF FINDINGS: The proposed framework allows a fast and reproducible way to segment the lungs and create a skeletonized map of the airways that are independent of clinical training. In addition, this framework will be extended to obtain measurements of airway dilation and branching level, which could provide a deeper insight of the airways in CF patients.
A framework for translating tauopathy therapeutics: Drug discovery to clinical trials
(Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of Medicine
The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.
A T Cell‐Engaging Tumor Organoid Platform for Pancreatic Cancer Immunotherapy
(Wiley, 2023) Zhou, Zhuolong; Van der Jeught, Kevin; Li, Yujing; Sharma, Samantha; Yu, Tao; Moulana, Ishara; Liu, Sheng; Wan, Jun; Territo, Paul R.; Opyrchal, Mateusz; Zhang, Xinna; Wan, Guohui; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite a small percentage of cases with defective mismatch DNA repair (dMMR), PDA is included in the most immune‐resistant cancer types that are poorly responsive to immune checkpoint blockade (ICB) therapy. To facilitate drug discovery combating this immunosuppressive tumor type, a high‐throughput drug screen platform is established with the newly developed T cell‐incorporated pancreatic tumor organoid model. Tumor‐specific T cells are included in the pancreatic tumor organoids by two‐step cell packaging, fully recapitulating immune infiltration in the immunosuppressive tumor microenvironment (TME). The organoids are generated with key components in the original tumor, including epithelial, vascular endothelial, fibroblast and macrophage cells, and then packaged with T cells into their outside layer mimicking a physical barrier and enabling T cell infiltration and cytotoxicity studies. In the PDA organoid‐based screen, epigenetic inhibitors ITF2357 and I‐BET151 are identified, which in combination with anti‐PD‐1 based therapy show considerably greater anti‐tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up‐regulates the MHC‐I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.
Aging x Environment x genetic risk for late onset Alzheimer’s disease results in alterations in cognitive function in mice independent of amyloid and tau pathology
(Wiley, 2025-01-03) Williams, Sean-Paul Gerard; Santos, Diogo Francisco Silva; Haynes, Kathryn A.; Heaton, Nicholas; Hart, Jason T.; Kotredes, Kevin P.; Pandey, Ravi S.; Persohn, Scott C.; Eldridge, Kierra; Ingraham, Cynthia M.; Lloyd, Christopher D.; Wang, Nian; Sasner, Michael; Carter, Gregory W.; Territo, Paul R.; Lamb, Bruce T.; Howell, Gareth R.; Oblak, Adrian L.; Sukoff Rizzo, Stacey J.; Neurology, School of Medicine
Background: Alzheimer’s disease (AD) research has been historically dominated with studies in mouse models expressing familial AD mutations; however, the majority of AD patients have the sporadic, late‐onset form of AD (LOAD). To address this gap, the IU/JAX/PITT MODEL‐AD Consortium has focused on development of mouse models that recapitulate LOAD by combining genetic risk variants with environmental risk factors and aging to enable more precise models to evaluate potential therapeutics. The present studies were undertaken to characterize cognitive and neurophysiological phenotypes in LOAD mice. Method: Two genetic risk factors, APOE4 and Trem2*R47H, were incorporated into C57BL/6J mice with humanized amyloid‐beta to produce the LOAD2 model (JAX# 030670). Male and female LOAD2 and WT mice were exposed to ad libitum 45% high‐fat diet from 2‐months of age (LOAD2+HFD or WT+HFD, respectively) throughout their lifespan and compared to LOAD2 and WT mice on control diet (+CD). Cognitive training began at 14‐months of age using a touchscreen testing battery, similar to previously described methods (Oomen et al 2013). At the conclusion of touchscreen testing, subjects were implanted with wireless telemetry devices (DSI) for evaluation of electroencephalography (EEG) signatures. Result: All subjects met the touch‐reward association criteria. During task acquisition LOAD2+CD mice demonstrated impaired acquisition relative to WT+CD, while both LOAD2+HFD and WT+HFD failed to learn the task as indicated by accuracy less than chance (<50%); which was confirmed in a separate cohort. LOAD2+HFD mice demonstrated increased spikewave events as measured by EEG, relative to LOAD2+CD. At 18‐months of age +CD mice that met acquisition criteria were evaluated in a location discrimination task with LOAD2+CD mice demonstrating modest impairments in pattern separation relative to age‐matched WT+CD. Conclusion: These data are the first reports of cognitive deficits and neurophysiological alterations in mice with environmental x genetic risk for LOAD, independent of amyloid and tau pathology. Importantly, the present findings demonstrate the sensitivity of the translational touchscreen testing battery for detecting mild cognitive impairment in LOAD mice with corresponding neurophysiologic alterations, and extend previous characterization data for the LOAD2 model and its utility for the study of the biology of LOAD.
Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction
(bioRxiv, 2024-03-13) Onos, Kristen; Lin, Peter B.; Pandey, Ravi S.; Persohn, Scott A.; Burton, Charles P.; Miner, Ethan W.; Eldridge, Kierra; Nyandu Kanyinda, Jonathan; Foley, Kate E.; Carter, Gregory W.; Howell, Gareth R.; Territo, Paul R.; Neurology, School of Medicine
Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. Results: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.
Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction
(Wiley, 2024) Onos, Kristen D.; Lin, Peter B.; Pandey, Ravi S.; Persohn, Scott A.; Burton, Charles P.; Miner, Ethan W.; Eldridge, Kierra; Nyandu Kanyind, Jonathan; Foley, Kate E.; Carter, Gregory W.; Howell, Gareth R.; Territo, Paul R.; Neurology, School of Medicine
Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. Results: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. Highlights: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.
Association of Pancreatic Steatosis With Chronic Pancreatitis, Obesity, and Type 2 Diabetes Mellitus
(Lippincott, Williams & Wilkins, 2019-03) Tirkes, Temel; Jeon, Christie Y.; Li, Liang; Joon, Aron Y.; Seltman, Ted A.; Sankar, Meghana; Persohn, Scott A.; Territo, Paul R.; Radiology and Imaging Sciences, School of Medicine
Objective: The aim of this study was to determine the association of the pancreatic steatosis with obesity, chronic pancreatitis (CP), and type 2 diabetes mellitus. Methods: Patients (n = 118) were retrospectively identified and categorized into no CP (n = 60), mild (n = 21), moderate (n = 27), and severe CP (n = 10) groups based on clinical history and magnetic resonance cholangiopancreatography using the Cambridge classification as the diagnostic standard. Visceral and subcutaneous compartments were manually segmented, and fat tissue was quantitatively measured on axial magnetic resonance imaging. Results: Pancreatic fat fraction showed a direct correlation with fat within the visceral compartment (r = 0.54). Patients with CP showed higher visceral fat (P = 0.01) and pancreatic fat fraction (P < 0.001): mild, 24%; moderate, 23%; severe CP, 21%; no CP group, 15%. Patients with type 2 diabetes mellitus showed higher pancreatic steatosis (P = 0.03) and higher visceral (P = 0.007) and subcutaneous fat (P = 0.004). Interobserver variability of measuring fat by magnetic resonance imaging was excellent (r ≥ 0.90–0.99). Conclusions: Increased visceral adipose tissue has a moderate direct correlation with pancreatic fat fraction. Chronic pancreatitis is associated with higher pancreatic fat fraction and visceral fat. Type 2 diabetes mellitus is associated with higher pancreatic fat fraction and visceral and subcutaneous adiposity.
Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing
(MDPI, 2020-10-01) Demine, Stephane; Schulte, Michael L.; Territo, Paul R.; Eizirik, Decio L.; Radiology and Imaging Sciences, School of Medicine
There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2γa as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.
Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease
(Wiley, 2024) Chumin, Evgeny J.; Burton, Charles P.; Silvola, Rebecca; Miner, Ethan W.; Persohn, Scott C.; Veronese, Mattia; Territo, Paul R.; Medicine, School of Medicine
Introduction: Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. Methods: We performed 18 F-FDG positron emission tomography (PET) imaging in 4-, 6-, and 12-month-old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis. Results: The 5XFAD model mice showed age-related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. Discussion: The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.

Browsing by Author "Territo, Paul R."

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