Browsing by Subject "Perfusion"

Now showing 1 - 9 of 9
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    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.
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    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.
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    Computational fluid dynamic analysis of bioprinted self-supporting perfused tissue models
    (Wiley, 2020-03) Sego, T. J.; Prideaux, Matthew; Sterner, Jane; McCarthy, Brian Paul; Li, Ping; Bonewald, Lynda F.; Ekser, Burcin; Tovar, Andres; Smith, Lester Jeshua; Anatomy and Cell Biology, School of Medicine
    Natural tissues are incorporated with vasculature, which is further integrated with a cardiovascular system responsible for driving perfusion of nutrient‐rich oxygenated blood through the vasculature to support cell metabolism within most cell‐dense tissues. Since scaffold‐free biofabricated tissues being developed into clinical implants, research models, and pharmaceutical testing platforms should similarly exhibit perfused tissue‐like structures, we generated a generalizable biofabrication method resulting in self‐supporting perfused (SSuPer) tissue constructs incorporated with perfusible microchannels and integrated with the modular FABRICA perfusion bioreactor. As proof of concept, we perfused an MLO‐A5 osteoblast‐based SSuPer tissue in the FABRICA. Although our resulting SSuPer tissue replicated vascularization and perfusion observed in situ, supported its own weight, and stained positively for mineral using Von Kossa staining, our in vitro results indicated that computational fluid dynamics (CFD) should be used to drive future construct design and flow application before further tissue biofabrication and perfusion. We built a CFD model of the SSuPer tissue integrated in the FABRICA and analyzed flow characteristics (net force, pressure distribution, shear stress, and oxygen distribution) through five SSuPer tissue microchannel patterns in two flow directions and at increasing flow rates. Important flow parameters include flow direction, fully developed flow, and tissue microchannel diameters matched and aligned with bioreactor flow channels. We observed that the SSuPer tissue platform is capable of providing direct perfusion to tissue constructs and proper culture conditions (oxygenation, with controllable shear and flow rates), indicating that our approach can be used to biofabricate tissue representing primary tissues and that we can model the system in silico.
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    Deep Learning-Based Segmentation and Uncertainty Assessment for Automated Analysis of Myocardial Perfusion MRI Datasets Using Patch-Level Training and Advanced Data Augmentation
    (IEEE, 2021) Yalcinkaya, Dilek Mirgun; Youssef, Khalid; Heydari, Bobby; Zamudio, Luis; Dharmakumar, Rohan; Sharif, Behzad; Medicine, School of Medicine
    In this work, we develop a patch-level training approach and a task-driven intensity-based augmentation method for deep-learning-based segmentation of motion-corrected perfusion cardiac magnetic resonance imaging (MRI) datasets. Further, the proposed method generates an image-based uncertainty map thanks to a novel spatial sliding-window approach used during patch-level training, hence allowing for uncertainty quantification. Using the quantified uncertainty, we detect the out-of-distribution test data instances so that the end-user can be alerted that the test data is not suitable for the trained network. This feature has the potential to enable a more reliable integration of the proposed deep learning-based framework into clinical practice. We test our approach on external MRI data acquired using a different acquisition protocol to demonstrate the robustness of our performance to variations in pulse-sequence parameters. The presented results further demonstrate that our deep-learning image segmentation approach trained with the proposed data-augmentation technique incorporating spatiotemporal (2D+time) patches is superior to the state-of-the-art 2D approach in terms of generalization performance.
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    Design and Rationale for the Use of Magnetic Resonance Imaging Biomarkers to Predict Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium
    (Wolters Kluwer, 2022) Tirkes, Temel; Chinchilli, Vernon M.; Bagci, Ulas; Parker, Jason G.; Zhao, Xuandong; Dasyam, Anil K.; Feranec, Nicholas; Grajo, Joseph R.; Shah, Zarine K.; Poullos, Peter D.; Spilseth, Benjamin; Zaheer, Atif; Xie, Karen L.; Wachsman, Ashley M.; Campbell-Thompson, Martha; Conwell, Darwin L.; Fogel, Evan L.; Forsmark, Christopher E.; Hart, Phil A.; Pandol, Stephen J.; Park, Walter G.; Pratley, Richard E.; Yazici, Cemal; Laughlin, Maren R.; Andersen, Dana K.; Serrano, Jose; Bellin, Melena D.; Yadav, Dhiraj; Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC); Radiology and Imaging Sciences, School of Medicine
    This core component of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study will examine the hypothesis that advanced magnetic resonance imaging (MRI) techniques can reflect underlying pathophysiologic changes and provide imaging biomarkers that predict diabetes mellitus (DM) following acute pancreatitis (AP). A subset of participants in the DREAM study will enroll and undergo serial MRI examinations using a specific research protocol. We aim to differentiate at-risk individuals from those who remain euglycemic by identifying parenchymal features following AP. Performing longitudinal MRI will enable us to observe and understand the natural history of post-AP DM. We will compare MRI parameters obtained by interrogating tissue properties in euglycemic, prediabetic and incident diabetes subjects and correlate them with metabolic, genetic, and immunological phenotypes. Differentiating imaging parameters will be combined to develop a quantitative composite risk score. This composite risk score will potentially have the ability to monitor the risk of DM in clinical practice or trials. We will use artificial intelligence, specifically deep learning, algorithms to optimize the predictive ability of MRI. In addition to the research MRI, the DREAM study will also correlate clinical computerized tomography and MRI scans with DM development.
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    Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide-dependent mechanisms
    (American Physiological Society, 2017-05-01) Jensen, Amanda R.; Drucker, Natalie A.; Khaneki, Sina; Ferkowicz, Michael J.; Markel, Troy A.; Surgery, School of Medicine
    Hydrogen sulfide (H2S) is an endogenous gasotransmitter that has vasodilatory properties. It may be a novel therapy for intestinal ischemia-reperfusion (I/R) injury. We hypothesized that 1) H2S would improve postischemic survival, mesenteric perfusion, mucosal injury, and inflammation compared with vehicle and 2) the benefits of H2S would be mediated through endothelial nitric oxide. C57BL/6J wild-type and endothelial nitric oxide synthase knockout (eNOS KO) mice were anesthetized, and a midline laparotomy was performed. Intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using laser Doppler. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery. Following ischemia, the clamp was removed, and the intestines were allowed to recover. Either sodium hydrosulfide (2 nmol/kg or 2 µmol/kg NaHS) in PBS vehicle or vehicle only was injected into the peritoneum. Animals were allowed to recover and were assessed for mesenteric perfusion, mucosal injury, and intestinal cytokines. P values < 0.05 were significant. H2S improved mesenteric perfusion and mucosal injury scores following I/R injury. However, in the setting of eNOS ablation, there was no improvement in these parameters with H2S therapy. Application of H2S also resulted in lower levels of intestinal cytokine production following I/R. Intraperitoneal H2S therapy can improve mesenteric perfusion, intestinal mucosal injury, and intestinal inflammation following I/R. The benefits of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.NEW & NOTEWORTHY H2S is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear whether H2S works through nitric oxide-dependent pathways in the intestine. We appreciate that H2S was able to improve postischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.
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    Retrospective Detection and Suppression of Dark-Rim Artifacts in First-Pass Perfusion Cardiac MRI Enabled by Deep Learning
    (IEEE, 2021) Unal, Hazar Benan; Beaulieu, Taylor; Rivero, Luis Zamudio; Dharmakumar, Rohan; Sharif, Behzad; Medicine, School of Medicine
    The dark-rim artifact (DRA) remains an important challenge in the routine clinical use of first-pass perfusion (FPP) cardiac magnetic resonance imaging (cMRI). The DRA mimics the appearance of perfusion defects in the subendocardial wall and reduces the accuracy of diagnosis in patients with suspected ischemic heart disease. The main causes for DRA are known to be Gibbs ringing and bulk motion of the heart. The goal of this work is to propose a deep-learning-enabled automatic approach for the detection of motion-induced DRAs in FPP cMRI datasets. To this end, we propose a new algorithm that can detect the DRA in individual time frames by analyzing multiple reconstructions of the same time frame (k-space data) with varying temporal windows. In addition to DRA detection, our approach is also capable of suppressing the extent and severity of DRAs as a byproduct of the same reconstruction-analysis process. In this proof-of-concept study, our proposed method showed a good performance for automatic detection of subendocardial DRAs in stress perfusion cMRI studies of patients with suspected ischemic heart disease. To the best of our knowledge, this is the first approach that performs deep-learning-enabled detection and suppression of DRAs in cMRI.
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    The route and timing of hydrogen sulfide therapy critically impacts intestinal recovery following ischemia and reperfusion injury
    (Elsevier, 2018-06) Jensen, Amanda R.; Drucker, Natalie A.; te Winkel, Jan P.; Ferkowicz, Michael J.; Markel, Troy A.; Surgery, School of Medicine
    PURPOSE: Hydrogen sulfide (H2S) has many beneficial properties and may serve as a novel treatment in patients suffering from intestinal ischemia-reperfusion injury (I/R). The purpose of this study was to examine the method of delivery and timing of administration of H2S for intestinal therapy during ischemic injury. We hypothesized that 1) route of administration of hydrogen sulfide would impact intestinal recovery following acute mesenteric ischemia and 2) preischemic H2S conditioning using the optimal mode of administration as determined above would provide superior protection compared to postischemic application. METHODS: Male C57BL/6J mice underwent intestinal ischemia by temporary occlusion of the superior mesenteric artery. Following ischemia, animals were treated according to one of the following (N=6 per group): intraperitoneal or intravenous injection of GYY4137 (H2S-releasing donor, 50mg/kg in PBS), vehicle, inhalation of oxygen only, inhalation of 80ppm hydrogen sulfide gas. Following 24-h recovery, perfusion was assessed via laser Doppler imaging, and animals were euthanized. Perfusion and histology data were assessed, and terminal ileum samples were analyzed for cytokine production following ischemia. Once the optimal route of administration was determined, preischemic conditioning with H2S was undertaken using that route of administration. All data were analyzed using Mann-Whitney. P-values <0.05 were significant. RESULTS: Mesenteric perfusion following intestinal I/R was superior in mice treated with intraperitoneal (IP) GYY4137 (IP vehicle: 25.6±6.0 vs. IP GYY4137: 79.7±15.1; p=0.02) or intravenous (IV) GYY4137 (IV vehicle: 36.3±5.9 vs. IV GYY4137: 100.7±34.0; p=0.03). This benefit was not observed with inhaled H2S gas (O2 vehicle: 66.6±11.4 vs. H2S gas: 81.8±6.0; p=0.31). However, histological architecture was only preserved with intraperitoneal administration of GYY4127 (IP vehicle: 3.4±0.4 vs. IP GYY4137: 2±0.3; p=0.02). Additionally, IP GYY4137 allowed for significant attenuation of inflammatory chemokine production of IL-6, IP-10 and MIP-2. We then analyzed whether there was a difference between pre- and postischemic administration of IP GYY4137. We found that preconditioning of animals with intraperitoneal GYY4137 only added minor improvements in outcomes compared to postischemic application. CONCLUSION: Therapeutic benefits of H2S are superior with intraperitoneal application of an H2S donor compared to other administration routes. Additionally, while intraperitoneal treatment in both the pre- and postischemic period is beneficial, preischemic application of an H2S donor was found to be slightly better. Further studies are needed to examine long term outcomes and further mechanisms of action prior to widespread clinical application. TYPE OF STUDY: Basic science. LEVEL OF EVIDENCE: N/A.
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    Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease
    (Elsevier, 2018-09-27) Joseph-Mathurin, Nelly; Su, Yi; Blazey, Tyler M.; Jasielec, Mateusz; Vlassenko, Andrei; Friedrichsen, Karl; Gordon, Brian A.; Hornbeck, Russ C.; Cash, Lisa; Ances, Beau M.; Veale, Thomas; Cash, David M.; Brickman, Adam M.; Buckles, Virginia; Cairns, Nigel J.; Cruchaga, Carlos; Goate, Alison; Jack, Clifford R., Jr.; Karch, Celeste; Klunk, William; Koeppe, Robert A.; Marcus, Daniel S.; Mayeux, Richard; McDade, Eric; Noble, James M.; Ringman, John; Saykin, Andrew J.; Thompson, Paul M.; Xiong, Chengjie; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L. S.; Dominantly Inherited Alzheimer Network; Radiology and Imaging Sciences, School of Medicine
    Introduction: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.