Person: Sakadzic, Sava
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Sakadzic
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Sava
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Sakadzic, Sava
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Publication Potential Circadian Effects on Translational Failure for Neuroprotection(Springer Science and Business Media LLC, 2020-06-03) Esposito, Elga; Li, Wenlu; Mandeville, Emiri; Park, Ji-Hyun; Sencan, Ikbal; Guo, Shuzhen; Shi, Jingfei; Lan, Jing; Lee, Janice; Hayakawa, Kazuhide; Sakadzic, Sava; Ji, Xunming; Lo, EngNeuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.Publication Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke(Public Library of Science, 2013) Srinivasan, Vivek J.; Mandeville, Emiri; Can, Anil; Blasi, Francesco; Climov, Mihail; Daneshmand, Ali; Lee, Jeong Hyun; Yu, Esther; Radhakrishnan, Harsha; Lo, Eng; Sakadzic, Sava; Eikermann-Haerter, Katharina; Ayata, CenkProgress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.Publication Cell type specificity of neurovascular coupling in cerebral cortex(eLife Sciences Publications, Ltd, 2016) Uhlirova, Hana; Kılıç, Kıvılcım; Tian, Peifang; Thunemann, Martin; Desjardins, Michèle; Saisan, Payam A; Sakadzic, Sava; Ness, Torbjørn V; Mateo, Celine; Cheng, Qun; Weldy, Kimberly L; Razoux, Florence; Vandenberghe, Matthieu; Cremonesi, Jonathan A; Ferri, Christopher GL; Nizar, Krystal; Sridhar, Vishnu B; Steed, Tyler C; Abashin, Maxim; Fainman, Yeshaiahu; Masliah, Eliezer; Djurovic, Srdjan; Andreassen, Ole A; Silva, Gabriel A; Boas, David; Kleinfeld, David; Buxton, Richard B; Einevoll, Gaute T; Dale, Anders M; Devor, AnnaIdentification of the cellular players and molecular messengers that communicate neuronal activity to the vasculature driving cerebral hemodynamics is important for (1) the basic understanding of cerebrovascular regulation and (2) interpretation of functional Magnetic Resonance Imaging (fMRI) signals. Using a combination of optogenetic stimulation and 2-photon imaging in mice, we demonstrate that selective activation of cortical excitation and inhibition elicits distinct vascular responses and identify the vasoconstrictive mechanism as Neuropeptide Y (NPY) acting on Y1 receptors. The latter implies that task-related negative Blood Oxygenation Level Dependent (BOLD) fMRI signals in the cerebral cortex under normal physiological conditions may be mainly driven by the NPY-positive inhibitory neurons. Further, the NPY-Y1 pathway may offer a potential therapeutic target in cerebrovascular disease. DOI: http://dx.doi.org/10.7554/eLife.14315.001Publication CD200 restrains macrophage attack on oligodendrocyte precursors via toll-like receptor 4 downregulation(SAGE Publications, 2016) Hayakawa, Kazuhide; Pham, Loc-Duyen; Seo, Ji-Hae; Miyamoto, Nobukazu; Maki, Takakuni; Sakadzic, Sava; Boas, David; van Leyen, Klaus; Waeber, Christian; Kim, Kyu-Won; Arai, Ken; Lo, EngThere are numerous barriers to white matter repair after CNS injury and the underlying mechanisms remain to be fully understood. In this study, we propose the hypothesis that inflammatory macrophages in damaged white matter attack oligodendrocyte precursor cells (OPCs) via TLR4 signaling thus interfering with this endogenous progenitor recovery mechanism. Primary cell culture experiments demonstrate that peritoneal macrophages can attack and digest OPCs via TLR4 signaling, and this phagocytosis of OPCs can be inhibited by using CD200-Fc to downregulate TLR4. In an in vivo model of white matter ischemia induced by endothelin-1, treatment with D200-Fc suppressed TLR4 expression in peripherally circulating macrophages, thus restraining macrophage phagocytosis of OPCs and leading to improved myelination. Taken together, these findings suggest that deleterious macrophage effects may occur after white matter ischemia, whereby macrophages attack OPCs and interfere with endogenous recovery responses. Targeting this pathway with CD200 may offer a novel therapeutic approach to amplify endogenous OPC-mediated repair of white matter damage in mammalian brain.Publication Microstructural characterization of myocardial infarction with optical coherence tractography and two‐photon microscopy(John Wiley and Sons Inc., 2016) Goergen, Craig J.; Chen, Howard; Sakadzic, Sava; Srinivasan, Vivek J.; Sosnovik, DavidAbstract Myocardial infarction leads to complex changes in the fiber architecture of the heart. Here, we present a novel optical approach to characterize these changes in intact hearts in three dimensions. Optical coherence tomography (OCT) was used to derive a depth‐resolved field of orientation on which tractography was performed. Tractography of healthy myocardium revealed a smooth linear transition in fiber inclination or helix angle from the epicardium to endocardium. Conversely, in infarcted hearts, no coherent microstructure could be identified in the infarct with OCT. Additional characterization of the infarct was performed by the measurement of light attenuation and with two‐photon microscopy. Myofibers were imaged using autofluorescence and collagen fibers using second harmonic generation. This revealed the presence of two distinct microstructural patterns in areas of the infarct with high light attenuation. In the presence of residual myofibers, the surrounding collagen fibers were aligned in a coherent manner parallel to the myofibers. In the absence of residual myofibers, the collagen fibers were randomly oriented and lacked any microstructural coherence. The presence of residual myofibers thus exerts a profound effect on the microstructural properties of the infarct scar and consequently the risk of aneurysm formation and arrhythmias. Catheter‐based approaches to segment and image myocardial microstructure in humans are feasible and could play a valuable role in guiding the development of strategies to improve infarct healing.Publication Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation(Frontiers Media S.A., 2016) Gagnon, Louis; Smith, Amy F.; Boas, David; Devor, Anna; Secomb, Timothy W.; Sakadzic, SavaOxygen is delivered to brain tissue by a dense network of microvessels, which actively control cerebral blood flow (CBF) through vasodilation and contraction in response to changing levels of neural activity. Understanding these network-level processes is immediately relevant for (1) interpretation of functional Magnetic Resonance Imaging (fMRI) signals, and (2) investigation of neurological diseases in which a deterioration of neurovascular and neuro-metabolic physiology contributes to motor and cognitive decline. Experimental data on the structure, flow and oxygen levels of microvascular networks are needed, together with theoretical methods to integrate this information and predict physiologically relevant properties that are not directly measurable. Recent progress in optical imaging technologies for high-resolution in vivo measurement of the cerebral microvascular architecture, blood flow, and oxygenation enables construction of detailed computational models of cerebral hemodynamics and oxygen transport based on realistic three-dimensional microvascular networks. In this article, we review state-of-the-art optical microscopy technologies for quantitative in vivo imaging of cerebral microvascular structure, blood flow and oxygenation, and theoretical methods that utilize such data to generate spatially resolved models for blood flow and oxygen transport. These “bottom-up” models are essential for the understanding of the processes governing brain oxygenation in normal and disease states and for eventual translation of the lessons learned from animal studies to humans.Publication Large arteriolar component of oxygen delivery implies safe margin of oxygen supply to cerebral tissue(2014) Sakadzic, Sava; Mandeville, Emiri; Gagnon, Louis; Musacchia, Joseph J.; Yaseen, Mohammad; Yücel, Meryem A.; Lefebvre, Joel; Lesage, Frédéric; Dale, Anders M.; Eikermann-Haerter, Katharina; Ayata, Cenk; Srinivasan, Vivek J.; Lo, Eng; Devor, Anna; Boas, DavidWhat is the organization of cerebral microvascular oxygenation and morphology that allows adequate tissue oxygenation at different activity levels? We address this question in the mouse cerebral cortex using microscopic imaging of intravascular O2 partial pressure and blood flow combined with numerical modeling. Here we show that parenchymal arterioles are responsible for 50% of the extracted O2 at baseline activity and the majority of the remaining O2 exchange takes place within the first few capillary branches. Most capillaries release little O2 at baseline acting as an O2 reserve that is recruited during increased neuronal activity or decreased blood flow. Our results challenge the common perception that capillaries are the major site of O2 delivery to cerebral tissue. The understanding of oxygenation distribution along arterio-capillary paths may have profound implications for the interpretation of BOLD fMRI signal and for evaluating microvascular O2 delivery capacity to support cerebral tissue in disease.Publication In Vivo Imaging of Cerebral Energy Metabolism with Two-Photon Fluorescence Lifetime Microscopy of NADH(Optical Society of America, 2013) Yaseen, Mohammad; Sakadzic, Sava; Wu, Weicheng; Becker, Wolfgang; Kasischke, Karl A.; Boas, DavidMinimally invasive, specific measurement of cellular energy metabolism is crucial for understanding cerebral pathophysiology. Here, we present high-resolution, in vivo observations of autofluorescence lifetime as a biomarker of cerebral energy metabolism in exposed rat cortices. We describe a customized two-photon imaging system with time correlated single photon counting detection and specialized software for modeling multiple-component fits of fluorescence decay and monitoring their transient behaviors. In vivo cerebral NADH fluorescence suggests the presence of four distinct components, which respond differently to brief periods of anoxia and likely indicate different enzymatic formulations. Individual components show potential as indicators of specific molecular pathways involved in oxidative metabolism.Publication Phasor analysis of NADH FLIM identifies pharmacological disruptions to mitochondrial metabolic processes in the rodent cerebral cortex(Public Library of Science, 2018) Gómez, Carlos A.; Sutin, Jason; Wu, Weicheng; Fu, Buyin; Uhlirova, Hana; Devor, Anna; Boas, David; Sakadzic, Sava; Yaseen, MohammadInvestigating cerebral metabolism in vivo at a microscopic level is essential for understanding brain function and its pathological alterations. The intricate signaling and metabolic dynamics between neurons, glia, and microvasculature requires much more detailed understanding to better comprehend the mechanisms governing brain function and its disease-related changes. We recently demonstrated that pharmacologically-induced alterations to different steps of cerebral metabolism can be distinguished utilizing 2-photon fluorescence lifetime imaging of endogenous reduced nicotinamide adenine dinucleotide (NADH) fluorescence in vivo. Here, we evaluate the ability of the phasor analysis method to identify these pharmacological metabolic alterations and compare the method’s performance with more conventional nonlinear curve-fitting analysis. Visualization of phasor data, both at the fundamental laser repetition frequency and its second harmonic, enables resolution of pharmacologically-induced alterations to mitochondrial metabolic processes from baseline cerebral metabolism. Compared to our previous classification models based on nonlinear curve-fitting, phasor–based models required fewer parameters and yielded comparable or improved classification accuracy. Fluorescence lifetime imaging of NADH and phasor analysis shows utility for detecting metabolic alterations and will lead to a deeper understanding of cerebral energetics and its pathological changes.