Quantitative Susceptibility Mapping-Based Microscopy of Magnetic Resonance Venography (QSM-mMRV) for In Vivo Morphologically and Functionally Assessing Cerebromicrovasculature in Rat Stroke Model

RESEARCH ARTICLE Quantitative Susceptibility Mapping-Based Microscopy of Magnetic Resonance Venography (QSM-mMRV) for In Vivo Morphologically and Functionally Assessing Cerebromicrovasculature in Rat Stroke Model Meng-Chi Hsieh1,2,3, Ching-Yi Tsai4, Min-Chiao Liao4, Jenq-Lin Yang4, Chia-Hao Su4,5*, Jyh-Horng Chen1,2,3* 1 Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan, 2 Molecular Imaging Center, National Taiwan University, Taipei 106, Taiwan, 3 Department of Electrical Engineering, National Taiwan University, Taipei 106, Taiwan, 4 Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan, 5 Department of Biomedical Imaging and Radiological Sciences, National Yang Ming University, Taipei 112, Taiwan OPEN ACCESS Citation: Hsieh M-C, Tsai C-Y, Liao M-C, Yang J-L, Su C-H, Chen J-H (2016) Quantitative Susceptibility Mapping-Based Microscopy of Magnetic Resonance Venography (QSM-mMRV) for In Vivo Morphologically and Functionally Assessing Cerebromicrovasculature in Rat Stroke Model. PLoS ONE 11(3): e0149602. doi:10.1371/journal. pone.0149602 Editor: Quan Jiang, Henry Ford Health System, UNITED STATES Received: May 31, 2015 Accepted: February 3, 2016 Published: March 14, 2016 Copyright: © 2016 Hsieh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by grants from the National Taiwan University under Excellent Research Projects (NTU-ERP-105R891602), the Ministry of Science and Technology (NSC-104-2321B-002-040 to JHC; MOST103-2320-B-182A-004MY3 and MOST103-2633-B-182A-001- to CHS), the National Health Research Institute (NHRI-EX10510424EI), and Chang Gung Medical Foundation, * (JHC); (CHS) Abstract Abnormal cerebral oxygenation and vessel structure is a crucial feature of stroke. An imaging method with structural and functional information is necessary for diagnosis of stroke. This study applies QSM-mMRV (quantitative susceptibility mapping-based microscopic magnetic resonance venography) for noninvasively detecting small cerebral venous vessels in rat stroke model. First, susceptibility mapping is optimized and calculated from magnetic resonance (MR) phase images of a rat brain. Subsequently, QSM-mMRV is used to simultaneously provide information on microvascular architecture and venous oxygen saturation (SvO2), both of which can be used to evaluate the physiological and functional characteristics of microvascular changes for longitudinally monitoring and therapeutically evaluating a disease model. Morphologically, the quantification of vessel sizes using QSMmMRV was 30% smaller than that of susceptibility-weighted imaging (SWI), which eliminated the overestimation of conventional SWI. Functionally, QSM-mMRV estimated an average SvO2 ranging from 73% to 85% for healthy rats. Finally, we also applied QSM to monitor the revascularization of post-stroke vessels from 3 to 10 days after reperfusion. QSM estimations of SvO2 were comparable to those calculated using the pulse oximeter standard metric. We conclude that QSM-mMRV is useful for longitudinally monitoring blood oxygen and might become clinically useful for assessing cerebrovascular diseases. PLOS ONE | DOI:10.1371/journal.pone.0149602 March 14, 2016 1 / 22 QSM-mMRV in Rat Stroke Model Taiwan (CMRPG8C1171, CMRPG8C1172, and CMRPG8E1461 to CHS). The authors have declared that no additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Introduction Stroke is the leading cause of long-term disability, also one of the commonest causes of mortality in aging countries [1]. Abnormal structure and blood oxygen saturation (SO2) of cerebral microvessels (diameter:
100 μm) [2] is a critical feature of stroke. Characterizing unusual microvascular change and extraordinary SO2 might be useful for the diagnosis and the prognosis of stroke [1,3]. Thus, measuring cerebral blood oxygen saturation might be necessary for an accurate diagnosis, to predict disease outcomes, and to monitor the treatment response in stroke. The most commonly used noninvasive methodologies of medical imaging in clinical and experimental neuroscience for assessing the cerebral microvessels in cerebrovascular diseases like stroke, glioma, and vascular malformation are computed tomography angiography (CTA) and magnetic resonance angiography (MRA). Although CTA with a contrast agent can rapidly and accurately detect the structure of blood vessels [4], it has the potential negative side affect of ionizing radiation. In contrast, MRA-based techniques, such as time-of-flight (TOF)-MRA and contrast-enhanced (CE)-MRA, are not radioactive. TOF-MRA is sensitive to the fast-flowing signals in arteries and depends on the motion of water protons [5]. However, TOF-MRA is limited to measuring small cerebral vessels (venules, arterioles, and capillaries) because of slow-flowing signals in the cerebral microvessels. CE-MRA uses gadolinium (Gd)-based contrast agents to detect these slow-flowing signals [6]. Nonetheless, CE-MRA might not satisfy the long acquisition time required for high-resolution MRA application because it has a short intravascular half-life and rapidly redistributes into the extracellular space. Deoxyhemoglobin, however, provides natural contrast enhancement. Based on this advantage, susceptibility-weighted imaging (SWI) has been proposed for visualizing venous vascular architecture and has provided structural information for more than a decade [7]. Furthermore, SWI combines MR magnitude and phase images, and it is more sensitive for detecting magnetic substances such as deoxyhemoglobin, hemorrhage, iron, etc. Moreover, SWI is also widely used clinically to visualize and diagnose venous vascular malformations, stroke, and traumatic brain injuries. It has also been used to longitudinally assess ischemic vessel size in a rat stroke model [8]. Although it can characterize vascular structure, SWI cannot provide functional information about blood vessels. To quantify vascular information, previous studies assessed venous oxygen saturation (SvO2) with the relaxation time T2 [9,10]. However, T2 is not a high-specificity index because it depends on the measurement conditions of B0 inhomogeneity, on the relaxation time T2 (without the effect of B0 inhomogeneity), and on the properties of blood vessels. Additionally, T2 produces inconsistent results under various B0s because of the dependence between T2 and (...truncated)