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MOST - Construction and Application of Medical Image Database in TMU Healthcare System

Project Period: 2017.11.01 ~ 2020.10.31

In this project, a multidisciplinary team led by Taipei Medical University (TMU) is formed to achieve three specific aims, including the construction of Taiwanese medical imaging archive, accomplishment of data sharing, and the promotion of clinical and industrial applications. Experts of radiology, image analysis, medical informatics, database management, big data analysis, and artificial intelligence (AI) are recruited from TMU Healthcare System and National Central University. Enormous data of medical imaging will be retrieved and collected from three TMU affiliated hospitals, including Taipei Medical University Hospital (TMUH), Shuang Ho Hospital (SHH), and Wanfang Hospital (WFH), into the data warehouses in TMU and National Center for High-performance Computing. The assistance in database management and usage regulation of Taiwanese medical imaging archive is promised. Customized AI techniques and deep-learning platforms will be developed based on the clinical researches of medical imaging in TMUH (study of lung cancer), SHH (study of cerebral small vessel diseases), and WFH (study of coronary artery diseases), respectively to facilitate lesion detection, disease classification, and outcome prediction.

MOST - International Cooperation with NIH Title: Characterization of Thalamocortical Dysrhythmia in Mild Traumatic Brain Injury using Simultaneous MRI and EEG Measurements and Preclinical N-acetylcysteine Treatment Response

Project Period: 2015.08.01 ~ 2018.07.31

The relation between thalamocortical dysrhythmia (TCD) and post-concussive syndrome (PCS) in mild traumatic brain injury (mTBI) patients has recently been recognized in several studies; however the potential imaging biomarkers to evaluate neurological functional deficits and to localize TCD, in particular the thalamocortical circuits, have not been established. Based on the current understanding of the mTBI, network dysfunction of thalamocortical circuits is the one of main points of investigation which is characterized by microstructural injuries, disrupted functional connectivity, and the altered interplay between excitatory and inhibitory neurotransmitters. The elevated synaptic glutamate levels after mTBI can further exacerbate the post-traumatic cellular injury. Recent studies have indicated that mTBI patients can benefit from N-acetylcysteine (NAC) treatment by effectively improving the behavioral deficits which had a significant impact on neuropsychological test results.

Though the cognitive tests outcome after administration of NAC is promising, the neuroimaging evidence of NAC treatment efficacy on mTBI and its prevention of subsequent brain atrophy had not been well explored. The purpose of this study is to propose a TCD model in mTBI by simultaneous measurements of MRI and MR-compatible EEG on human participants followed by a pre-clinical experiment using animal mTBI model to evaluate the therapeutic effect of NAC on mTBI. Through the characterization of the neural network dysfunction from the perspectives of neural electrophysiology, microstructure integrity, and hemodynamic synchrony, we will be able to have a complete vision on the pathophysiological mechanism in mTBI. In addition, this study can help provide the neuroimaging evidence of the NAC efficacy in treating mTBI.

MOST Title: Radiogenomics of Malignant Gliomas by linking Physiological MR Imaging, Histopathological patterns, and Genetic alternations: A Translational study from Rat to Man

Project Period: 2015.08.01 ~ 2018.07.31

Glioblastoma is the most common malignant tumor of the central nervous system. Over 90% of diagnosed glioblastoma are primary cases, originating from glial cells and making up 80% of malignant brain tumors through multi-step oncogenesis. Despite the advances of treatment, the cure of malignant GBM remains elusive and the prognosis appears poor, partly due to under-sampling and mis-grading that influence the therapeutic strategy. Moreover, intra-tumoral and individual genetic heterogeneity remains another important issue. Therefore, an accurate grading of glioma by advanced imaging biomarkers that can address the heterogeneity of glioblastoma cannot be overemphasized. In addition to the heterogeneity at the histology level, primary glioblastoma are also characterized by heterogeneous alterations of gene expression, which consist of EGFR amplification, loss of PTEN, and loss of cyclin-dependent kinase inhibitors. The incorporation of oncogenomics to the imaging biomarkers, the radiogenomic, has recently emerged for cancer management. The key pathological features of glioblastoma, including cellularity, invasiveness, mitotic activity, angiogenesis, and necrosis can be evaluated with advanced MR imaging which can be used as glioma genomic signatures. By linking specific imaging biomarkers with specific gene expression profile could allow for more accurate diagnosis, prognosis prediction and better therapeutic guidance. In this three-year translational glioma project, we aim to investigate the advanced MR imaging biomarkers, the phonotypical expression, of gliomas with respect to their gene expression in preclinical animal model at 7T MRI and human subjects at 3T. To study intra-tumoral and inter-tumoral heterogeneity of glioblastomas, advanced MR imaging biomarkers such as perfusion-weighted imaging (PWI), CBF measurements by arterial spin labeling (ASL), high resolution diffusion tensor imaging (DTI), MR spectroscopy (MRS), Amide proton transfer (APT) image and Vessel size image will be used to depict the physiological as well as molecular events within the tumor. Genomic information will be acquired from microarray analysis. In addition to the frequently affected pathway including proliferation and angiogenesis, we will also focus on the DNA damage/repair genes, as radiation response of glioblastomas in Taiwanese is uniquely different from that Caucasian glioblastoma population. With the combined application of genomic information and multiparametric MRI, the tumor extent can be accurately defined, the therapeutic response can be better monitored and the prognosis can be well predicted. In summary, with the establishment of tumor radiogenomic platform, we will be able to unveil the genomic modification of glioblastoma from the perspective of molecular MRI through a bedside-to-bench translational research.

MOST Title: Motion-Sensitive MR Imaging in Characterizing Brain Compliance in Cerebral Venous Hypertension: A Translational Study between Humans and Rats

Project Period: 2015.08.01 ~ 2018.07.31

Brain compliance is a parameter introduced very early to describe brain homeostasis with an intracranial pressure–volume relationship based on the Monro-Kellie doctrine. The intracranial constituents (blood, cerebrospinal fluid (CSF), and brain parenchyma) create a state of volume equilibrium to maintain a normal range of intracranial pressure (ICP) for a limited change in compartmental volume. Once the inter-compartmental volume compensation fails, the intracranial hypertension occurs and the brain compliances decreases. The measurement of brain compliance therefore provides comprehensive information about compensatory volume reserve and the risk of developing high ICP.

Previous studies have used various techniques to assess brain compliance either in an invasive manner,the Spiegelberg compliance monitor, or with an over-simplified model of cerebral flow system. At present, a non-invasive and accurate method to monitoring the brain compliance is demanded in clinical routines for intensive care units, cerebrovascular diseases, or traumatic brain injuries. Superior to the conventional invasive monitoring, magnetic resonance (MR) motion-sensitive imaging shows strength on in-vivo and non-invasive measurements of volume arterial inflow, venous blood outflow, and CSF movement method during a cardiac cycle, and therefore allows the compartmentalization of brain compliance. The technique of cine displacement-encoded MRI further enables the visualization of pulsatile brain motion in a scale of sub-millimeter within a cardiac cycle.
In this three-year study, the advanced motion-sensitive MR techniques will be employed using a 3T scanner for human and a 7T scanner for rat imaging. We aim to establish the dynamic relation between 4 main intracranial compartments, i.e., the arterial inflow, venous outflow, CSF movement, and brain motion, within a cardiac cycle to reveal the underlying physiological mechanism. We also aim to propose a modified computational model to improve the accuracy and repeatability of MR-based measurement of brain compliance to promote its clinical impact. A norm of MR-based brain compliance for healthy controls will be established through the proposed model and tested in variability in the first year. Based on the current understanding, both CSF and venous blood are considered to be the key buffers for maintaining the brain parenchyma and sufficient cerebral perfusion. We hypothesize that when the deficits of cerebral venous system occur, such as the cerebral venous hypertension (CVH), the brain compliance may reduce,reflecting the altered state of brain homeostasis. The CVH can cause an elevated ICP and therefore decreased cerebral perfusion pressure (CPP), resulting in the ischemic brain injury and cytotoxic edema, followed by breakdown of blood vessel walls.
To test our hypothesis, we will use a rat venous hypertension model with the arteriovenous anastomosis in the second year to investigate the induced alterations of brain compliance. The motion-sensitive MRI, MR techniques in imaging edema (ADC), venous dilation (SWI), oxygen extraction fraction (OEF), and invasive measurements of CPP and draining vein pressure (DVP) will be collected at Day 2, 7, 28 after operation to reveal the time evolution of brain compliance. Finally, the constructed MR-based measurement of brain compliance will be applied to patients with CVH in the third year of this study. The outcomes of this study can facilitate the clinical applications of MRI in monitoring brain homeostasis and assisting disease diagnosis.

MOST Title: Restoration of Thalamocortical Oscillation as a Potential Treatment for mTBI: a Small Animal MRI Research

Project Period: 2015.08.01 ~ 2018.07.31

Thalamocortical oscillation, the coherent rhythm modulated by the intrinsic membrane potential of thalamic neurons and then propagated between the thalamus and the cortex, is not only critical for the processing of sensory information but also related to the emergence of multiple brain functions including awake and sleep, conscious awareness, cognitive functions, etc. T-type Ca2+ channels play a pivotal role in regulating thalamic firing patterns and have been implicated as the pacemaker in thalamocortical oscillation. It was lately shown that neurological disease may alter the thalamocortical oscillation likely due to excessive inhibition of thalamic relay neurons, and inactivation of T-type Ca2+ channels would ameliorate functional impairment. However, spatiotemporal features of thalamocortical oscillation remain to be characterized and how mTBI progression impacts on thalamocortical connectivity is largely unexplored.
In this study, we will probe thalamocortical connectivity using magnetic resonance imaging (MRI) and address an important question whether restoration of thalamocortical oscillation can be a potential therapeutic strategy of mTBI. In this 3-year project, we propose to characterize thalamocortical oscillation following mTBI in the modified controlled cortical injury (CCI) model, which mimics the pathophysiology of concussive injury caused by motorcycle accidents in Taiwan. We will use state-of-the-art tools for the observation of thalamocortical connectivity in functional and structural aspects by using resting state functional MRI (rsfMRI) and diffusion tensor image (DTI), respectively.

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CECR Title: Advanced MR Imaging Evaluation of Primary Brain Tumor Extent and Response to Treatment

Project Period: 2015.04.01 ~ 2016.03.31

Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor. Current aggressive treatments consist of surgical resection followed by radiation therapy, and chemotherapy still result in a poor prognosis with a median survival of 14 months after diagnosis. Though the resistance mechanism of GBM to Temozolomide (TMZ), the standard prescription of chemotherapy, has been well-documented by several studies, reliable image biomarkers for predicting TMZ outcome and personalized medicine were less explored. In next year project, a translational radiogenomic study combining the genomic profile and advanced MRI techniques in both human and animal GBM model will be performed to unravel the links between image phenotypes and underlying gene alterations. Advanced MR imaging is capable to define biological features of GBM in vivo and therefore provides a possibility to assess the potential TMZ resistant pathway for the purpose of predicting treatment effect and applying personalized medicine.

CECR Title: Advanced MR Imaging Evaluation of Primary Brain Tumor Extent and Response to Treatment

Project Period: 2015.04.01 ~ 2016.03.31

Imaging Core is served as a platform of magnetic resonance imaging (MRI) and computed tomography (CT) to support the four cancer programs in CECR. This imaging research platform can provide the measurements of tumor structure and physiological status in vivo, and therefore facilitate the early diagnosis of tumor, longitudinal monitoring, new drug development, and clinical trial. In next year project, the service and research directions of Imaging Core will focus on three subjects including (1) imaging service and consultation, (2) research team collaboration, and (3) development of advanced imaging and analysis techniques. For the imaging service and consultation to the four cancer programs, the in-vivo imaging of cell, small animal, and human by the 7T MRI at Taipei Medical University, 3T human MRI (service will start from Dec. 2015), and dual-source computed tomography at Taipei Medical University Hospital will be provided. The Imaging Core team, including two radiologists, two assistant professors, two assistant research fellows, and one medical physicist, will assist investigators to resolve the issues of imaging parameters, sequence selection, and image analysis. Regarding the research team collaboration, the collaborations will start from the studies of glioblastoma and extend to all four programs in the perspective of both basic and clinical researches and new drug development. The initial collaborations with four research teams include (a) radiogenomic study of intra- and inter-tumor heterogeneity with Prof. Yung-Hsioa Chiang, (b) imaging of permeability and histologic section to assess the dynamics of blood tumor barrier with Prof. Ruei-Ming Chen, (c) prediction of treatment efficacy of Temozolomide-resistant glioblastoma by MR image phenotypes with Prof. Jian-Ying Chuang, and (d) preclinical animal experiments of a new drug, MPT0B291, for chemical therapy with Prof. Chia-Yi Wang. In the development of advanced imaging and analysis techniques, Imaging Core will keep adjusting and developing the imaging protocols and analysis methods at 7T animal and 3T human MRI, including the Ktrans permeability map for assessing the integrity of blood tumor barrier, diffusion kurtosis imaging (DKI) for elevating the sensitivity in malignant tumor detection, and chemical exchange saturation transfer (CEST) for measuring tumor metabolism. With the achievements of all three subjects, Imaging Core will be able to expedite the progression of cancer researches.