임상연구를 위한 신경수초물영상

학위논문 (박사)-- 서울대학교 대학원 : 공과대학 전기·정보공학부, 2019. 2. 이종호.신경수초는 몸 안의 전기적 신호를 전달하는데 있어 중요한 역할을 한다. 신경퇴행성질환은 신경수초 손상과 연관성이 있으며 이는 전기적 신호 전달의 손실을 유발한다. 병원에서 사용하는 자기 공명 영상법인 T1, T2 강조영상들은 신경수초의 양을 정량화 할 수 없고 신경퇴행성질환 환자의 신경수초의 손상된 정도를 확인 할 수 없다. 본 연구에서는 신경수초의 손상된 정도를 예측하기 위해 새롭게 개발 된 신경수초물영상을 신경퇴행성질환에 적용하였다. 이를 위해 신경다발의 물교환 및 머리로 유입되는 혈류로 인한 신경수초물영상법에 미치는 영향에 대하여 탐구하였다. 또한, 신경수초물영상법을 이용한 임상적 연구를 위하여 분석 파이프라인을 개발하였다. 첫째로 신경다발의 생물, 물리적학적 특성을 시뮬레이션화한 Monte-Carlo 시뮬레이션 모델을 개발하였다. 시뮬레이션에서 계산된 신경수초물의 거주 시간을 이용하여 신경수초물영상법이 신경수초물을 측정하고 있는 것을 검증하였다. 둘째로 본 연구에서는 머리로 유입되는 혈류로 인한 artifact을 제거하기 위해 혈류 시뮬레이션 모델을 개발하였다. 혈류 시뮬레이션 모델을 통하여 유입되는 혈류로 인한 artifact을 최소화 하는 혈류포화펄스의 최적 시간을 제안하였다. 최종적으로, 신경수초물 영상의 임상연구 적용을 위하여 분석 파이프 라인을 개발 및 요약하였다. 이를 이용하여 신경퇴행성질환인 다발성경화증, 시신경척수염, 외상성 뇌손상 환자의 정상으로 보이는 영역에서 신경수초물변화를 관찰하였다. 본 연구의 결과는 추후 수초관련 뇌 질환의 진단, 치료의 효용성 및 예후 평가뿐 아니라 학습에 의한 뇌 가소성 연구 및 재활 치료 효과 평가에 이용될 수 있을 것이라 사료된다.Myelin plays an important role in transmitting electrical signals in the body. Neurodegenerative diseases are associated with myelin damage and induce a loss of the electrical signals. The conventional T1 and T2 weighted imaging, used in clinics, cannot quantify the amount of myelin and confirm the degree of myelin damage in patients with neurodegenerative diseases. This thesis applied newly developed myelin water imaging, named ViSTa, to the neurodegenerative diseases to estimate changes in myelin. To utilize ViSTa myelin water imaging in clinical studies, I explored the effects of water exchange and inflow in ViSTa myelin water imaging. Then, I developed new data analysis pipelines to apply ViSTa myelin water imaging for the clinical studies. First, the Monte-Carlo simulation model that has the biological and physical properties of white matter fiber was developed for myelin water residence time. The simulation model validated the origin of ViSTa as myelin water. Second, the thesis developed a flow simulation model to compensate artifacts from inflow blood in ViSTa myelin water imaging. The flow simulation model suggested the optimal timing of flow saturation pulse(s) to suppress the inflow of blood. Finally, I summarized new data analysis pipelines for clinical applications. Using the analysis pipelines, ViSTa myelin water imaging revealed reduced apparent myelin water fraction in normal-appearing white matter for three prominent brain diseases and injury (neurodegenerative diseases): multiple sclerosis, neuromyelitis optica spectrum disorders, and traumatic brain injury. The developments in this thesis can be utilized not only in the diagnosis, treatment, and prognosis of various diseases but also in neuroplasticity and rehabilitation studies to explore the answer for the questions related to myelin issues.Chapter 1. Introduction 1 1.1 Myelin 1 1.2 Myelin Water 1 1.3 ViSTa Myelin Water Imaging 4 1.4 Purpose of Study 7 Chapter 2. Water Exchange Model 8 2.1 Introduction 8 2.2 Methods 8 2.3 Results 14 2.4 Discussion 16 Chapter 3. Blood Flow Simulation Model 17 3.1 Introduction 17 3.2 Methods 18 3.3 Results 25 3.4 Discussion 30 Chapter 4. Clinical Applications 32 4.1 Multiple Sclerosis 32 4.1.1 Introduction 32 4.1.2 Methods 33 4.1.3 Results 42 4.1.4 Discussion 52 4.2 Neuromyelitis Optica Spectrum Disorder 56 4.2.1 Introduction 56 4.2.2 Methods 57 4.2.3 Results 60 4.2.4 Discussion 65 4.3 Traumatic Brain Injury 68 4.3.1 Introduction 68 4.3.2 Methods 69 4.3.3 Results 75 4.3.4 Discussion 80 Chapter 5. Conclusion 84 Reference 85 Abstract 100Docto

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Quantitative Susceptibility Imaging of Tissue Microstructure Using Ultra-High Field MRI

This thesis has used ultra-high field (UHF) magnetic resonance imaging (MRI) to investigate the fundamental relationships between tissue microstructure and such susceptibility-based contrast parameters as the apparent transverse relaxation rate (R2*), the local Larmor frequency shift (LFS) and quantitative volume magnetic susceptibility (QS). The interaction of magnetic fields with biological tissues results in shifts in the LFS which can be used to distinguish underlying cellular architecture. The LFS is also linked to the relaxation properties of tissues in a gradient echo MRI sequence. Equally relevant, histological analysis has identified iron and myelin as two major sources of the LFS. As a result, computation of LFS and the associated volume magnetic susceptibility from MRI phase data may serve as a significant method for in vivo monitoring of changes in iron and myelin associated with normal, healthy aging, as well as neurological disease processes. In this research, the cellular level underpinnings of the R2* and LFS signals were examined in a model rat brain system using 9.4 T MRI. The study was carried out using biophysical modeling and correlation with quantitative histology. For the first time, multiple biophysical modeling schemes were compared in both gray and white matter of excised rat brain tissue. Suprisingly, R2* dependence on tissue orientation has not been fully understood. Accordingly, scaling relations were derived for calculating the reversible, mesoscopic magnetic field component, R2\u27, of the apparent transverse relaxation rate from the orientation dependence in gray and white matter. Our results demonstrate that the orientation dependence of R2* and LFS in both white and cortical gray matter has a sinusoidal dependence on tissue orientation and a linear dependence on the volume fraction of myelin in the tissue. A susceptibility processing pipeline was also developed and applied to the calculation of phase-combined LFS and QS maps. The processing pipeline was subsequently used to monitor myelin and iron changes in multiple sclerosis (MS) patients compared to healthy, age and gender-matched controls. With the use of QS and R2* mapping, evidence of statistically significant increases in iron deposition in sub-cortical gray matter, as well as myelin degeneration along the white matter skeleton, were identified in MS patients. The magnetic susceptibility-based MRI methods were then employed as potential clinical biomarkers for disease severity monitoring of MS. It was demonstrated that the combined use of R2* and QS, obtained from multi-echo gradient echo MRI, could serve as an improved metric for monitoring both gray and white matter changes in early MS

Macromolecular proton fraction as a myelin biomarker: principles, validation, and applications

Macromolecular proton fraction (MPF) is a quantitative MRI parameter describing the magnetization transfer (MT) effect and defined as a relative amount of protons bound to biological macromolecules with restricted molecular motion, which participate in magnetic cross-relaxation with water protons. MPF attracted significant interest during past decade as a biomarker of myelin. The purpose of this mini review is to provide a brief but comprehensive summary of MPF mapping methods, histological validation studies, and MPF applications in neuroscience. Technically, MPF maps can be obtained using a variety of quantitative MT methods. Some of them enable clinically reasonable scan time and resolution. Recent studies demonstrated the feasibility of MPF mapping using standard clinical MRI pulse sequences, thus substantially enhancing the method availability. A number of studies in animal models demonstrated strong correlations between MPF and histological markers of myelin with a minor influence of potential confounders. Histological studies validated the capability of MPF to monitor both demyelination and re-myelination. Clinical applications of MPF have been mainly focused on multiple sclerosis where this method provided new insights into both white and gray matter pathology. Besides, several studies used MPF to investigate myelin role in other neurological and psychiatric conditions. Another promising area of MPF applications is the brain development studies. MPF demonstrated the capabilities to quantitatively characterize the earliest stage of myelination during prenatal brain maturation and protracted myelin development in adolescence. In summary, MPF mapping provides a technically mature and comprehensively validated myelin imaging technology for various preclinical and clinical neuroscience applications

Quantitative MRI and machine learning for the diagnosis and prognosis of Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated, inflammatory, neurological disease affecting myelin in the central nervous system, whose driving mechanisms are not yet fully understood. Conventional magnetic resonance imaging (MRI) is largely used in the MS diagnostic process, but because of its lack of specificity, it cannot reliably detect microscopic damage. Quantitative MRI provides instead feature maps that can be exploited to improve prognosis and treatment monitoring, at the cost of prolonged acquisition times and specialised MR-protocols. In this study, two converging approaches were followed to investigate how to best use the available MRI data for the diagnosis and prognosis of MS. On one hand, qualitative data commonly used in clinical research for lesion and anatomical purposes were shown to carry quantitative information that could be used to conduct myelin and relaxometry analyses on cohorts devoid of dedicated quantitative acquisitions. In this study arm, named bottom-up, qualitative information was up-converted to quantitative surrogate: traditional model-fitting and deep-learning frameworks were proposed and tested on MS patients to extract relaxometry and indirect-myelin quantitative data from qualitative scans. On the other hand, when using multi-modal MRI data to classify MS patients with different clinical status, different MR-features contribute to specific classification tasks. The top-down study arm consisted in using machine learning to reduce the multi-modal dataset dimensionality only to those MR-features that are more likely to be biophysically meaningful with respect to each MS phenotype pathophysiology. Results show that there is much more potential to qualitative data than lesion and tissue segmentation, and that specific MRI modalities might be better suited for investigating individual MS phenotypes. Efficient multi-modal acquisitions informed by biophysical findings, whilst being able to extract quantitative information from qualitative data, would provide huge statistical power through the use of large, historical datasets, as well as constitute a significant step forward in the direction of sustainable research

Understanding progression in primary progressive multiple sclerosis: a longitudinal clinical and magnetic resonance imaging study

The work in this thesis applies magnetization transfer imaging (MTI) and conventional MRI measures (brain volume, T2 lesion load and enhancing lesions) to investigate the mechanisms underlying progression in primary progressive multiple sclerosis (PPMS), and identifies MR markers to predict and monitor progression. First, we demonstrated that MTI was sensitive to change in the normal appearing brain tissues over one year, and that clinical progression over this period was predicted by baseline normal appearing white matter (NAWM) MT ratio (MTR). However, our second study showed that over three years, grey matter MTR became a better predictor of progression than any other MRI measure. Grey matter MTR and T2 lesion load changes reflected concurrent progression during this study. To localize the baseline grey matter injury more precisely, we developed a voxelbased technique to identify areas of grey matter MTR reduction and volume loss in patients compared with controls. The regions of grey matter MTR reduction identified correlated with clinical function in anatomically related systems. Finally, because our studies showed that lesion load influenced progression, we used contrast enhanced T1-weighted imaging to examine active focal inflammation. We found that while lesion activity declined over five years, levels of activity at the start of the study could influence mobility five years later. The work presented in this thesis suggests that grey matter damage has a predilection for certain brain regions and is an important determinant of progression in early PPMS. In the white matter, changes in lesion volume and activity continue to influence progression, but NAWM injury may have a declining role. MTR is a sensitive and responsive tool for predicting, monitoring, and localizing clinically relevant brain injury in early PPMS

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI‐based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel‐wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue‐states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2‐weighted hyperintense lesional tissue without T1‐weighted hypointensity (T2L), and T1‐weighted hypointense lesional tissue with corresponding T2‐weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue‐states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions

Dual-encoded magnetization transfer and diffusion imaging and its application to tract-specific microstructure mapping

We present a novel dual-encoded magnetization transfer (MT) and diffusion-weighted sequence and demonstrate its potential to resolve distinct properties of white matter fiber tracts at the sub-voxel level. The sequence was designed and optimized for maximal MT contrast efficiency. The resulting whole brain 2.6 mm isotropic protocol to measure tract-specific MT ratio (MTR) has a scan time under 7 minutes. Ten healthy subjects were scanned twice to assess repeatability. Two different analysis methods were contrasted: a technique to extract tract-specific MTR using Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT), a global optimization technique; and conventional MTR tractometry. The results demonstrate that the tract-specific method can reliably resolve the MT ratios of major white matter fiber pathways and is less affected by partial volume effects than conventional multi-modal tractometry. Dual-encoded MT and diffusion is expected to both increase the sensitivity to microstructure alterations of specific tracts due to disease, ageing or learning, as well as lead to weighted structural connectomes with more anatomical specificity.Comment: 26 pages, 7 figure

Assessing Functional Deficits at Optic Neuritis Onset in EAE Mice Using Manganese-Enhanced MRI (MEMRI) and Diffusion fMRI

Optic neuritis: ON) is frequently a first sign of multiple sclerosis: MS), which is an inflammatory demyelinative disease of the central nerve system: CNS), including brain, optic nerve, and spinal cord. Investigating ON provides an approach to improve MS diagnosis and treatment monitoring. Experimental autoimmune encephalomyelitis: EAE) is a widely used animal model of MS and exhibits pathologies similar to the human disease. Magnetic resonance imaging: MRI) is a non-invasive tool to detect disease progress and as a standard diagnose procedure for MS in the clinic. In biological samples, the hydrogen nuclei are used to produce the MR signal due to its abundance in water and fat. As a result of tissue microstructural differences, 1H nuclei exhibit tissue-specific and pathology-specific relaxation and diffusion properties, which are reflected in the resulting MR image contrast. Therefore, the pathologies of MS, such as inflammation, demyelination, and axonal injury can be detected using different MR-related tools, including T1- and T2-weighted imaging, diffusion-weighted imaging, and diffusion tensor imaging, and so on. Importantly, direct non-invasive assessment of functional deficits could be important for understanding pathology mechanisms or provide a useful bio-index to validate treatment strategies. In this dissertation, manganese-enhanced MRI: MEMRI) and diffusion fMRI were introduced to explore the functional deficits, including axonal transport disruption and axon-activity dysfunction, at optic neuritis onset in EAE mice