京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22351号 / 医博第4592号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 溝脇 尚志, 教授 戸井 雅和 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The development of fluent reading requires coordinated development of key fiber pathways. While several fiber pathways have been implicated in reading, including the recently re-identified vertical occipital fasciculus (VOF), inferior longitudinal fasciculus (ILF), arcuate fasciculus and its 3 components, and inferior fronto-occipital fasciculus (IFOF), whether these fiber pathways support reading in young children with little to no exposure to print remains poorly understood. Consequently, over the course of three studies, the current dissertation aimed to narrow this research gap by addressing the following research questions: 1) Which fiber pathways support early literacy skill in young children 5-10 years old? 2) Are microstructural properties of these tracts predictive of age-related changes in reading across an interval of two years? 3) Do different components of the recently identified VOF differentially support reading? To answer these questions, we used diffusion-weighted imaging to measure white-matter development and to relate the microstructural properties of each fiber pathway to early literacy and literacy development. We report several novel findings that contribute to our growing understanding of the white matter connections supporting early literacy and literacy. For the first time, these studies revealed that the re-identified VOF can be reliably tracked in young children, bilaterally and is composed of three main components, which project from occipital temporal sulcus to angular, and middle and superior occipital gyri. We also found that the left AF, bilateral ILF, and particular components of the VOF play a role in early literacy and literacy development. Implications for contemporary models of reading development are discussed.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12889号 / 論医博第2089号 / 新制||医||1007(附属図書館) / 31643 / (主査)教授 福山 秀直, 教授 千葉 勉, 教授 平岡 眞寛 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Objective: Chronic recurrent multifocal osteomyelitis/ chronic non-bacterial osteomyelitis (CRMO/CNO) is a rare auto-inflammatory disease and typically manifests in terms of musculoskeletal pain. Because of a high frequency of musculoskeletal disorders in children/ adolescents, it can be quite challenging to distinguish CRMO/ CNO from nonspecific musculosketetal pain or from malignancies. The purpose of this study was to evaluate the visibility of CRMO lesions in a whole-body diffusion-weighted imaging (WB-DWI) technique and its potential clinical value to better characterize MR-visible lesions. Materials and methods: Whole-body imaging at 3T was performed in 16 patients (average: 13 years) with confirmed CRMO. The protocol included 2D Short Tau Inversion Recovery (STIR) imaging in coronal and axial orientation as well as diffusion-weighted imaging in axial orientation. Visibility of lesions in DWI and STIR was evaluated by two readers in consensus. The apparent diffusion coefficient (ADC) was measured for every lesion and corresponding reference locations. Results: A total of 33 lesions (on average 2 per patient) visible in STIR and DWI images (b = 800 s/mm2 and ADC maps) were included, predominantly located in the long bones. With a mean value of 1283 mm2/s in lesions, the ADC was significantly higher than in corresponding reference regions (782 mm2/s). By calculating the ratio (lesion to reference), 82% of all lesions showed a relative signal increase of 10% or higher and 76% (25 lesions) showed a signal increase of more than 15%. The median relative signal increase was 69%. Conclusion: This study shows that WB-DWI can be reliably performed in children at 3T and predominantly, the ADC values were substantially elevated in CRMO lesions. WB-DWI in conjunction with clinical data is seen as a promising technique to distinguish benign inflammatory processes (in terms of increased ADC values) from particular malignancies.

Cancer is one of the major causes of worldwide mortality. Imaging plays a vital role in the staging, follow-up, and evaluation of therapeutic response in cancer patients. Whole-body (WB) magnetic resonance imaging (MRI), as a non-ionizing imaging technique, is a promising procedure to assess tumor spreading in a single examination. New MRI technological developments now enable the application of diffusion-weighted imaging (DWI) of the entire body. DWI reflects the random motion of water molecules and provides functional information of body tissues. DWI can be quantified with the use of the apparent diffusion coefficient (ADC). The aim of this dissertation was to demonstrate the value of WB MRI including DWI in cancer patients. WB MRI including DWI, 18F-NaF PET/CT, and bone scintigraphy was performed on 49 patients with newly diagnosed, high-risk prostate cancer, for the purpose of detecting bone metastases. WB DWI showed higher specificity, but lower sensitivity compared to 18F-NaF PET/CT. In addition, WB MRI including DWI, and CT of the chest and abdomen was performed in 23 patients with malignant melanoma. We concluded that WB MRI could not completely supplant CT for the staging of malignant melanoma, especially with respect to the detection of lesions in the chest region. In this study, WB MRI and DWI were able to detect more bone lesions compared to CT, and showed several lesions outside the CT field of view, reinforcing the advantage of whole-body examination. WB MRI, including DWI, was performed in 71 patients with testicular cancer. This modality demonstrated its feasibility for use in the follow-up of such patients. WB MRI, including DWI, and 18F-FDG PET-CT, were carried out in 50 patients with malignant lymphoma. Both these imaging modalities proved to be promising approaches for predicting clinical outcomes and discriminating between different subtypes of lymphomas. In conclusion, WB MRI, including DWI, is an evolving technique that is continuing to undergo technical refinement. Standardization of image acquisition and analysis will be invaluable, allowing for more accurate comparison between studies, and widespread application of this technique in clinical practice. Both WB MRI, including DWI and PET/CT, have their particular strengths and weaknesses in the evaluation of metastatic disease. DWI and PET/CT are different functional techniques, so that combinations of these techniques may provide complementary and more comprehensive information of tumor tissue.

A ressonância magnética (RM) tem sido amplamente utilizada no diagnóstico por imagem de alterações de glândulas salivares. No entanto, a presença de aspectos similares nas imagens com técnicas convencionais de RM dificulta a distinção do diagnóstico entre patologias inflamatórias e neoplásicas. O objetivo deste estudo foi comparar valores dos coeficientes de difusão aparentes (ADC - Apparent Diffusion Coefficient) de imagem ponderada em difusão (DWI - Difusion Weighted Imaging) com ressonância magnética, entre glândulas salivares normais, casos com sialoadenite e com adenoma pleomórfico das glândulas salivares maiores. Vinte e dois pacientes (totalizando 44 glândulas salivares maiores) diagnosticados com sialoadenite unilateral (em glândula parótida ou submandibular) ou adenoma pleomórfico (apenas em parótida) foram selecionados. Todas as glândulas contralaterais não afetadas também foram analisadas. Imagens de RM ponderadas em T1, T2 e DWI foram obtidas utilizando sequências de pulso spin-eco (SE) com um aparelho de ressonância magnética de 1.5 Tesla. Primeiramente, a performance diagnóstica (sensitividade, especificidade e acurácia) foi calculada para três observadores após analisarem imagens de RM e DWI, separadamente. Em seguida, os valores médios de ADC foram comparados entre os três grupos analisados (glândulas normais contralateral, sialoadenite e adenoma pleomórfico). O uso da DWI rendeu uma melhor performance diagnóstica em geral para todos os observadores. Além disso, casos de adenoma pleomórfico apresentaram os maiores valores de ADC do estudo. Dentro das limitações deste estudo, os resultados sugerem que DWI permite a diferenciação entre sialoadenite e adenoma pleomórfico. / Alterations of the salivary glands are usually detected by conventional magnetic resonance imaging (MRI) techniques. However, their imaging presentation may present similar aspects. The aim of this study was to compare apparent diffusion coefficient (ADC) values from diffusion-weighted MRI (DWI) among normal salivary glands, cases with sialadenitis and with pleomorphic adenoma of major salivary glands. Twenty-two patients (totaling 44 major salivary glands) diagnosed with either unilateral sialadenitis (on either parotid or submandibular gland) or parotid gland pleomorphic adenoma were selected. Contralateral non-affected glands (normal) were also analyzed. DWI images were achieved using a spin-echo (SE) pulse sequence with a 1.5T MRI device. Mean ADC values were compared among the three groups analyzed (contralateral normal glands, sialadenitis and pleomorphic adenoma). Furthermore, diagnostic performance of MRI and DWI were calculated for three observers. DWI also presented better diagnostic performance results. In addition, cases of pleomorphic adenoma presented the highest ADC values of the study. Within the limitations of this study, the present results suggest that DWI allows for differentiation between parotid sialadenitis and pleomorphic adenoma.

Radiological imaging already has a key role in the detection and management of patients with metastatic colorectal cancer (mCRC). With the evolution of personalised medicine there is a need for non-invasive imaging biomarkers that can detect early tumour response to targeted therapies. Translation from bench to bedside requires a multicentre approach that follows an agreed development roadmap to ensure that the proposed biomarker is precise (reproducible/ repeatable) and accurate in its characterisation of a meaningful physiological, pathological or post treatment response. The following thesis (organized in the alternative format with experimental studies written as individual complete manuscripts) investigates methods to improve precision and accuracy of the Apparent Diffusion Coefficient (ADC), a proposed quantitative imaging biomarker with a potential role in characterisation of post treatment responses in mCRC. The first objective was to establish baseline multicentre reproducibility (n=20) for ADC. A change in ADC greater than 21.1% was required to determine a post treatment response. Using a statistical error model, the dominating factors that influenced reproducibility were motion artefact and tumour volume. In the second study these factors were addressed using a single centre cohort with pre and post treatment data. Correcting for errors due to motion and tumour volume improved sensitivity from 30.3% to 1.7%, so a post treatment response was detected in 6/12 tumours compared to 0/12 using the baseline approach. In the third study, motion correction was implemented and the statistical error model was applied successfully to a multicentre cohort of 15 patients (1.9% sensitivity). The results of this thesis highlights that with careful consideration and correction of factors that negatively influence sensitivity, ADC is a potential imaging biomarker for use in post treatment response for patients with mCRC.

The logistical complexities of performing multi-site longitudinal diffusion-weighted imaging (DWI) studies requires careful construction of analysis tools and procedures. Proposed clinical trials for therapies in neurodegenerative disease are known to re- quire several hundred subjects, thus mandating multiple site participation to obtain sufficient sample sizes. DWI is an important tool for monitoring diffusivity properties of white matter (WM) in disease progression. The multi-site nature of clinical trials requires new strategies in DWI processing and analysis to reliably measure longitudi- nal WM changes. This work describes the process of developing and validating robust analysis methodologies to process multi-site DWI data in a rare, neurodegenerative disease. Key processing components to accomplish a robust DWI processing system include: DICOM conversion, automated quality control, unbiased atlas construction, fiber tracking, and statistical analysis. Extensive validation studies were performed to characterize methodological results within and across the common confounds inherent in multi-site clinical trials. The conversion and automated quality control tools optimized for this work both enhanced the ability to reliably obtain repeat diffusion tensor image (DTI) scalar measurements in a reliability analysis of healthy controls scanned at multiple sites using multiple scanner vendors. A DTI scalar analysis performed on focused WM regions showed it was possible to detect significant mean differences of DTI scalars among separate groups of a neurodegenerative disease population. The DTI scalar analysis paved the way for an atlas-based cross-sectional fiber tracking analysis. In the cross-sectional fiber tracking analysis, multi-site data was brought into the same space, making major fiber tracts terminating in the focused WM regions of the scalar analysis from all participants comparable. Significant differences in diffusivity were found throughout each tract among separate groups of the neurodegenerative disease population. In addition, multiple neuropsychological cognitive variables that have a documented ability to track disease progression of the neurodegenerative disease, strongly correlated with many of the DTI scalars in each tract. The findings of the cross-sectional fiber tracking analysis were reinforced by similar findings produced by a longitudinal fiber tracking analysis. Collectively, these findings suggest that cogni- tive deficits seen in the neurodegenerative disease population could be explained by changes in diffusivity of the tracts explored in this work. In addition to the longi- tudinal fiber tracking analysis examining diffusivity, methods for a WM morphology analysis using parallel transport to apply longitudinal volume changes to a template was explored.

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings.

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