Background: Given that brain pathology precedes clinical symptoms in Alzheimer’s disease (AD), identifying pre-symptomatic biomarkers is critical in order to implement symptom-delaying strategies as early as possible. Magnetic resonance imaging (MRI) is an ideal method for detecting early brain changes in Alzheimer's disease, as it is non-invasive, easily repeatable, and widely available. To date, MRI biomarker research has largely focused on neuronal loss in grey matter, but there is a lack of research on white matter and its relationship with cognitive performance. Diffusion tensor imaging (DTI) is a MRI-based technique that is particularly sensitive to microstructural white matter characteristics, making it an ideal method to study white matter changes. Methods: Longitudinal DTI and clinical data from the Alzheimer’s Disease Neuroimaging Initiative 2 database were used to examine the 1) within-group microstructural white matter changes in individuals with AD and healthy aging controls at baseline and year one; 2) the between-group microstructural differences in individuals with AD and controls at both time points; and 3) the relationship between white matter and cognitive performance at both time points. Results: 1) Within-group: Tract-based Spatial Statistics reveal that individuals with AD have reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in the corpus callosum; internal and external capsule; corona radiata; posterior thalamic radiations; superior and inferior longitudinal fasciculus; fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; tapetum; medial lemniscus; cerebellar and cerebral peduncle; and hippocampal cingulum at year one compared to baseline. Controls also had reduced FA and increased MD at year one compared to baseline, but such changes were less extensive and did not include the hippocampal cingulum. 2) Between-group: Relative to controls, individuals with AD had lower FA and higher MD in the corpus callosum, internal and external capsule; corona radiata; posterior thalamic radiation; superior and inferior longitudinal fasciculus and fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; tapetum and hippocampal cingulum. 3) There was a positive relationship between FA and an ADNI- derived memory composite score in individuals with AD. Conclusion: The results revealed that DTI holds potential as an AD biomarker given its sensitivity to detect microstructural white matter characteristics. Longitudinal tracking of brain imaging and AD clinical signs in large cohorts are necessary to further evaluate potential clinical utility. / Graduate

Orientadores: Anelyssa Cysne Frota D'Abreu, Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T01:17:26Z (GMT). No. of bitstreams: 1 Pinheiro_GiordannaLuizaSelingardi_M.pdf: 1372164 bytes, checksum: e02f4b5ec43afe35e676ab843e98cda0 (MD5) Previous issue date: 2015 / Resumo: A distonia é uma síndrome caracterizada por espasmos e contrações musculares, prolongados e involuntários, causando movimentos de torção e posturas anormais, frequentemente dolorosos. A distonia craniocervical (DCC) ocorre quando há contração das musculaturas da cabeça, face e pescoço; podendo ser focal ou segmentar. Estas são as distonias mais frequentes em indivíduos adultos. O tratamento com a toxina botulínica é o mais indicado para a DCC, mas seu efeito é temporário. Disfunção ou lesão dos gânglios da base sempre foi considerado o componente central na sua fisiopatologia, porém estudos mais recentes mostram o envolvimento de diversas outras regiões cerebrais como o córtex sensorio-motor e cerebelo. O presente estudo avaliou as alterações estruturais da substância branca em 40 pacientes comparando-os a 40 controles saudáveis. Secundariamente os mesmos pacientes foram divididos em 4 grupos: blefarospasmo, blefarospasmo + oromandibular, blefarospasmo + oromandibular + cervical e cervical. Todos passaram por uma avaliação clínica detalhada, envolvendo revisão do histórico, exame neurológico e exame de ressonância magnética. As análises da técnica de imagem por tensor de difusão (DTI) foram feitas através do software Trato baseado em estatística espacial (TBSS), onde foram avaliados anisotropia fracional (FA) e difusividade média (MD). Também foram realizadas técnicas baseada em região de interesse (ROI) e tractografia nesses pacientes. Não encontramos diferenças significativas no FA e MD nas análises realizadas, sugerindo que a microestrutura da substância branca dos pacientes com DCC encontra-se preservada. Futuros estudos utilizando análises funcionais podem desvendar um acometimento funcional dos circuitos cerebrais, sem que haja necessariamente acometimento estrutural da substância branca / Abstract: Dystonia is a syndrome characterized by involuntary muscle contractions, causing twisting movements and abnormal postures, which are often painful. Craniocervical dystonia (CCD) involves the contraction of the head and neck muscles. It is the most frequent dystonia in adults, and it can be focal or segmental. Botulinum toxin is the best treatment for CCD, although the effect is temporary. Classically considered secondary to a dysfunction or lesion in the basal ganglia circuit, recent studies have shown the involvement of the sensorimotor areas and the cerebellum. In the present study, we evaluated the structural brain changes in 40 patients comparing them to 40 healthy controls. Secondarily, we divided the patients into 4 groups based on dystonia localization: blepharospasm, blepharospasm + oromandibular, blepharospasm + oromandibular + cervical and cervical. Patients and controls underwent the same MRI acquisition protocol in a 3T Philips Achieva MRI scanner. All patients were assessed by an experienced neurologist specialized in Movement Disorders. We performed DTI analyzes with Tract-Based Spatial Statistics (TBSS) and we evaluated the fractional anisotropy and the mean diffusivity. We performed two confirmatory analyses using a ROI based approach and tractography. There were no microstructural alterations neither in the primary nor the secondary analysis. We did not find microstructure changes in the white matter of subjects with craniocervical dystonia. Further studies should evaluate the presence of functional and connectivity abnormalities in these subjects / Mestrado / Fisiopatologia Médica / Mestra em Ciências

Motion capture technology and Magnetic Resonance Imaging with Diffusion Tensor Imaging (MRI-DTI) were used in this work to detect subtle abnormalities in patients with mild traumatic brain injury (MTBI). A new concept, termed dynamic variability, is introduced in this work to quantify and localize gait variability. Three chronic MTBI patients were recruited from the Veterans Affair Medical Center in Iowa City, IA, and three healthy controls with height, weight, and gender matched to the patients were recruited from the Reserve Officers' Training Corps in Iowa City, IA. Kinematic and kinetic data of the subjects were collected during the performance of three gait testing scenarios. The first test involved single-task walking and was used as a baseline. The second and third tests were dual tasks that involved walking while performing a cognitive or motor task and were designed to magnify gait abnormalities. The results showed that MTBI patients had reduced gait velocity, shortened stride length, and larger step width; findings that are consistent with those published in the literature. The new dynamic variability factor found that, as compared to controls, MTBI patients had more variability in their hip and ankle joint moments. MRI-DTI has been used to detect dysfunction of the major white matter tracts in chronic MTBI patients; although, the sample size of this study was too small to detect a difference between the MTBI and control subjects. The imaging and gait abnormalities are suggestive of frontal lobe-white matter tracts dysfunction.

Episode dépressif caractérisé (EDC) devient de plus en plus fréquent dans le monde entier. Les imageries fonctionnelles et volumétriques ont trouvé des activations anormales et des réductions de la substance grise cérébrale des patients d’EDC. Pourtant, le pattern des connexions cérébrales (le connectome structurel) des patients en EDC en imagerie de diffusion est peu connu et incomplet. L’objectif de ce travail est d’étudier le connectome structurel des patients d’EDC. Pendant 3 ans du 03/2014 au 03/2017, 56 patients d’EDC et 31 sujets sains de contrôles ont inclus dans l’étude. Tous ces patients ont reçu le même traitement de dépression de venlafaxine et ont été suivi 3 mois. Ils ont reçu l’évaluation clinique et d’IRM anatomique et de la diffusion cérébrale à l’inclusion et à 3 mois.Les contrôles ne sont évalués qu’à l’inclusion. A 3 mois, 37 patients sur 56 ont fini toutes les évaluations.On a trouvé que l’ancienne usage de l’antidépresseur (AD) et l’ancien épisode de dépression lient respectivement à l’augmentation et à la diminution de l’anisotropie cérébrale des patients déprimés. Aucune différence de l’anisotropie cérébrale entre les patients et les sujets sains à l’inclusion et à 3 mois du traitement n’a été détectée. La réponse à l’AD ne lie pas à l’anisotropie cérébrale des patients à l’inclusion et à 3 mois. La topographie des connexions semble modifiée mais pas significative. Ce résultat a mis en évidence pour la première fois 2 affections opposites de l’AD et de la dépression sur le connectome structurel cérébral à long terme. / Major depressive disorder (MDD) is expanding on worldwide. Functional and volumetric imaging found abnormal activities and reductions in cerebral gray matter in MDD patients. However, the pattern of brain connections (structural connectome) of MDD patients in diffusion imaging remains unclear. The objective of this work is to study the structural connectome of MDD patients. For 3 years from 03/2014 to 03/2017, 56 MDD patients and 31 healthy controls (HC) were included in the study. All of these patients received the same venlafaxine depression treatment and were followed for 3 months. They received clinical evaluation and anatomical MRI and cerebral diffusion at baseline and at 3 months. HC are evaluated once at inclusion. At 3 months, 37 out of 56 patients completed all assessments. The old use of the antidepressant drugs (AD) and the previous episode of depression have been found to be related to the increased and decreased of cerebral anisotropy in depressed patients, respectively. No differences in cerebral anisotropy between patients and HC at baseline and at 3 months of treatment were detected. The response to AD is not related to patients’ cerebral anisotropy at baseline and at 3 months. The topography of the connections seems modified but not significant. This result showed for the first time 2 opposing affections of AD and depression on the cerebral structural connectome in long term.

Blast-related mild traumatic brain injury (mTBI) is a common injury among Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans due to the frequent use of improvised explosive devices (IEDs). A significant minority of veterans with blast-related mTBI complain of postconcussion symptoms (PCS) and cognitive difficulties, even years after the injury. Studies have suggested that these behavioral sequelae are primarily linked to mental health disorders such as posttraumatic stress disorder (PTSD). However, mTBI is associated with neural changes and the impact of these changes on behavioral sequelae is unclear. As such, this dissertation had three goals. First, this dissertation assessed whether the severity of PCS in blast-exposed individuals is associated with the extent of mTBI-related neural injury. Results revealed that individuals with mTBI with loss of consciousness (LOC) had significantly more white matter abnormalities than no-TBI controls and that these white matter abnormalities were spatially variable across individuals. Importantly, the extent of white matter abnormality was associated with physical PCS severity and mediated the relationship between mTBI with LOC and physical PCS. Second, this dissertation examined whether these white matter abnormalities were also associated with overall cognitive impairment. In light of the observed variability in white matter injury, a measure of overall cognitive status that takes into account heterogeneity of cognitive impairment was used. Results showed that the extent of white matter abnormality was associated with cognitive status and mediated the relationship between mTBI with LOC and cognitive impairment. Third, this dissertation examined performance and brain function in the context of an experimental measure of cognitive control known to be sensitive to residual effects of mTBI. Results revealed that although behavioral performance was similar across groups, the mTBI group had enhanced functional connectivity between brain networks important for task performance, suggesting a potential compensatory mechanism in mTBI. Together, the findings of this dissertation suggest that mTBI is associated with structural and functional connectivity alterations years after the injury. Further, this dissertation suggests that whereas structural connectivity changes may have negative behavioral consequences, changes in functional connectivity may serve as a compensatory mechanism for successful performance.

BACKGROUND: White matter (WM) aberrations have been broadly characterized in schizophrenia using standard diffusion tensor imaging (DTI) techniques. The present study aims to distinguish WM alterations in the early course of schizophrenia using advanced diffusion measures of free-water corrected fractional anisotropy (FAt) and free-water fractional volume (FW), in addition to examining their association with neurocognition, social cognition, and clinical measures. We report baseline results from a longitudinal study investigating the effects of cognitive enhancement therapy (CET) on brain structure and function in schizophrenia. METHODS: The sample consisted of 46 early course schizophrenia patients and 20 healthy controls. Diffusion-weighted images were processed using a free-water imaging pipeline, that separately models diffusion of water in tissue (FAt) and the extracellular space (FW). Tract-Based Spatial Statistics was performed on the FAt and FW diffusion tensor maps and average measures from 24 bilateral regions of interest (ROIs) were extracted. We examined WM structural differences between patients and controls and further investigated WM relations to neurocognition, social cognition, and clinical measures specifically in schizophrenia. RESULTS: Patients showed significant FAt reductions in the body of the corpus callosum, posterior thalamic radiation (PTR), cingulate gyrus, anterior corona radiata, corpus callosum, and corona radiata and FW elevations in the posterior corona radiata (PCR), uncinate fasciculus (UNC), and PTR compared to controls. For patients, positive correlations between FAt and working memory were observed in the PCR and fornix & stria terminalis (FXST). Negative associations between FW and attention/vigilance were observed in the UNC. Positive correlations between FAt and theory of mind (ToM) were observed in average whole-brain and FXST. Negative associations between FW and ToM were observed in average whole-brain and PCR. Positive correlations between FW and negative symptom severity were observed in the external capsule. CONCLUSION: Using free-water imaging, we report WM aberrations and FW elevations in the early course of schizophrenia in addition to neural correlates associated with cognition and clinical measures. Future investigations on the longitudinal effects of CET are warranted for a greater understanding of the underlying neural correlates of clinical manifestations in schizophrenia. / 2020-06-14T00:00:00Z

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18174号 / 医博第3894号 / 新制||医||1003(附属図書館) / 31032 / 京都大学大学院医学研究科医学専攻 / (主査)教授 金子 武嗣, 教授 髙橋 良輔, 教授 河野 憲二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19931号 / 医博第4151号 / 新制||医||1017(附属図書館) / 33017 / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 髙橋 良輔, 教授 大森 孝一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Military personnel often experience mild traumatic brain injury (mTBI) from exposure to improvised explosive devices (IEDs). Soldiers typically endure blast trauma from the IED pressure wave as well as blunt trauma from ensuing head impacts. Researchers have not reached a consensus on whether the biomechanical response from blunt or blast trauma plays a more dominant role in mTBI because the specific biomechanical sources of injury are often undetermined. Consequently, the goal of this dissertation was to conduct three separate studies in order to characterize the mechanical behavior of the brain after exposure to mTBI conditions. For Study 1, mild blunt and blast trauma were induced in Sprague-Dawley rats using a custom-built device. In-house diffusion tensor imaging (DTI) software was used to make 3-D reconstructions of white matter fiber tracts before and after injury (1, 4, and 7 days). Axonal integrity was characterized by examining the fiber count, fiber length, and fractional anisotropy (FA). In-house image analysis software also quantified the microstructural variations in Hematoxylin and Eosin (H&E) stained brain sections, where significant differences in parameters such as the area fraction (AF) and nearest neighbor distance (NND) correlated to voids that formed after water diffused extracellularly from axons. Study 2 employed a computational approach involving the development of a finite element (FE) model for the rat head followed by the simulation of blunt and blast trauma, respectively. FE parameters such as von Mises stress, pressure, and maximum principal strain were analyzed at various locations including the skull, cerebral cortex, corpus callosum, and hypothalamus to compare injury cases. Study 3 involved interruption mechanical testing of porcine brain, a suitable animal surrogate of human brain. Compression, tension, and shear experiments were performed at a strain rate of 0.1 s-1 to examine the differential mechanical response. Microstructural changes in H&E stained brain sections were analyzed with in-house image analysis software to quantify differences among stress states at strains of 0.15, 0.30, and 0.40. Studies 1 and 2 confirmed that the brain behaves differently in response to blunt and blast trauma, respectively, while Study 3 further demonstrated the stress state dependent behavior of brain tissue.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24512号 / 医博第4954号 / 新制||医||1064(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 花川 隆, 教授 古川 壽亮, 教授 中本 裕士 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM