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abstract: The objective of this small animal pre-clinical research project was to study quantitatively the long-term micro- and macro- structural brain changes employing multiparametric MRI (Magnetic Resonance Imaging) techniques. Two separate projects make up the basis of this thesis. The first part focuses on obtaining prognostic information at early stages in the case of Traumatic Brain Injury (TBI) in rat animal model using imaging data acquired at 24-hours and 7-days post injury. The obtained parametric T2 and diffusion values from DTI (Diffusion Tensor Imaging) showed significant deviations in the signal intensities from the control and were potentially useful as an early indicator of the severity of post-traumatic injury damage. DTI was especially critical in distinguishing between the cytotoxic and vasogenic edema and in identification of injury regions resolving to normal control values by day-7. These results indicate the potential of quantitative MRI as a clinical marker in predicting prognosis following TBI. The second part of this thesis focuses on studying the effect of novel therapeutic strategies employing dendritic cell (DC) based vaccinations in mice glioma model. The treatment cohorts included comparing a single dose of Azacytidine drug vs. mice getting three doses of drug per week. Another cohort was used as an untreated control group. The MRI results did not show any significant changes in between the two treated cohorts with no reduction in tumor volumes compared to the control group. The future studies would be focused on issues regarding the optimal dose for the application of DC vaccine. Together, the quantitative MRI plays an important role in the prognosis and diagnosis of the above mentioned pathologies, providing essential information about the anatomical location, micro-structural tissue environment, lesion volume and treatment response. / Dissertation/Thesis / Masters Thesis Bioengineering 2014

Introdução: Os transtornos depressivos constituem um problema de saúde pública na terceira idade, e estima-se que a depressão será uma das três principais causas de sobrecarga de doença no mundo nas próximas decadas. Métodos de neuroimagem têm sido amplamente utilizados em estudos de depressão em idosos, pois são técnicas não invasivas que permitem a detecção de alterações cerebrais estruturais e funcionais. Fração de Anisotropia (FA) e Difusividade Média (MD) são índices indiretos da integridade micro-estrutural da substância branca, mensurados através de imagens de tensor de difusão (DTI). A maioria dos estudos a respeito de depressão e neuroimagem tem focado apenas em possíveis diferenças em regiões de interesse (ROI) previamente determinadas. Pesquisas sobre depressão em idosos e as alterações estruturais por tensor de difusão em todo o cérebro são escassos. O objetivo deste estudo foi investigar a existência de alterações nos parâmetros de FA ou MD em todo o cérebro, sem uma região de interesse previamente definida, comparando idosos deprimidos a idosos sem depressão. Métodos: Exames de imagem cerebral por ressonância magnética foram obtidos de 47 idosos deprimidos (idade média=70,94 ± 6,98), segundo critérios diagnósticos do DSM-IV, e 36 idosos sem depressão (idade média=69,39 ± 7,21) (p=0,32). O exame de neuroimagem dos sujeitos foi realizado em aparelho de ressonância magnética (RM) de 1,5 T, (TE mínimo, TR=10000ms, FOV=26, matriz=128x128, espessura=5mm). Os parâmetros de difusão das imagens de RM foram obtidos a partir de 25 direções não colineares com um b-valor de 1000s/mm2 juntamente com imagem sem gradientes de difusão b=0. Antes da aquisição dos exames de imagem, um psiquiatra administrou os seguintes testes: Mini-Exame do Estado Mental (MEEM), Teste Cognitivo Cambridge (CAMCOG), Escala Montgomery-Aberg de Depressão (MADRS) e Escala de Depressão de Hamilton (HAM-D). Não foram encontradas diferenças significativas nos dados demográficos entre os grupos. A análise estatística baseada no voxel dos dados de FA foi realizada com uso da ferramenta TBSS, parte do programa FSL, que projeta a FA de cada indivíduo em um esqueleto de FA média antes de aplicar a análise estatística baseada no voxel entre os sujeitos da amostra. Diferenças entre os grupos foram controladas para idade. Resultados: Os escores médios da avaliação cognitiva para o grupo de idosos deprimidos foram: CAMCOG=82,94 ± 13,95 e MEEM=25,21 ± 3,74; e para o grupo controle: CAMCOG=90,83 ± 8,88 (p=0,017) e MEEM=27,86 ± 1,99 (p=0,004). Quanto às escalas de sintomatologia depressiva, tem-se no grupo de idosos deprimidos: MADRS=23,23 ± 8,60 HAM-D=18,64 ± 6,17; e no grupo de idosos sem depressão: MADRS=1,39 ± 1,20, HAM-D=2,67 ± 1,57. Após o ajuste por idade, o grupo de idosos deprimidos não apresentou diferenças significativas nos parâmetros de FA e de MD. Os escores da avaliação cognitiva (CAMCOG e MEEM) não se correlacionaram significativamente aos parâmetros de FA nem de MD. Resultados semelhantes foram obtidos após a correlação com escores das escalas de sintomatologia depressiva (MADRS e HAM-D). Conclusão: Não houve diferença significativa, na amostra estudada, dos parâmetros de FA ou MD entre os idosos deprimidos e idosos sem depressão quando o cérebro é analisado sem a utilização de ROI. Não houve correlação, na presente amostra, entre avaliação cognitiva e FA ou MD nem entre gravidade da depressão e estes parâmetros de avaliação de alteração de substância branca / Introduction: Depressive disorders constitute a public health problem in old age, and depression is projected to be one of the three leading causes of burden of disease worldwide in the next decades. Neuroimaging methods have been widely used in studies of depression in the elderly, because they are noninvasive techniques that allow the detection of structural and functional brain changes. Fractional Anisotropy (FA) and Mean Diffusivity (MD) are neuroimaging index of micro-structural white matter integrity, measured using diffusion tensor imaging. Most studies investigating depression and neuroimaging have focused only in possible differences in regions of interesting (ROI) previously selected. Studies investigating correlation between elderly depression and structural alterations measured by diffusion tensor in the whole brain are scarce. The aim of this study was to investigate the existence of FA or MD differences in the whole brain, without a region of interest previously determined, between elderly depressed and elderly without depression. Methods: Brain magnetic resonance imaging scans were obtained on 47 elderly depressed subjects (mean age=70.9 ± 6.9), according to DSM-IV criteria, and 36 healthy elderly controls (mean age=69.4 ± 7.2) (p=0.32). Scanning of subjects was performed on a 1,5T MRI scanner (TE minimum, TR=10000ms, FOV=26, matrix=128x128, section thickness=5mm). Diffusion MR images were obtained from 25 non-colinear directions with a b-value of 1000 s/mm2 along with a b=0 image with no diffusion gradients. Before MRI acquisition, a psychiatrist administered the following psychiatric tests: Cambridge Cognitve Test Examination (CAMCOG), Mini-Mental State Examination (MMSE), Montgomery-Aberg Depression Rating Scale (MADRS), and Hamilton Rating Scale of Depression (HAM-D). No significant differences were found on demographic data between groups. Voxelwise statistical analysis of FA data was carried out using Tract-Based Spatial Statistics (TBSS), part of FSL program. TBSS projects all subjects\' FA data onto a mean FA tract skeleton, before applying voxelwise cross-subject statistics. Differences between groups were assessed controlling for age. Results: The mean score from cognitive assessment for the whole depression group was: CAMCOG=82,94 ± 13,95 and MMSE=25,21 ± 3,74; and for controls: CAMCOG=90,83 ± 8,88 (p=0,017) and MMSE=27,86 ± 1,99 (p=0,004). Results of depressive symptom assessment for the patient group were MADRS=23.23 ± 8.60 HAM-D=18.64 ± 6.17 and MADRS=1.39 ± 1.20, HAM-D=2.67 ± 1.57 for control group. After controlling for age, geriatric depressed subjects had no significant differences on FA and on MD parameters. No significant correlations were found between scores from cognitive tests (CAMCOG and MMSE), and FA or MD parameters. Similar results were obtained after correlating scores from scales measuring depressive symptoms (MADRS and HAM-D) and FA or MD parameters. Conclusions: There was no significant difference in FA or MD values between elderly depressed and elderly without depression when the brain is analyzed without a ROI previously determined. There was no correlation, in the present sample, between cognitive assessment and FA or MD, neither between severity of depression and these brain white matter parameters

Orientador: Elizabeth Maria Aparecida Barasnevicius Quagliato / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T22:29:43Z (GMT). No. of bitstreams: 1 Martins_SergilainePereira_D.pdf: 2688714 bytes, checksum: 50e69a64ddbe919094b642d6fcc2f77a (MD5) Previous issue date: 2014 / Resumo: A ressonância magnética por tensor de difusão (DTI) proporciona aumento da sensibilidade para estudar a alterações na microestrutura da substância branca aparentemente normal (SBAN) in vivo e é especialmente indicada para estudar doenças que apresentam lesão axonal e desmielinização. No presente estudo, sugerimos a hipótese de que a neurodegeneração produz alterações microestruturais na SBAN de indivíduos com DA e CCL, especialmente em regiões específicas do cérebro. Foram estudados 71 participantes (21 com DA leve, 25 com CCL e 25 controles normais-CN) que foram recrutados de serviço médico neurológico em Campinas. Os indivíduos foram avaliados por um protocolo de avaliação clínica padronizada que incluiu: escala de depressão geriátrica (GDS), questionário de atividades funcionais (FAQ - Pfeffer), mini exame do estado mental (MEEM), teste de aprendizado auditivo-verbal de REY (RAVLT), testes de memória prospectiva (MP) (consulta e pertence) (subtestes do Teste de Memória Comportamental Rivermead), teste de fluência verbal (FV) (animais e FAS), teste desenho do relógio (TDR) e teste de nomeação de Boston (TNB). As imagens de RNM foram adquiridas usando um scanner MRT 1.5. A anisotropia fracionada (FA) e as difusividades axial (DAx) e radial (DRa) foram analisadas em regiões de interesse (ROI) alocados nos lobos frontal, parietal, temporal e occipital. FA, DAx e DRa foram calculadas para cada ROI. Em seguida, calculamos as médias de todas as seções para FA, DAx, e DRa para cada região da SBAN bilateralmente. Resultados: Nossos resultados mostraram que: (1) Comparado com CN, o grupo CCL demonstrou diminuição da FA no lobo frontal (parte do fórceps menor e do fascículo uncinado e coroa radiada), região importante para a memória episódica. (2) Na avaliação por análise de regressão múltipla, FA e DAx frontal, DAx temporal e parietal e FA occipital formaram um padrão de parâmetros associados ao maior risco para CCL e DA. (3) O estudo da acurácia revelou que a DTI da região frontal é a que apresenta maior sensibilidade e especificidade para identificar CCL. Em relação à DA, as variáveis FA frontal e temporal e DAx parietal apresentaram maior especificidade para identificar DA. (4) Não encontramos correlação robusta entre variáveis neuropsicológicas e de neuroimagem / Abstract: MRI technique, diffusion tensor imaging (DTI), provides increased sensitivity to alterations in the microstructure of white matter in vivo and is especially indicative for diseases causing axonal damage and demyelination. In the present study, we hypothesized that neurodegeneration produces microstructural changes in the cerebral white matter of subjects with AD and MCI, especially in specific regions in the brain. We studied 71 participants (21 mild AD, 25 MCI, and 25 normal controls-NC) that were recruited from neurological medical service in Campinas. Subjects were evaluated by using a standardized clinical evaluation protocol, which included: Geriatric depression Scal (GDS), the functional activities questionnaire (FAQ-Pfeffer), mini-mental status examination (MMSE), Rey auditory verbal learning test (RAVLT), prospective memory (Rivermead Behavioral Memory Test), verbal fluency test (animal and FAS), clock drawing test and Boston naming test. MR images were acquired using a 1.5 T MR scanner. Fractional anisotropy (FA) and axial and radial diffusivities (DA and DR) were analyzed in regions of interest (ROIs) in frontal, parietal, temporal and occipital lobes. FA, DA, and DR were calculated for each ROI. Then the measures of FA, DA, and DR were averaged across all the sections of each white matter region bilaterally. Our results showed that: (1) Compared to NC, MCI group showed decreased FA in the frontal lobe (the minor forceps and the uncinate fasciculus, and corona radiata), important region to episodic memory. (2) The evaluation by multiple regression analysis, frontal FA and DA, temporal and parietal DA and occipital FA formed a pattern of parameters associated with increased risk for MCI and AD. (3) The accuracy revealed that the frontal area has the greatest sensitivity and specificity to identify MCI. Regarding the AD, the frontal FA and temporal and parietal DA have the greatest specificity for identifying AD. (4) We did not find correlation between neuropsychological and neuroimaging variables / Doutorado / Neurologia / Doutora em Ciências Médicas

In study 1, thirty-eight healthy controls were used for optimization of the method. Fifteen patients with progressive supranuclear palsy and an equal number of age-matched healthy controls underwent diffusion tensor MRI and were then investigated and compared groupwise. It was shown that tractography analyses may preferably be performed regionally, such as along the tracts or in different segments of the tracts. Normalization of white matter tracts can be performed using anatomical landmarks. In study 2, 104 males and 153 females in the age interval 13 to 84 years of age participated as healthy individuals in order to investigate age-related changes with diffusion tensor MRI. It was shown that spatially differences in age-related changes exist between subdivided segments within white matter tracts. The aging processes within the CB and the IFO vary regionally. In study 3, 38 human brains were used for investigation of the white matter tract inferior longitudinal fasciculus (ILF) and its subcomponents. Of these, white matter anatomical dissection was performed in 14 post-mortem normal human brains. The remaining 24 brains were investigated in vivo with diffusion tensor MRI in healthy individuals. It was validated that fibers of the ILF in the occipito-temporal region have a clear, constant and detailed organisation. The anatomical connectivity pattern, and quantitative differences between the ILF subcomponents, confirmed a pivotal role of the ILF. In study 4, 12 patients with iNPH were included in the study and examined with diffusion tensor at three time points. For comparison, 12 healthy controls, matched by gender and age were also included. Controls were examined with MRI only once. It was shown that DTI measures differ significantly between patients with iNPH and healthy controls. DTI measures of the CC, the CST and the SLF, correlated to changes in clinical symptoms after shunt surgery. Deeper knowledge about functions of the brain increases possibilities to take advantages from DTI analyses with tractography.

In der vorliegenden Arbeit wird der Hypothalamus, eine kleine, aber bedeutsame Struktur des Zwischenhirns untersucht. Er spielt unter anderem eine Rolle bei der Regulation des Schlaf-Wach-Rhythmus, des Sexualverhaltens, der Stimmungslage, autonomer und Stoffwechsel-Funktionen. Veränderungen einzelner oder mehrerer spezifischer Kerngruppen sind bei neuropsychiatrischen bzw. -endokrinologischen Erkrankungen, wie Narkolepsie, Schizophrenie, affektiver Störung, Demenz, Borderline-Persönlichkeitsstörung, Pädophilie oder Adipositas zu beobachten. Die Substrukturierung und Darstellung der einzelnen Kerngruppen gelang bisher nur in Postmortem-Studien. Im Rahmen dieser Studie konnte mit Hilfe der Diffusions-Tensor-Bildgebung erstmals eine in-vivo Substrukturierung des Hypothalamus konsistent bei zehn gesunden Probanden vorgenommen werden. Dabei wurden nach einem Algorithmus zunächst die Segmentierung und anschließend die Parzellierung durchgeführt, woraus sich drei konsistente Cluster ergaben. Der topografische Vergleich der erhaltenen Cluster mit Postmortem-Studien der Literatur ergab vergleichbare und anatomisch plausible Korrelate. Mit der von uns entwickelten Methode könnten anhand einer größeren Patientengruppe pathophysiologische Zusammenhänge neuropsychiatrischer und –endokrinologischer Störungen genauer eruiert werden und zu einem besseren Verständnis des Krankheitsverlaufs und der Therapie beitragen.:1 Einleitung 1.1 Topographie und Funktion des Hypothalamus 1.2 MRT- Kartierung des Hypothalamus 1.3 Diffusions-Tensor- Bildgebung 1.3.1 Diffusionsellipsoid 1.3.2 Fraktionelle Anisotropie 1.3.3 Clusteranalyse 1.3.4 k-means- Clusteralgorithmus 1.4 Pathomorphologische Veränderungen des Hypothalamus bei neuropsychiatrischen Erkrankungen 1.4.1 Narkolepsie 1.4.2 Schizophrenie 1.4.3 Affektive Störung 1.4.4 Demenz 1.4.5 Borderline- Persönlichkeitsstörung 1.4.6 Pädophilie 1.4.7 Adipositas 1.4.8 Zusammenfassung 2 Fragestellung: Ist eine Subpartialisierung des Hypothalamus in-vivo mit struktureller Bildgebung möglich? 3 Material und Methoden 3.1 Probanden 3.2 Bilderfassung und -bearbeitung 3.3 Segementierung des Hypothalamus - Definition der ROI`s („region of interest“) 3.3.1 Präoptischer Hypothalamus 3.3.2 Anteriorer Hypothalamus 3.3.3 Tuberaler Hypothalamus 3.3.4 Posteriorer Hypothalamus, Mamillarkörperchen 3.4 Parzellierung und Clusteranalyse 4 Ergebnisse: Mit qualitativen Analysen konnte gezeigt werden, dass eine Subpartialisierung des Hypothalamus möglich ist. 4.1 Segmentierung des Hypothalamus 4.2 Substrukturen/Cluster 5 Diskussion der Ergebnisse 5.1 Neuroanatomie des Hypothalamus 5.1.1 Kerngruppen des Hypothalamus 5.1.2 Faserverbindungen des Hypothalamus 5.1.3 Zusammenfassung der Faserverbindungen der Kerngruppen 5.2 Interpretation der einzelnen Cluster 5.2.1 Anteriore Substruktur 5.2.2 Posteromediale Substruktur 5.2.3 Laterale Substruktur 5.3 Topografische Beziehung der drei Cluster untereinander 5.3.1 Ähnlichkeiten der Cluster der zehn Probanden 5.3.2 Unterschiede der Cluster der zehn Probanden 5.4 Verbesserung der Hypothalamusmaske 6 Zusammenfassung 7 Literaturverzeichnis

Prostatectomy, surgical resection of the whole prostate is a common treatment for high- risk prostate cancer. Common side effects include long-time urinary and or erectile dysfunction due to damage inflicted to periprostatic nerves. The aim of this study was to identify an optimal magnetic resonance diffusion tensor imaging protocol for visualization and quantification of these nerves, as pre-surgery visualization may help nerve-sparing surgery. Both scanner filter, parameters for accelerated scan techniques, diffusion-related acquisition parameters and post- processing tractography parameters were investigated. Seven healthy volunteers were scanned with a state-of-art 3 T MRI scanner with varying protocol parameters. Diffusion data were processed and analysed using Matlab and Explore DTI. The resulting protocol recommendation included a normalized scanner filter, a parallel imaging acceleration factor of 2, partial Fourier sampling of 6/8, a right-left phase encoding direction, a b-value of 600 s/mm2, monopolar gradient polarity with applied eddy current correction, four acquisitions of 12 diffusion- sensitizing gradient directions, and a reverse phase encoding approach for correction of geometrical image distortions induced by static field inhomogeneity. For post-processing tractography, the recommended parameters were a lower limit for fractional anisotropy of 0.05, a minimum tract length of 3 centimetres and a maximum turning angle between voxels of 60 degrees. The limited parameter range that was tested and the low number of volunteers can be regarded as limitations to this study. Future work should address these issues. Furthermore, feasibility of periprostatic nerve tracking with the optimized protocol should be tested in a patient study.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19270号 / 医博第4034号 / 新制||医||1011(附属図書館) / 32272 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 渡邉 大, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: Somatosensory evoked potentials (SSEP) play a pivotal role in the diagnosis and disease monitoring of multiple sclerosis (MS). Delayed latencies are a surrogate for demyelination along the sensory aerence. This study aimed to evaluate if SSEP latencies are representative of demyelination of the brain overall, by correlating with cerebral microstructural integrity as measured by Magnetic resonance (MR) diusion tensor imaging (DTI). Analysis was performed in a hypothesis-free whole brain approach using tract-based spatial statistics (TBSS). Material and methods: A total of 46 patients with MS or clinically isolated syndrome were included in the study. Bilateral SSEPs of the median nerve measuring mean N20 latencies (mN20) and Central Conduction Time (CCT), were acquired. MRI scans were performed at 3T. DTI acquisition was done with a single-shot echoplanar imaging technique with 80 diusion directions. The FSL software package was used to process the DTI datasets and to calculate maps of fractional anisotropy (FA), axial diusivity (AD), and radial diusivity (RD). These maps were then further analyzed using the TBSS module. The mean N20 and CCT and the right- and left-sided N20 and CCT were separately correlated to FA, AD, and RD, controlled for age, gender, and EDSS as variables of non-interest. Results: Widespread negative correlations of SSEP latencies with FA (p = 0.0005) and positive correlations with RD (p = 0.0003) were measured in distinct white matter tracts, especially the optic tracts, corpus callosum, and posterior corona radiata. No correlation with AD was found in any white matter tract. Conclusion: Highly significant correlations of FA and RD to SSEPs suggest that their latency is representative of widespread microstructural change, and especially demyelination in patients suering from MS, reaching beyond the classic somatosensory regions. This points to the usefulness of SSEPs as a non-invasive tool in the evaluation of microstructural damage to the brain.

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