Orientadores: Fernando Cendes, Leonilda Maria Barbosa dos Santos / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T03:48:39Z (GMT). No. of bitstreams: 1 Damasceno_Alfredo_D.pdf: 4121143 bytes, checksum: 3ff224aadab1a5ba6aa115d98a6c533e (MD5) Previous issue date: 2013 / Resumo: A esclerose múltipla (EM) é uma doença inflamatória e desmielinizante do sistema nervoso central que afeta cerca de 2,5 milhões de pessoas em todo o mundo e implica em um importante impacto social e econômico para o estado, resultante de incapacidades funcionais sensitivo-motoras e cognitivas. Nas últimas décadas, o estudo e o entendimento da EM se beneficiaram dos avanços das técnicas de neuroimagem. A Ressonância Magnética (RM) tem sido usada para estudar tanto a história natural da doença quanto para monitorar a eficácia de tratamentos, mas a correlação dos achados da RM convencional com os dados clínicos ainda é insatisfatória. Com isso, tem surgido o interesse em outras técnicas de RM, entre elas a avaliação da substância cinzenta cerebral. Entretanto, apesar dos avanços em neuroimunologia e neuroimagem, ainda existem poucos dados que possam predizer a incapacidade em longo prazo. Com isso, nosso objetivo foi identificar fatores clínicos e de RM relacionados a uma pior evolução clínica em pacientes com EM. Inicialmente nós realizamos um levantamento dos dados de 197 pacientes acompanhados no ambulatório de EM do HC-UNICAMP, levando em conta informações clínicas e epidemiológicas e o tempo que cada paciente levou para atingir escores específicos de incapacidade. Nós observamos que o grupo levou 25,8 anos para atingir o EDSS de 6,0, mas que pacientes do sexo masculino, e principalmente aqueles com surtos frequentes nos primeiros anos e com envolvimento do tronco cerebral ou cerebelo apresentaram uma evolução pior. Posteriormente, estabelecemos um subgrupo menor de pacientes a fim de estudar o comportamento longitudinal da patologia cerebral e sua relação com a incapacidade clínica e cognitiva. Foram acompanhados, durante um período de 24 meses, 43 pacientes com EM forma remitente-recorrente e 29 indivíduos controles, submetidos a exame neurológico, neuropsicológico e RM cerebral. O desempenho nos testes clínicos e neuropsicológicos foi pior no grupo dos pacientes, e 44,2% deles foram classificados como tendo disfunção cognitiva. Um pior desempenho cognitivo estava associado à presença de atividade subclínica da doença na RM, com uma alta carga lesional cortical e com a atrofia do corpo caloso. Além disso, uma maior incapacidade clínica também estava relacionada com estas lesões corticais, tanto cerebrais quanto aquelas presentes no córtex cerebelar. Como a presença de atividade subclínica foi um indicador importante de disfunção cognitiva, foi avaliado em um subgrupo de 15 pacientes a produção de citocinas pró-inflamatórias comparando com os dados de RM. Aqueles pacientes com lesões ativas na RM apresentaram uma produção significativamente maior de citocinas pró-inflamatórias, 10 vezes maior de INF-? e 22 vezes maior de TNF-?. O grupo de 43 pacientes foi acompanhado longitudinalmente e no final de 24 meses a atrofia cortical foi de 2,57% e da substância cinzenta subcortical de 3,8%, ambos significativamente maiores que no grupo controle. A presença de atrofia do tálamo no início estava relacionada a um maior risco de disfunção cognitiva após dois anos. Além disso, a presença de uma alta carga de lesões corticais no início do estudo estava relacionada a um risco 5,14 vezes maior de incapacidade clínica após 24 meses. Pode-se concluir que a substância cinzenta, cortical e subcortical, está difusamente afetada nos pacientes com EM, e que este dano progride consideravelmente em um período de dois anos, com importante impacto clínico e cognitivo / Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects about 2.5 million people worldwide. MS entails a significant economic impact due to both motor and cognitive functional impairments. In recent decades, the study and understanding of MS have benefited from advances in neuroimaging techniques. Magnetic resonance imaging (MRI) has been used to study both the natural history and to monitor the effectiveness of treatments, but the correlation of conventional MRI findings with clinical data is not yet fully satisfactory. Thus, there has been great interest in other MRI techniques, including the assessment of grey matter. Nevertheless, despite advances in neuroimmunology and neuroimaging, there are few data that can predict the long-term disability in MS patients. Therefore, our goal was to identify clinical and MRI factors related to a worse clinical outcome in patients with MS. Initially, we surveyed the data of 197 patients followed in the outpatient clinic of the MS center at UNICAMP University Hospital, gathering clinical and epidemiologic information and the time to achieve specific scores on EDSS disability scale. The median time from onset to the assignment of a disability score of 6 was 25.8 years, but male patients, especially those with frequent relapses in the first years of disease, and with involvement of the brainstem or cerebellum showed a worse outcome. Subsequently, we established a smaller subgroup of patients in order to study the longitudinal behavior of brain pathology as seen by MRI and its relationship to clinical and cognitive disability. We followed for a period of 24 months, 43 patients with relapsing-remitting MS and 29 healthy subjects, who underwent neurological examination, neuropsychological testing and brain MRI. At baseline, performance on clinical and neuropsychological tests was worse in the patients group, and 44.2% were classified as having cognitive dysfunction. Worse performance on neuropsychological battery was associated with the presence of subclinical MRI activity, with a high burden of cortical lesions and atrophy of the corpus callosum. In addition, worse clinical disability was also associated with these cortical lesions, both those in the brain as those present in the cerebellar cortex. As the presence of MRI subclinical disease activity was an important indicator of cognitive impairment, coupled with the fact that there are no strong biological markers so far, we assessed the production of proinflammatory cytokines in a subgroup of 15 patients and compared with MRI data. We found that patients with subclinical active MRI lesions had significantly higher production of proinflammatory cytokines, 10-fold greater in IFN-? and 22-fold in TNF-?. The group of 43 patients was followed longitudinally and after 24 months grey-matter atrophy was 2.57% in the cortex and 3.8% in subcortical structures, both rates significantly higher than in the control group. The presence of thalamus atrophy at the baseline was associated with an increased risk of cognitive dysfunction after 2 years. Furthermore, the presence of a high load of cortical lesions at baseline was related to a 5.14 fold increased risk of clinical disability after 24 months. It can be concluded that both cortical and subcortical grey matter are diffusely affected in MS patients, and that this damage progresses considerably over a period of two years, with important clinical and cognitive impact / Doutorado / Neurologia / Doutor em Ciências Médicas

Orientador: Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T22:39:04Z (GMT). No. of bitstreams: 1 Collin_Greize_M.pdf: 5813301 bytes, checksum: cca632f33b2c0f7db3ef862ea7b00df4 (MD5) Previous issue date: 2012 / Resumo: A depressão tem sido um dos transtornos mentais mais comumente relatados em associação com ELTM, com uma prevalência estimada de 20 a 55%, contra 9% na população em geral, e os aspectos que interagem na associação das epilepsias e da depressão são ainda hoje muito fragmentados, fazendo com que a fisiopatologia da depressão nas epilepsias ainda não esteja inteiramente esclarecida. Sendo assim, o objetivo deste trabalhou foi investigar a associação das alterações volumétricas das amígdalas, hipocampos e tálamos em pacientes com ELTM e depressão, e também correlacionar os dados volumétricos obtidos com os dados clínicos de cada paciente, como frequência de crises e intensidade de sintomas depressivos mensurados através do BDI. Para isso, foram adquiridas imagens de RM em 4 grupos de 20 indivíduos cada: Grupo ED: pacientes com ELTM e depressão; Grupo E: pacientes com ELTM; Grupo D: pacientes com depressão e o Grupo C: controles saudáveis. A segmentação das Amígdalas, Hipocampos e Tálamos foram realizadas através do software DISPLAY, de acordo com protocolos específicos para cada estrutura. Também avaliamos o Índice de Assimetria (IA), que é a razão entre o volume do menor/maior lado apresentado por cada estrutura. O diagnóstico para o transtorno depressivo foi realizado através de avaliação neuropsicológica de acordo com os critérios do DSM-IV aplicando a SCID-I. O Inventário para Depressão de Beck (BDI) foi utilizado para mensurar a intensidade dos sintomas depressivos. Para a análise estatística, foi utilizado o programa SYSTAT 9®, com os testes de ANOVA, Teste-t de Student e correlação de Spearman. Foram incluídas neste estudo 80 mulheres com idade média ± desvio padrão 40±9,4 anos. Comparamos as médias dos volumes absolutos corrigidos da AD (t=5,552, p=0,002) e AE (t=14,571, p<0,0001) entre os grupos, e observamos que os grupos C e E apresentaram diferença significativa em relação à AD (p=0,004) e AE (p<0,0001). Já nos grupos D e E, houve diferença significativa apenas na AE (p<0,0001). Nos grupos E e ED, encontramos diferença significativa em relação a AD (p=0,004) e AE (p<0,0001). Não houve diferença significativa em relação à média dos volumes corrigidos do HD (F= 0,461, p=0,711) e HE (F=2,329, p=0,081) e dos TD (F=0,786, p=0,505) e TE (F=0,492, p=0,689) entre os grupos. Em relação aos IAH (t=9,793, p<0,0001), somente os grupos C e E (p=0,001), C e ED (p=0,001), D e E (p=0,004) e D e ED (p=0,003) revelaram assimetria significativa. Em relação ao IAT (t=2,483, p=0,067) encontramos assimetria significativa somente entre os grupos E e ED (p=0,039). Não houve diferença significativa referente ao IAA entre os grupos. Observamos correlação positiva entre frequência de crises e escore do BDI (rs=0,481), em que a média da frequência mensal de crises foi maior para o grupo com ELTM associada à depressão (7,45±8,28) do que para o grupo somente com ELTM (3,05±2,85), havendo uma diferença significativa entre os grupos (t=-2,245, p=0,031). Nós concluímos que não houve relação significativa entre o grau de atrofia das estruturas límbicas e a presença de transtorno de humor em pacientes com ELTM. Entretanto, nossos resultados indicaram que a frequência de crises está relacionada à gravidade dos sintomas depressivos nos pacientes com ELTM / Abstract: Depression has been one of the most commonly related mental disorders associated with MTLE, reaching approximately 20% to 55% of the cases, whereas its prevalence is 9% in the general population. Since the aspects that interact in the association MTLE-depression are still quite fragmented, the physiopathology of depression in MTLE is not fully understood. This study has the aim of investigating the association of volumetric differences of amygdala, hippocampus and thalamus in MTLE and depressed patients, as well as correlating these with each patient's clinical data (such as seizure frequency and intensity of depressive symptoms). Magnetic Resonance images were acquired in 4 groups of 20 patients each: group ED - patients with MTLE and depression; group E - patients with MTLE; group D - patients with depression; and group C - healthy controls. The segmentation of amygdala, hippocampus and thalamus was performed using DISPLAY software, according to protocols validated by our group. We evaluated the asymmetry index (AI), which represents the ratio between the smallest and the largest side of each structure. The diagnosis for depressive disorder was performed in accordance with DSM-IV criteria obtained through the SCID-I applied by a trained professional. To measure the intensity of depressive symptoms we used Beck Depression Inventory (BDI), and SYSTAT 9®, ANOVA, Student's t-test and Spearman correlation for statistical analysis. 80 women with mean age of 40 years (SD=9.4) were analyzed. We compared the mean absolute volumes of RA (t=5.552, p=0.002) and LA (t=14.571, p<0.0001) between groups, and observed there was a significant difference between groups C and E related to RA (p=0.004) and LA (p<0.0001). Regarding groups D and E, there was a significant difference only in AE (p<0.0001), and groups E and ED in AD (p=0.004) and AE (p<0.0001). There was neither significant difference between RH (F= 0.461, p=0.711) and LH (F=2.329, p=0.081) mean volumes nor RT (F=0.786, p=0.505) and LT (F=0.492, p=0.689) between groups. In relation to HAI (t=9.793, p<0.0001), only the groups C and E (p=0.001), C and ED (p=0.001), D and E (p=0.004) and D and ED (p=0.003) presented a significant asymmetry. Concerning TAI (t=2.483, p=0.067), we found significant difference only between groups E and ED (p=0.039) and we did not find difference of AAI between any groups. We observed a positive correlation between BDI scores and seizure frequency (rs=0.481), in which the average monthly seizure frequency was higher (t=-2.245, p=0.031) for the ED group (7.45±2.85) than E group (3.05±2.85). It is concluded that there was no significant relationship between the degree of atrophy of limbic structures and the presence of mood disorder in patients with MTLE. However, our results indicate that seizure frequency is related to severity of depressive symptoms in patients with MTLE / Mestrado / Fisiopatologia Médica / Mestre em Ciências

Abstract Eddy currents and susceptibility differences are the most important sources that interfere with the quality of MR images in the presence of an artificial macroscopic object in the volume to be imaged. In this study, both of these factors have been examined. The findings show that the RF field is the most important cause of induced eddy currents when gradients with relatively slow slew rates are used. The induced eddy currents amplify or dampen the RF field with the result that the flip angle changes. At the proximal end in the vicinity of the hip prosthesis surface, there have been areas where the flip angle is nearly threefold compared to the reference flip angle. Areas with decreased flip angles have also been found near the surface of the prosthesis top. The incompleteness of the image due to eddy currents manifests as signal loss areas. Two different methods based on MRI were developed to estimate the susceptibility of a cylindrical object. One of them is based on geometrical distortions in SE magnitude images, while the other takes advantage of phase differences in GRE phase images. The estimate value of the Profile™ test hip prosthesis is χ = (170 ± 13) 10-6. A remapping method was selected to correct susceptibility image distortions. Correction was accomplished with pixel shifts in the frequency domain. The magnetic field distortions were measured using GRE phase images. The method was tested by simulations and by imaging a hip prosthesis in a water tank and in a human pelvis. The main limitations of the method described here are the loss of a single-valued correction map with higher susceptibility differences and the problems with phase unwrapping in phase images. Modulation transfer functions (MTF) were exploited to assess the effect of correction procedure. The corrected image of a prosthesis in a human hip after total hip arthroplasty appears to be equally sharp or slightly sharper than the corresponding original images. The computer programs written for this study are presented in an appendix.

Abstract Magnetic resonance imaging (MRI) provides important information about structural and biochemical changes in organs. MRI is also an effective imaging method for the evaluation of spinal disorders. However, many of its potential applications - particularly diffusion imaging - have not yet been thoroughly explored. The purpose of this study was to determine the MRI-detectable changes in the intervertebral disc after trauma and to test the feasibility of diffusion-weighted MR imaging of the intervertebral discs. A minipig model was used in the experimental study to determine the MRI changes in the intervertebral disc after peripheral annular lesions in different time frames. Three of eight discs with experimental annular lesions had a normal annular appearance in MRI. Annular lesions, when detectable, were manifested as a bulging of the disc or as a high-intensity zone (HIZ) inside the annulus. Either the signal intensity or the area of bright signal intensity in the nucleus had nearly always decreased after one month, but they were still detectable even in cases where no signs of annular trauma could be seen in the MR images. The histology of HIZ is presented for the first time: clusters of nuclear cells and disorganized granulation tissue with capillaries were detected in the HIZ area. Fourteen patients 8 to 21 years of age with histories of vertebral fracture at least one year previously and 14 asymptomatic healthy control subjects 8 to 22 years of age were studied by MRI. In these young people a vertebral fracture, especially with end-plate injury, proved to be a notable risk factor for initiating disc degeneration. The apparent diffusion coefficients (ADCs) of the thoracolumbar intervertebral discs were determined in three orthogonal directions in 18 healthy young volunteers aged 8-22 years. The ADCs were also determined in 10 young patients with previous vertebral fractures, and clear decreases were found in the ADCx and ADCy directions, but in the ADCz direction values had not changed significantly as compared to the values in the controls. The most marked changes were observed in the degenerated discs, followed by those in the discs with a normal signal intensity adjacent to the primary trauma area. Diffusion-weighted MR imaging affords a useful tool for evaluating disc diseases in the early phases. Additionally, 37 adult volunteers without back symptoms were studied by MRI and by magnetic resonance angiography (MRA) and it was found that the status of the lumbar arteries significantly explained the diffusion values in the lumbar intervertebral discs. The correlation between disc degeneration and diffusion was mostly linear, but not significant.

Philosophiae Doctor - PhD / Lumbo-sacral radiculopathy (LSR) is clinically defined as low back and referred leg symptoms accompanied by an objective sensory and/or motor deficit due to nerve root compromise. LSR is a common condition encountered by physiotherapists in clinical practice and the assessment and diagnosis remains a challenge owing to the complex anatomy of the lumbo-sacral spine segment and the various differentials. Moreover, LSR imposes a significant impact on patients’ health, functional ability, socio-economic status and quality of life. There are several diagnostic tools and procedures which are commonly utilised in practice, including diagnostic neuropathic pain screening questionnaires, clinical neurological tests, electro-diagnostics and imaging. However, the diagnostic utility and correlation of these tests have not been fully explored and remains debatable among clinicians and researchers in the fields of musculo-skeletal health and neurology. The aim of this study was to determine a correlation of the S-LANSS score, clinical neurological examination (CNE) findings and magnetic resonance imaging (MRI) reports in the diagnosis of LSR among patients who presented with low back and referred leg symptoms. The study was conducted in three phases. In phase one, two systematic literature reviews were conducted; firstly, to establish the evidence-based accuracy of CNE in diagnosing LSR, and secondly, to establish the evidence-based accuracy of MRI in diagnosing LSR. In both systematic literature reviews, the diagnostic tests accuracy (DTA) protocol was used in planning, design and execution of literature search, selection of relevant studies, quality assessment, data analysis and presentation of the results. In phase two, clinical validation of an adopted S-LANSS scale and lumbar MRI reporting protocol were established, and a standardised evidence based lumbar CNE protocol developed.The face and content validity of the original S-LANSS score was established among a sample of Kenyan physiotherapists and patients who presented with low back and referred leg symptoms, using both quantitative and qualitative research designs. This was followed by a test-re-test reliability study on the adapted version of the S- LNASS score. The face and content validity of the adopted lumbar MRI reporting protocol was established among a sample of Kenyan radiologists followed by an inter-rater reliability. An evidence-based lumbar CNE protocol was developed; standardised and inter-examiner reliability was also examined among a sample of Kenyan physiotherapists. Finally, in phase three, a cross-sectional blinded validity study was conducted in six different physiotherapy departments. Participants (patients, physiotherapists and radiologists) were recruited using strict in- and exclusion criteria and data was collected using a pain and demographic questionnaire, the S-LANSS scale, the CNE protocol, the Oswestry Disability Index (ODI) and the MRI lumbar spine reporting protocol. Data was captured, cleaned and analysed using SPSS version 21. Descriptive analysis was done using frequencies, means and percentages, while inferential analysis was conducted using Spearman’s rank correlation coefficient test r to establish the correlation between the diagnostic tests. Cross tabulations, receiver operating curves (ROC) and scatter plots were used to establish the sensitivity and/or specificity of S-LANSS scale and individual CNE tests as defined by MRI. In phase three, which formed the main study of the research project, a total of 102 participants were recruited in this study with a gender distribution of 57% females and 43% males. The majority (67%) had neuropathic pain according to the S-LANSS scale and their pain intensity ranged from moderate (4-6) to severe (7-9) as recorded on a Numeric Pain rating Scale (NPRS), and was more common among manual workers. Similarly, patients whose pain had a neuropathic component had moderate to severe disability. The S-LANSS scale and lower limb neuro-dynamic tests were the most sensitive tests 0.79 and 0.75 respectively, while deep tendon reflexes were the most specific tests (0.87). The S-LANSS and CNE correlated fairly but significantly with MRI (r=0.36, P=0.01).LSR is a common condition and its assessment and diagnosis remains a clinical challenge among physiotherapists. MRI is a high-cost diagnostic tool but is being used by many clinicians in making decisions regarding the management of patients. Rapid and low-cost neuropathic pain screening by the use of the S-LANSS scale, together with use of evidence-based CNE of neuro-conduction and neuro-dynamic tests may be used in confirming nerve-root related MRI findings. These may be used in making a decision on whether to manage a patient conservatively using pharmacological agents and manual physiotherapy and therapeutic exercise, or consider surgery in the initial management of patients with clinical suspicion of LSR. This is especially valuable in the resource-poor settings like Kenya and other sub-Saharan African countries where MRI is costly or unavailable.

No description available.

Glioblastoma is the most common primary brain tumor in adults, and it is associated with a dismal prognosis with a median survival of 15 months. Despite treatment with chemotherapy, radiation therapy and surgery, patients inevitably have disease recurrence. Bevacizumab is a monoclonal humanized antibody that inhibits vascular endothelial growth factor signaling, and it has been shown to be effective in recurrent glioblastoma with respect to prolonging progression-free survival (PFS). The use of bevacizumab and other anti-angiogenic agents in recurrent glioblastoma have created novel challenges in interpreting magnetic resonance imaging (MRI) of patients. Furthermore, since only some patients appear to have a durable benefit from bevacizumab, there is a need for imaging biomarkers that can reliably identify this subgroup of patients. Partly due to the challenges created by anti-angiogenic agents, the Response Assessment in Neuro-Oncology (RANO) was proposed to address some of the limitations with traditional response assessment criteria. In the first part of this project, we attempted to validate the RANO criteria by performing a comparative analysis of the RANO criteria vs. the Macdonald criteria using imaging from the phase II BRAIN trial. As we hypothesized, the RANO criteria yielded a significantly decreased PFS by identifying a subset of patients who had progression of nonenhancing tumor evident on T2-weighted imaging. Additionally, response and progression as defined by the RANO criteria correlated with subsequent overall survival (OS) in landmark analyses. While this supports the implementation of RANO criteria for response assessment in glioma clinical trials, future research will be necessary to further improve response assessment by incorporating advanced techniques such as volumetric anatomic assessment, perfusion-weighted MR (PWI-MR), diffusion-weighted MR (DWI-MR), MR spectroscopy (MRS) and positron emission tomography (PET). Advanced imaging techniques are becoming increasingly recognized for their ability to provide objective, non-invasive assessment of treatment response but also to serve as predictive and prognostic biomarkers allowing for stratification of patient subgroups with better treatment outcome. In the second part of the project, we attempted to perform volumetric analysis of tumor size based on conventional MRI, as well as a histogram analysis of apparent diffusion coefficients (ADC) derived from diffusion-weighted MRI, to evaluate imaging parameters as predictors for PFS and OS in a single institution database of recurrent glioblastoma patients initiated on bevacizumab. Volumetric percentage change and absolute early post-treatment volume (3-6 weeks after initiation) of enhancing tumor can stratify survival for patients with recurrent glioblastoma receiving bevacizumab therapy. ADC histogram analysis using a multi-component curve-fitting technique within both enhancing and nonenhancing components of tumor prior to the initiation of bevacizumab can also be used to stratify OS in recurrent glioblastoma patients. While prospective studies are necessary to validate findings, future studies will increasingly incorporate multiparametric approaches to elucidate biomarkers that combine the value of conventional MRI with advanced techniques such as DWI-MR, PWI-MR, MRS and PET to obtain better predictors for PFS and OS in recurrent glioblastoma.

By sensitising the magnetic resonance signal to the diffusion of water molecules in tissue, diffusion-weighted magnetic resonance imaging provides a means of assessing tumour microstructure non-invasively. Such measurements have the potential to provide important information about tumour development and the response of tumours to treatment, but the way in which different tissue properties affect the diffusion-weighted signal remains unclear. Through simulations, in vivo studies and phantom experiments, this thesis investigates the relationship between the diffusion-weighted signal, the pulse sequence parameters used for acquisition, and microstructural properties of tumours. The use of oscillating gradient pulse sequences on a clinical scanner was investigated initially, with theoretical and practical considerations leading subsequent work to focus on pulsed gradient sequences. The forward problem of predicting the diffusion-weighted signal for given combinations of tissue properties and sequence parameters was addressed numerically through Monte Carlo simulations, focussing on how tumour cell size, intracellular volume fraction and membrane permeability affect the signal. These simulations allowed the sensitivity of the signal to changes in these tissue properties to be investigated, revealing how sensitivity depends on sequence parameters as well as the specific microstructural configuration. By repeating the simulations using the specific sequence parameters used in a clinical and preclinical study, the sensitivity of the implemented protocols was assessed, and linked to the experimental findings. The preclinical study illustrated the importance of the diffusion time in determining the sensitivity to treatment-induced changes in tumours, with larger post-treatment signal changes observed at longer diffusion times. These trends were qualitatively reflected in the sensitivity analysis derived from the simulations. Finally, the inverse problem of estimating microstructural properties from the diffusion-weighted signal was addressed using a physical phantom designed as a simple mimic of tumour tissue. By fitting a biophysical model to the diffusion data, the size and volume fraction of the approximately spherical 'cells' were estimated. The radius was slightly underestimated compared with that determined from independent measurements, the fitted volume fraction was plausible, and parameters were found to be estimated with reasonably good precision.

It was hypothesized that superparamagnetic nanoparticles encapsulated in a silica shell with a fluorescent dye could be functionalized with axonal tracers and could be used for serial, non-invasive imaging with magnetic resonance imaging (MRI) for axon tract tracing. Nanoparticles functionalized with amine, octadecyl, silica, and biotinylated dextran amine were manufactured and characterized with MRI, scanning electron microscopy, and UV-visible, infrared, and fluorescence spectroscopy. Nanoparticle concentrations of 10 mM were not toxic to adult rat neural progenitor cells (NPCs) and labeled approximately 90% of cells. Nanoparticles were assessed for anterograde and retrograde tract tracing in adult rat models. With MRI and microscopy, the nanoparticles did not appear to trace axons but did provide an MRI signal for up to 3 weeks post implantation. While functionalized nanoparticles did not appear to trace axons, they are not toxic to NPCs and may be used as a MRI contrast agent in the neural axis.

Problems with the low back resulting from diseases of the lumbar disc account for much human suffering and medical expense. Through early identification of changes in the disc, Magnetic Resonance Imaging offers a potential method for recognition of those at risk of low back trouble. An understanding of the chemical and structural basis of the MR image will therefore be of great help in understanding the degenerative mechanism itself. With this in mind, NMR studies of human intervertebral discs were performed to extract data that could be correlated with different stages of degeneration. In vitro samples of anulus fibrosus and nucleus pulposus of grades II and IV discs were examined. The Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence was used to obtain T₂ relaxation data, which were analysed with a non-negative least squares algorithm and presented as a continuous spectrum of exponentials. An inversion-recovery sequence was used to obtain T₁ data which were analysed with the same algorithm, then presented as a discrete exponential spectrum. The same procedures were used to produce relaxation times from samples of isolated disc collagen and proteoglycan. Also, T₂ relaxation data were obtained with a twelve-echo CPMG imaging sequence from healthy volunteers, and these data analysed with the same procedure used for in vitro data. In vivo and in vitro results were compared and found to agree in terms of the T₂ relaxation values. Most change between grades occurred in the nucleus, where both T₁ and T₂ values decreased from grade II to grade IV. The results of the proteoglycan and collagen studies support the theory that structure, not chemical composition, is responsible for the observed changes in relaxation times. Based on estimates of the percentages of protons in the nucleus due to water, proteoglycan and collagen, tentative assignments were made to the components of the T₂ spectra for grades II and IV nucleus, and these were supported by the results of all parts of the study. / Science, Faculty of / Physics and Astronomy, Department of / Graduate