Abstract Collagen XVIII is a multidomain basement membrane proteoglycan with three tissue-specific isoforms. Endostatin, the C-terminal part of collagen XVIII, has antiangiogenic properties, while the frizzled-like domain of the longest isoform is suggested to be capable of inhibiting the Wnt/β-catenin signaling network. This study utilized several genetically modified mouse lines and electron microscopy to achieve new information on the biological role of collagen XVIII, its different isoforms, and the frizzled domain. Lack of collagen XVIII was found to affect the integrity of basement membranes of various tissues, leading to an abnormally loosened network structure. In the choroid plexus, the change in the basement membrane ultrastructure caused alterations in the production of the cerebrospinal fluid and predisposed to the development of hydrocephalus. In the kidney, broadening of the proximal tubular basement membrane was shown to be due specifically to the lack of the short isoform, while the lack of the two longer isoforms led to podocyte foot process effacement. Moreover, lack of collagen XVIII was found to cause softening of the kidney glomeruli and the levels of serum creatinine were elevated in the mutant animals, indicating altered kidney function. The hair follicle cycle was used as a model to study the possible role of the frizzled domain of collagen XVIII in the Wnt/β-catenin signaling cascade. The longer collagen XVIII isoforms were shown to be expressed in the basement membrane facing the dermal papilla and in the hair follicle bulge, containing the follicular stem cells. Lack of the long isoforms led to abnormalities in the progression of the first hair cycle, and the phenotype could be rescued via transgenic delivery of the frizzled domain of the longest isoform, suggesting its involvement in the regulation of the Wnt/β-catening signaling network during the cyclic growth of the hair. / Tiivistelmä Kollageeni XVIII on useista toiminnallisista osista koostuva tyvikalvojen proteoglykaani, jolla on kolme eri kudoksissa esiintyvää isomuotoa. Sen C-terminaalisella endostatiini-osalla on verisuonten kasvua estäviä vaikutuksia, kun taas pisimmän isomuodon frizzled-osan uskotaan estävän Wnt/β-kateniini signalointireitin toimintaa. Tässä tutkimuksessa saatiin uutta tietoa kollageeni XVIII:n, sen eri isomuotojen sekä frizzled-osan biologisesta merkityksestä useiden geenimuunneltujen hiirimallien sekä elektronimikroskopian avulla. Kollageeni XVIII:n puutoksen todettiin vaikuttavan tyvikalvojen rakenteen eheyteen useissa eri kudoksisssa, johtaen epänormaalisti löyhtyvään verkkorakenteeseen. Suonipunoksessa tämä tyvikalvon hienorakenteen muutos vaikutti aivo-selkäydinnesteen tuottumiseen ja altisti vesipään kehittymiselle. Munuaisessa proksimaalisen munuaistiehyen tyvikalvon levenemisen osoitettiin johtuvan lyhyen isomuodon puutoksesta, kun taas kahden pidemmän isomuodon puuttuminen aiheutti podosyyttien jalkalisäkkeiden leviämistä. Lisäksi kollageeni XVIII:n puuttumisen osoitettiin johtavan hiirimallien munuaiskerästen pehmenemiseen sekä veren kreatiniinitason kohoamiseen, viitaten munuaistoiminnan häiriöihin. Karvatuppien syklistä kasvua käytettiin mallina tutkittaessa kollageeni XVIII:n frizzled-osan mahdollisia vaikutuksia Wnt/β-kateniini signalointireittiin. Pidempien kollageeni XVIII isomuotojen osoitettiin tuottuvan karvanystyn tyvikalvossa sekä karvatupin kantasolut sisältävällä pullistuma-alueella. Pitkien isomuotojen puuttuminen johti karvojen ensimmäisen kasvukierron epänormaaliin etenemiseen. Tämä voitiin estää siirtogeenisen frizzled-osan avulla, mikä viittasi sen osallisuuteen Wnt/β-kateniini signalointireitin säätelyyn karvan syklisen kasvun aikana.

<p>Hydrocephalus is a neurological disease characterized by abnormal accumulation of cerebral spinal fluid (CSF) in ventricle of brain. 1 in 1000 newborns are affected each year and it is life-threatening if left untreated. The golden standard of treatment is to surgically implant a shunt that divert excessive CSF away from ventricle to alleviate intraventricular pressure (ICP) in patient. Unfortunately, shunt failure rate is notoriously high because of obstruction of catheter intake pore. The obstruction is primary caused by normal and inflammatory tissue (biofilm) buildup over time. Shunt replacement surgery is typically required after only 1 year of implantation for 40% of patients. To prolong the lifespan of hydrocephalus shunt, we previously proposed and designed magnetic micro-actuators platform to remove biofilm mechanically. Removal of muscle cells and microbeads were demonstrated from wafer level devices on bench-top.</p><p> </p><p>To examine device efficacy in ventricular catheter, I developed magnetic actuator on polymer substrate. First, polyimide based flexible thin-film devices were microfabricated and integrated into a single-pore silicone catheter. A proof-of-concept self-clearing smart catheter was presented. Removal of microscopic biofilm was evaluated against bovine serum protein (BSA). Detachment of BSA up to 95% was achieved by shear stress from magnetic actuation. Next, I developed resistive deflection sensing using a metallic strain gauge, allowing device alignment with magnetic field for maximum energy delivery. In addition, auxiliary functionalities such as occlusion detection and flow rate measurement were demonstrated on catheter. Moreover, a new serpentine cantilever geometry with increased magnetic volume was proposed for improved delivery of torque and deflection. In a benchtop evaluation, we showed prolonged catheter drainage (7x) in a dynamic fluid environment containing macroscopic blood clots. Finally, using an intraventricular hemorrhage (IVH) porcine model, we observed that self-clearing catheter had longer survival than control catheter (80% vs. 0%) over the course of 6 weeks. Animals treated with magnetic actuation had significantly smaller ventricle size after 1 week of implantation.</p>

The aim of the study was to evaluate the importance of brain MRI's findings, and modify the criteria for brain MR imaging in NF1 patients according to this data, to improve the quality of life with early detection of important NF1 complications. Description of the whole cohort, with emphasise to possible cause of high range of sporadic NF1 cases. Evaluation the possibility diagnosis or follow up of brain gliomas by plasmatic values of neuron specific enolase (NSE) and S100B protein. Subjects and methods: I analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery. I evaluated the incidence of brain MRI findings, clinical development, age at gliomas manifestation and necessity of treatment. I also described the whole cohort and made statistic analysis of plasmatic values of NSE and S100B protein in NF1 patients, with and without brain gliomas. Results: OPGs were found in 77/285 (27 %) children and GOOPs in 29/285 (10.2 %) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30.5 %). Totally, 43/87 (49.4 %), respectively 43/285 (15.1 %) children with brain glioma were treated, and 4/285 (1.4 %) of this children died. Obstructive hydrocephalus was found in 22/285 (7.7 %) patients and was caused...

Despite decades of research of normal pressure hydrocephalus (NPH), a clear pathophysiological mechanism of the disease is sill unknown. This results in the absence of a unambiguous diagnostic biomarker. Moreover, NPH in contrast to similar neurodegenerative diseases is curable by insertion of a ventrikulo-peritoneal shunt. Now the diagnostics is based on invasive functional testing, on the contrary, imaging methods play only a supporting role. This work is processed with an effort to find a sufficiently sensitive and specific biomarker of MRI imaging using advanced analytical methods. For this reason, the structural volumetry and the phase contrast method were tested. The individual partial results of both of these modalities have already been described in the literature, but the conclusions were controversial. The main contribution of this work is the range of tested parameters and their to date untested advanced analysis - accurate automatic segmentation in volumetric study and machine learning algorithms in phase contrast study. In a volumetric study, we segmented a total of 26 structures in 74 patients (29 with diagnosed NPH, 45 without NPH). In the case of preoperative examination, we demonstrated statistically significant differences in the size of the left hippocampus, corpus callosum, left...

This work aims to contribute to the lack of computational methods for medical image analysis and diagnosis about the study of cerebrospinal fluid volumes. In the first part, we focus on the volume assessment of the fluid spaces, from whole body images, in a population consisting of healthy adults and hydrocephalus patients. To help segmentation, these images, obtained from a recent "tissue-specific" magnetic resonance imaging sequence, highlight cerebrospinal fluid unlike its neigh borhood structures. We propose automatic segmentation and separation methods of the different spaces, which allow efficient and reproducible quantification. We show that the ratio of the total subarachnoid space volume to the ventricular one is a proportionality constant for healthy adults, to support a stable intracranial pressure. However, this ratio decreases and varies significantly among patients suffering from hydrocephalus. This ratio provides a reliable physiological index to help in the diagnosis of hydrocephalus. The second part of this work is dedicated to the fluid volume distribution analysis within the superior cortical subarachnoid space. Anatomical complexity of this space induces that it remains poorly studied. We propose two complementary methods to visualize the fluid volume distribution, and which both produce two-dimensional images from the original ones. These images, called relief maps, are used to characterize respectively, the fluid volume distribution and the fluid network, to classify healthy adults and patients with hydrocephalus, and to perform patient monitoring before and after surgery

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.

Structural and diffusion imaging patterns that can be evaluated using MRI in patients with cognitive deficits are the central theme of the proposed work. First, the clinical and neuroimaging background of dementias has been reviewed in a broader context, with a special focus on Alzheimer's disease (AD) and differential diagnoses. The second part of this thesis contains four consecutive experimental studies. The primary objective of the first two studies was to obtain structural and microstructural information on the neurodegenerative processes characteristic for AD on global and regional levels. For this purpose, several complementary approaches were used and the focus was shifted from grey to white matter (GM/WM). The following two studies focused on the differential context of WM microstructural alterations in normal pressure hydrocephalus (NPH) and distinctive patterns of WM disintegrity in temporal lobe epilepsy (TLE). The most important conclusion of our studies is that structural and diffusion imaging proved to be useful in identifying regionally specific and disproportionate loss of brain volume and microstructure in several pathological processes underlying cognitive deterioration. The use of distinctive morphometric methods yielded complementary information on AD-related atrophy patterns,...

O presente estudo validou para a Língua Portuguesa a escala de graduação do paciente com hidrocefalia de pressão normal (HPN) desenvolvida na Língua Inglesa como \"Grading scale for idiopathic normal pressure hydrocephalus\". Duas traduções independentes da escala de HPN foram feitas por médicos brasileiros, fluentes na Língua Inglesa. Após harmonização dessas, a tradução resultante foi retrotraduzida independentemente por dois outros médicos, que desconheciam a escala original. Seguiu-se a última tradução e revisão para a Língua Portuguesa por uma profissional tradutora da área da saúde. A comparação da versão final traduzida com a escala original foi realizada pelo comitê multiprofissional que não estava envolvido no processo de tradução, pontuando-se para item distúrbio de marcha: 0 ausente; 1 marcha instável, mas independente; 2 anda com um apoio; 3 anda com 2 apoios ou andador e 4 não é possível andar. No item demência: 0 ausente; 1 sem demência aparente, mas apático; 2 socialmente dependente, mas independente na residência; 3 parcialmente dependente na residência e 4 totalmente dependente. Incontinência Urinária: 0 ausente; 1 ausente, mas com polaciúria ou urgência miccional; 2 às vezes, apenas à noite e 4 frequente. Para obtenção da pontuação final, devem-se somar os itens, sendo que, quanto maior o escore final, maior comprometimento do paciente. O resultado foi pré-testado em um estudo-piloto. A versão final da escala de HPN para o Português, bem como as escalas de equilíbrio de Berg, índice de marcha dinâmica e \"timed up and go\" foram aplicadas simultaneamente em cento e vinte e um pacientes consecutivos com diagnóstico médico de hidrocefalia de pressão normal (setenta e três homens e quarenta e oito mulheres) que procuraram o Ambulatório de Hidrodinâmica Cerebral, da Divisão de Neurocirurgia Funcional do Instituto de Psiquiatria do Hospital das Clínicas de São Paulo da FMUSP, no período de julho de 2010 a março de 2012. Foram testadas as propriedades psicométricas do questionário, como confiabilidade e validade. A idade mediana foi de 71,09 anos (intervalo de 35 a 92 anos). O período médio de reteste para a escala de HPN foi de sete dias. Nenhuma alteração do formato original da escala foi observada no final do processo de tradução e adaptação cultural. O grau de concordância e reprodutividade foi alta, como demonstrado pela medida de concordância Kappa, com excelente correlação intraobservador para itens da escala de HPN individualmente avaliados: marcha (0,8), demência (0,90) e incontinência (0,87). Na análise interobservador, o resultado foi excelente, com item marcha (0,91), demência (0,86) e incontinência (0,87). A correlação entre a escala de HPN com as demais escalas foi considerada de moderada a satisfatória para a maioria dos itens, variando de -,069 a 0,55 na correlação de Pearson. A avaliação individual entre escalas sobre os itens incontinência urinária, demência e marcha foram também satisfatórias e estatisticamente significantes. A versão para o Português da escala de graduação do paciente com HPN foi traduzida e validada com sucesso para aplicação em pacientes brasileiros de ambos os sexos, apresentando satisfatória confiabilidade e validade / The current study validated to Portuguese language the graduation scale for patients with normal pressure hydrocephalus (NPH) developed on English language as \"Grading scale for idiopathic normal pressure hydrocephalus\". Two translations independent of NPH scale were done by Brazilian doctors, fluent on English language. After harmonization of both, the resulting translation was back-translated independently by two other doctors, that unaware to the original scale. Followed the last translation and revision to Portuguese language by a professional translator of health area. The comparison of last translated version with original scale was performed by one multiprofessional committee not involved on translation process. Was established specific punctuation to components of NPH classical triad, the punctuation to gait: 0 absent; 1 unstable gait, but independent; 2 walk with a support; 3 walk with 2 supports or walker an 4 is not possible to walk. On dementia item: 0 absent; 1 without apparent dementia, but apathetic; 2 socially dependent, but independent on resistance; 3 partial dependent on resistance and totally dependent. Urinary incontinence: 0 absent, 1 absent but with pollakisuria or urinary urgency, 2 sometimes, just at night; 3 sometimes even during the day and 4 frequently. The obtained final punctuation was given by summation of three items, and the higher the final punctuation, greater involvement of the patient. The result was pre-tested in a pilot study. The last version of NPH to Portuguese, as well the Berg balance scales, Dynamic Gait Index and \"timed up and go\" were applied simultaneously in 121 consecutive patients with medical diagnostic of normal pressure hydrocephalus (73 men and 48 women) who sought the Ambulatory of Cerebral Hydrodynamics, Division of Functional Neurosurgery, Institute of Psychiatry, Hospital das Clínicas in Sao Paulo from FMUSP, on period July / 2010 to march / 2012. The psychometric properties, reliability and validity of questionnaire were tested. The mean age was 71,09 years, ranging from 35 to 92 years. The period of mean retest was 7 days. None change to the original format of the scale was observed at the end of the translation process and cultural adaptation. The rate of agreement and reproducibility was high, as confirmed by measure of agreement of Kappa, with excellent intra-observer correlation for NPH scale items individually evaluated: gait (0,80), dementia (0,90) and incontinence (0,87). The correlation between the NPH scale with the other scales was considered moderate to satisfactory for most items, ranging from - 069 to 0.55 in Pearson correlation. The individual evaluation between scales on the items on urinary incontinence, dementia and gait were also satisfactory and stistically significant. The Portuguese version of the graduation scale for patients with NPH was successfully translated and validated for use in Brazilian patients of both genders, with satisfactory reliability and validity

The purpose of this thesis is to explore the diverse experiences of accessing health and social services when living with a neurological condition in Manitoba. Using a qualitative research design, I conducted 15 in-depth semi-structured interviews with adults living with a neurological condition in Manitoba. Findings demonstrated how characteristics of patients, and their service providers/systems, either predisposed them to a lack of service coordination or enabled them to successfully navigate health and social services. In the event that those factors contributed to a need or desire for coordination, participants employed strategies to improve their experience accessing services by i. pursuing knowledge to improve access, ii. actively engaging in behaviours to improve services, or iii. mentally coping with inadequate services. To conclude, practical recommendations on possible initiatives to improve the daily experiences of individuals living with neurological conditions are also provided. / October 2015

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