Introdução: As leucoencefalopatias constituem um vasto grupo de doenças que desafiam a equipe médica. Dentre elas, a doença da Substância Branca Evanescente, é uma das mais comuns, com destaque nos últimos anos pelo significativo avanço na caracterização de suas bases clínicas, moleculares e de imagem. O fenótipo típico tem início dos 2 aos 6 anos, marcado por declínio neurológico crônico e progressivo, com episódios de deterioração desencadeados por trauma ou infecção, que podem levar a coma e até óbito. Essa é uma desordem genética, autossômica recessiva, relacionada a mutações nos genes que codificam o fator iniciador de tradução dos eucariontes 2B (eIF2B), complexo responsável por coordenar a tradução do RNA em proteína. As características típicas na Ressonância Magnética (RM) encefálica, com padrão de acometimento difuso da substância branca e degeneração cística, constituem a forma de diagnóstico mais acessível em associação com os dados clínicos. Objetivo: Caracterizar os casos de doença da Substância Branca Evanescente em relação ao aspecto de imagem, correlação com achados clínicos e moleculares, além de avaliação evolutiva da neuroimagem e comparação com dados da literatura. Método: Delineamento do tipo prospectivo histórico por meio de prontuários e imagens de RM de encéfalo de 13 pacientes com diagnóstico molecular de doença da Substância Branca Evanescente do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - HCFMRPUSP - do período de 2006 a 2016. Resultados: Os pacientes eram na maioria do sexo feminino, todos brancos, com idade média de início dos sintomas aos 10 anos. Todas as mutações foram no gene EIF2B5, sendo prevalente c.338G> A (p.Arg113His). Trauma ou infecção como desencadeante foi descrito em 38,4%. O sintoma mais frequente foi ataxia (100%). Falência ovariana afetou metade das mulheres. Todos os exames de RM mostraram comprometimento da substância branca profunda, poupando relativamente a subcortical, com preferência frontoparietal (84,6%). Todas apresentaram lesões no corpo caloso e envolvimento cerebelar. Atrofia óptica acometeu 46,1%. Espectroscopia de prótons mostrou redução dos valores de Nacetil-aspartato e pico de lactato. O seguimento em imagem evidenciou evolução das lesões na substância branca e da atrofia, com maior acometimento da alta convexidade e dilatação ventricular, porém sem colapso do parênquima. Concomitantemente, o seguimento clínico mostrou piora neurológica progressiva e desfecho desfavorável em 12 dos 13 pacientes. Conclusões: Este é um dos estudos brasileiros com maior casuística de pacientes com diagnóstico molecular de Doença da Substância Branca Evanescente. Embora sendo uma doença multifacetada, os dados epidemiológicos, clínicos e de imagem encontrados foram semelhantes aos classicamente descritos na literatura para outras populações. Ressalta-se, ainda, extrema importância da RM de encéfalo para diagnóstico, evolução e triagem genética dessa desordem. / Introduction: Leukoencephalopathies constitute a vast group of differential diagnoses that challenge the medical team. Among them, Vanishing White Matter (VWM) Disease is one of the most common, and has been highlighted nowadays for significant progress in the characterization of its clinical, molecular and imaging basis. The typical phenotype begins at 2 to 6 years old, marked by chronic and progressive neurological decline, with episodes of deterioration triggered by trauma or infection that can lead to coma and even death. This is a genetic, autosomal recessive disorder related to mutations in the genes that encode the eukaryotic translation initiator factor 2B (eIF2B), a complex responsible for coordinating the translation of RNA into protein. The typical features in brain Magnetic Resonance Imaging (MRI), with a pattern of diffuse white matter involvement and cystic degeneration, are the most accessible form of diagnosis in association with clinical data. Purpose: to characterize VWM disease cases in relation to brain MRI appearance, clinical and molecular correlation and evolution over the time, comparing with data already described. Methods: A prospective historical design was performed using a review of medical records and brain MRI images of 13 patients from Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - HCFMRPUSP - with imaging and molecular diagnostic of VWM disease during the period from 2006 to 2016. Results: The patients were mostly female, all white, with a mean age of symptoms onset at 10 years old. All mutations were in the EIF2B5 gene, the most prevalent of them was c.338G> A (p.Arg113His). Trauma or infection as a trigger was described in 38.4%. The most frequent symptom was ataxia (100%). Ovarian failure affected half of women. All MRI showed deep white matter impairment, in a less prominent degree in the subcortical region, with frontoparietal preference (84.6%). All had lesions in the corpus callosum and cerebellar white matter involvement. Optic atrophy affected 46.1%. Proton spectroscopy showed a reduction in NAA values and a lactate peak. Image follow-up revealed white matter lesions and atrophy progression, with ventricular dilatation, however without parenchymal collapse. Concomitantly, there was progressive neurological worsening and unfavorable outcome in 12 of the 13 patients. Conclusion: This is one of the Brazilian studies with the largest number of patients with molecular diagnosis of VWM Disease. Although it is a multifaceted disease, the epidemiological, clinical and imaging data found were similar to those classically described in the literature for other populations. The importance of brain MRI for the diagnosis, evolution and genetic screening of this disorder is also highlighted.

Introdução: As leucoencefalopatias constituem um vasto grupo de doenças que desafiam a equipe médica. Dentre elas, a doença da Substância Branca Evanescente, é uma das mais comuns, com destaque nos últimos anos pelo significativo avanço na caracterização de suas bases clínicas, moleculares e de imagem. O fenótipo típico tem início dos 2 aos 6 anos, marcado por declínio neurológico crônico e progressivo, com episódios de deterioração desencadeados por trauma ou infecção, que podem levar a coma e até óbito. Essa é uma desordem genética, autossômica recessiva, relacionada a mutações nos genes que codificam o fator iniciador de tradução dos eucariontes 2B (eIF2B), complexo responsável por coordenar a tradução do RNA em proteína. As características típicas na Ressonância Magnética (RM) encefálica, com padrão de acometimento difuso da substância branca e degeneração cística, constituem a forma de diagnóstico mais acessível em associação com os dados clínicos. Objetivo: Caracterizar os casos de doença da Substância Branca Evanescente em relação ao aspecto de imagem, correlação com achados clínicos e moleculares, além de avaliação evolutiva da neuroimagem e comparação com dados da literatura. Método: Delineamento do tipo prospectivo histórico por meio de prontuários e imagens de RM de encéfalo de 13 pacientes com diagnóstico molecular de doença da Substância Branca Evanescente do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - HCFMRPUSP - do período de 2006 a 2016. Resultados: Os pacientes eram na maioria do sexo feminino, todos brancos, com idade média de início dos sintomas aos 10 anos. Todas as mutações foram no gene EIF2B5, sendo prevalente c.338G> A (p.Arg113His). Trauma ou infecção como desencadeante foi descrito em 38,4%. O sintoma mais frequente foi ataxia (100%). Falência ovariana afetou metade das mulheres. Todos os exames de RM mostraram comprometimento da substância branca profunda, poupando relativamente a subcortical, com preferência frontoparietal (84,6%). Todas apresentaram lesões no corpo caloso e envolvimento cerebelar. Atrofia óptica acometeu 46,1%. Espectroscopia de prótons mostrou redução dos valores de Nacetil-aspartato e pico de lactato. O seguimento em imagem evidenciou evolução das lesões na substância branca e da atrofia, com maior acometimento da alta convexidade e dilatação ventricular, porém sem colapso do parênquima. Concomitantemente, o seguimento clínico mostrou piora neurológica progressiva e desfecho desfavorável em 12 dos 13 pacientes. Conclusões: Este é um dos estudos brasileiros com maior casuística de pacientes com diagnóstico molecular de Doença da Substância Branca Evanescente. Embora sendo uma doença multifacetada, os dados epidemiológicos, clínicos e de imagem encontrados foram semelhantes aos classicamente descritos na literatura para outras populações. Ressalta-se, ainda, extrema importância da RM de encéfalo para diagnóstico, evolução e triagem genética dessa desordem. / Introduction: Leukoencephalopathies constitute a vast group of differential diagnoses that challenge the medical team. Among them, Vanishing White Matter (VWM) Disease is one of the most common, and has been highlighted nowadays for significant progress in the characterization of its clinical, molecular and imaging basis. The typical phenotype begins at 2 to 6 years old, marked by chronic and progressive neurological decline, with episodes of deterioration triggered by trauma or infection that can lead to coma and even death. This is a genetic, autosomal recessive disorder related to mutations in the genes that encode the eukaryotic translation initiator factor 2B (eIF2B), a complex responsible for coordinating the translation of RNA into protein. The typical features in brain Magnetic Resonance Imaging (MRI), with a pattern of diffuse white matter involvement and cystic degeneration, are the most accessible form of diagnosis in association with clinical data. Purpose: to characterize VWM disease cases in relation to brain MRI appearance, clinical and molecular correlation and evolution over the time, comparing with data already described. Methods: A prospective historical design was performed using a review of medical records and brain MRI images of 13 patients from Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - HCFMRPUSP - with imaging and molecular diagnostic of VWM disease during the period from 2006 to 2016. Results: The patients were mostly female, all white, with a mean age of symptoms onset at 10 years old. All mutations were in the EIF2B5 gene, the most prevalent of them was c.338G> A (p.Arg113His). Trauma or infection as a trigger was described in 38.4%. The most frequent symptom was ataxia (100%). Ovarian failure affected half of women. All MRI showed deep white matter impairment, in a less prominent degree in the subcortical region, with frontoparietal preference (84.6%). All had lesions in the corpus callosum and cerebellar white matter involvement. Optic atrophy affected 46.1%. Proton spectroscopy showed a reduction in NAA values and a lactate peak. Image follow-up revealed white matter lesions and atrophy progression, with ventricular dilatation, however without parenchymal collapse. Concomitantly, there was progressive neurological worsening and unfavorable outcome in 12 of the 13 patients. Conclusion: This is one of the Brazilian studies with the largest number of patients with molecular diagnosis of VWM Disease. Although it is a multifaceted disease, the epidemiological, clinical and imaging data found were similar to those classically described in the literature for other populations. The importance of brain MRI for the diagnosis, evolution and genetic screening of this disorder is also highlighted.

Telomeres are the outermost parts of linear chromosomes. They consist of tandemly repeated non-coding short nucleotide sequences (TTAGGG in all vertebrates), in humans spanning over the last 2 to 15 kilobase pairs of the chromosome. Due to the end-replication problem, telomeres shorten with each cellular division. A critically short telomere will trigger the cell to enter a state of cellular senescence or to apoptose. The rate of telomere shortening can be accelerated by factors such as oxidative stress and inflammation. Taken together, this contributed to making telomere length a candidate biomarker of health and aging. Studies have shown that leukocyte telomere length progressively shortens with age, and that it independent of age is associated with age-related morbidity, lifestyle factors, and mortality. This thesis was aimed at exploring the relationships of leukocyte telomere length with various functional and structural attributes of the brain. In Paper I, telomere length was shown to be longer among non-demented carriers of the apolipoprotein E (APOE) ε4 allele, a well-established risk factor for Alzheimer’s disease. However, the rate of telomere shortening was greater among the ε4 carriers, possibly due to the higher levels of oxidative stress and inflammation associated with this allele. Furthermore, performance on episodic memory tests was inversely related to telomere length among ε4 carriers. The results may contribute to a better understanding of the pathophysiology related to the APOE ε4 allele. The volume of the hippocampus, a structure in the brain critical for episodic memory function, was in Paper II found to be inversely related to telomere length among non-demented APOE ε3/ε3 carriers. No correlation between hippocampal volume and telomere length was discernible among ε4 carriers, but they fit the pattern exhibited by the ε3/ε3 carriers as they tended to have smaller hippocampi and longer telomere length compared with the ε3/ε3 carriers. The results are possibly explained by a low proliferative activity among subjects with smaller hippocampi, which might also explain the inverse association between telomere length and episodic memory performance in Paper I. In Paper III, we describe results corroborating earlier findings of shorter telomere length among individuals suffering from depression. Moreover, we found that the shorter telomere length among the patients to a large extent could be linked to a hypocortisolemic state; a state which has been associated with chronic stress. The findings corroborate the link between telomere length and stress, and underline the role of stress in depressive illness. Two prominent manifestations of the aging brain are atrophy and white matter hyperintensities. In Paper IV, we report that white matter hyperintensities and cerebral subcortical atrophy were associated with shorter telomere length in aged non-demented individuals. Cortical atrophy was not associated with telomere length. Inflammation may be the underlying cause of the associations, as it is linked to telomere attrition, subcortical atrophy, and white matter hyperintensities. Taken together, these results show that leukocyte telomere length has the potential of being used as a biomarker for structural and functional attributes of the brain. Furthermore, the findings can provide new insights into mechanisms of disease and aging of the brain

Attention deficit hyperactivity disorder (ADHD) is a neurobehavior developmental disorder that affects around 7.5% of Taiwan children. With the use of magnetic resonance imaging , many results have been reported that ADHD patients have volume atrophy in gray matter and dysfunction in couples of cortical regions. In recent years, diffusion MR imaging with diffusion-sensitizing gradients has been used to investigate the abnormality of neural fibers in disease involved with central nervous system. In this study, the anisotropy of white matter in both ADHD patients and age-matched healthy subjects was estimated using diffusion tensor imaging to undergo inter-subject comparison. In this work, a significant decrease (FWE-corrected p-value <0.05) of FA values has been found in white matter of adolescents diagnosed as ADHD patients, compared with normal controls group. The areas that confirmed by two different algorithms of inter-subject comparison are mainly diffused on white matter region, including middle cerebellar peduncle, left inferior longitudinal fasciculus, internal capsule, left optic radiation, external capsule, splenium of the corpus callosum, superior longitudinal fasciculus, superior frontal and parietal-occipital nerve fibers.

Diffusion tensor imaging (DTI) is a noninvasive MRI technique used to assess white matter (WM) integrity, fiber orientation, and structural connectivity (SC) using water diffusion properties. DTI techniques are rapidly evolving and are now having a dramatic effect on depression research. Major depressive disorder (MDD) is highly prevalent and a leading cause of worldwide disability. Despite decades of research, the neurobiology of MDD remains poorly understood. MDD is increasingly viewed as a disorder of neural circuitry in which a network of brain regions involved in mood regulation is dysfunctional. In an effort to better understand the neurobiology of MDD and develop more effective treatments, much research has focused on delineating the structure of this mood regulation network. Although many studies have focused on the structural connectivity of the mood regulation network, findings using DTI are highly variable, likely due to many technical and analytical limitations. Further, structural connectivity pattern analyses have not been adequately utilized in specific clinical contexts where they would likely have high relevance, e.g., the use of white matter deep brain stimulation (DBS) as an investigational treatment for depression. In this dissertation, we performed a comprehensive analysis of structural WM integrity in a large sample of depressed patients and demonstrated that disruption of WM does not play a major role in the neurobiology of MDD. Using graph theory analysis to assess organization of neural network, we elucidated the importance of the WM network in MDD. As an extension of this WM network analysis, we identified the necessary and sufficient WM tracts (circuit) that mediate the response of subcallosal cingulate cortex DBS treatment for depression; this work showed that such analyses may be useful in prospective target selection. Collectively, these findings contribute to better understanding of depression as a neural network disorder and possibly will improve efficacy of SCC DBS.

No description available.

No description available.

INTRODUCTION: The association of Sleep-Related Movement Disorders (SRMDs) such as Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLMs) with cerebrovascular disease is underexplored. Emerging evidence links them to vascular disease, for which white matter hyperintensities (WMHs) are a well-recognized biomarker. METHODS: We conducted a cross-sectional hospital-based observational study in which high-risk TIA and minor stroke patients were assessed for vascular risk factors, WMHs and polysomnography-determined sleep variables. RESULTS: Ninety-seven patients were enrolled, of whom 44 completed polysomnography. Twenty-five percent had RLS, which was associated with lower quality of life. Independent of the effect of classical vascular risk factors, PLMs (but not RLS) were associated with WMHs on linear regression analyses (p=0.016). CONCLUSIONS: SRMDs are prevalent after minor stroke/TIA. RLS is associated with poor quality of life, while PLMs are associated with WMHs. Whether PLMs are implicated in the pathogenesis of WMHs or whether WMHs exacerbate PLMs remains uncertain.

La actividad cerebral exhibe complejos fenómenos oscilatorios similares a los que se observan en modelos de redes artificiales con osciladores acoplados. Por un lado, estudios sobre la actividad cerebral durante el reposo han demostrado la presencia de fluctuaciones lentas estructuradas y modulaciones de potencia a distintas frecuencias. Simultáneamente, estudios teóricos en el ámbito de la física muestran dinámicas similares usando osciladores acoplados. En este trabajo, por primera vez, se usan modelos de osciladores de fase en redes inspiradas en la arquitectura real del cerebro. Los resultados muestran la aparición espontánea de una dinámica similar a la observada experimentalmente. Además, esta correspondencia es comparable cuantitativamente con datos de neuroimagen, lo que sugiere procesos generales de integración subyacentes a la cognición. Por otra parte, se propone que la actividad cerebral alterada observada en algunas enfermedades psiquiátricas podría tener su origen en desconexiones estructurales que afectarían el comportamiento cooperativo de regiones corticales. / Neural activity in the brain exhibits complex oscillatory phenomena that can be compared with the ones observed in artificial network models of coupled oscillators. In particular, neuroimaging studies of brain activity during rest have reported slow spatiotemporally organized fluctuations and correlated band-limited power modulations. Simultaneously, theoretical works on the area of physics have reported similar dynamic behaviours using simple models of coupled oscillators with intermittent modular synchronization. In this work, for the first time, we use models of phase oscillators in networks inspired in the brain’s wiring architecture. Results show the spontaneous emergence of a dynamics similar to the one observed experimentally. In addition, this correspondence is quantitatively comparable to neuroimaging data, which is suggestive of general integrative processes underlying cognition. Furthermore, we propose that altered brain activity observed in some psychiatric diseases might originate from structural disconnections, which affect the cooperative behaviour of coupled cortical regions.

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.