Background: Alzheimer's disease (AD) prevalence has grown 68% in that timeframe, and has risen to the sixth leading cause of death in the United States. Hispanics are at increased risk of acquiring cardiovascular risk factors that contribute to AD pathology and are minimally 1.5 times more likely at any age to be diagnosed with AD. Identifying the roots of this ethnic disparity can lead to more effective personalized health interventions. Aim: To compare indices of vascular health to measures of gray matter integrity in middle-aged Hispanic and Caucasian adults. As a secondary outcome, we will examine these health statuses in relation to cognitive function. Methods: Sixty subjects in Caucasian (n=30) and Hispanic (n=30) groups were matched across racial classification by age, gender, years of education, and cognitive status. Participants' arterial stiffness (carotid-femoral pulse-wave velocity and [beta]-stiffness index), arterial wave reflection (augmentation index), endothelial function (flow-mediated dilation), and atherosclerosis (carotid arterial wall intima-media thickness) were characterized. Magnetic resonance imaging (MRI) estimated cortical thickness in a priori cortical regions of interest known to be susceptible to vascular risk factors. Cognitive function was assessed with a comprehensive cognitive battery covering the domains of global cognitive function, language function, visuo-spatial abilities, memory function and attention-executive function. Results: Carotid-femoral pulse wave velocity (cfPWV) (p=0.02), Carotid artery [beta]-stiffness index (p=0.01), and augmentation index (Aix) (p=0.05) were significantly greater in Hispanics than in Caucasians. Carotid intima-media thickness (IMT) and flow-mediated dilation (FMD) were not different between the groups. Hispanics exhibited thinner left inferior frontal gyrus (LIFG) cortical thickness (p=0.04) with concurrently lower language (p=0.02), memory (p=0.03), and attention-executive functioning (p=0.02). Conclusion: Hispanics exhibited significantly greater cfPWV, Aix, and [beta]-stiffness index as well as selective cortical thinning of the LIFG. Additionally, language, working memory and attention-executive domains of cognition were lower in the Hispanic group compared to their age-, gender-, education- and cognitive status-matched Caucasian counterparts. These results may form a basis for future investigations that aim to explain the increased prevalence and earlier onset of symptoms of AD in the Hispanic population through cardiovascular health. / text

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The aim of this research was to examine tactile sensitivity in the skin of the leg and foot sole of healthy control subjects and below knee amputees and to examine its association with balance. For control subjects, the glabrous skin of the foot had higher sensitivity compared to the hairy skin of the leg, similar to previous literature in the upper limb. For all diabetic amputees examined, tactile sensitivity acuity in the lower limb was considerably lower than age matched controls in both the amputated and intact limbs, due to peripheral neuropathy. The traumatic amputee examined showed elevated sensitivity compared to controls for vibration perception at 40Hz and 250Hz in both the intact and amputated limbs. This may be due to cortical reorganisation of the primary somatosensory cortex which is known to occur following amputation. Further investigation of the tactile sensitivity of lower limb amputees is recommended. / re-submission of previously rejected thesis. / NSERC Discovery Grant

Made available in DSpace on 2014-06-12T18:07:23Z (GMT). No. of bitstreams: 2 arquivo6467_1.pdf: 423037 bytes, checksum: 6a9ac1489ce46b2301f6605737cf6534 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2003 / Foi estudada uma família consangüínea extensa (13 afetados, 8 mulheres e 5 homens) com uma forma variante de doença de Van Buchem ou um tipo de displasia óssea esclerosante não descrito anteriormente. O padrão de herança da doença sugerido nesta família é autossômico recessivo. As características clínicas mais importantes são baixa estatura e arqueamento dos membros inferiores, que já se faziam presentes ao nascimento. Na ocasião em que foram examinados, os indivíduos afetados vivos tinham idade variando entre 10 e 64 anos, todos apresentando redução na capacidade de deambulação, com três deles tendo perdido a capacidade de andar. Arqueamento dos membros inferiores, altos valores de fosfatase alcalina sérica e hipofosfatemia na avaliação laboratorial foram características presentes em todos os pacientes afetados estudados. O estudo radiológico destes pacientes mostrou padrão hiperostótico por todo o esqueleto, com predominância de envolvimento cortical. Esclerose do crânio, esclerose dos ossos longos, arqueamento lateral do fêmur e tíbia, bem como alargamento da mandíbula, foram achados significativos em todos os afetados radiografados.

Despite extensive research in the field of aging neuroscience, it still remains unclear whether age related cortical changes can be detected in different functional networks of younger adults and whether these networks respond identically to healthy aging. We collected high-resolution brain anatomical data from 56 young healthy adults (mean age = 30.8 +/- 8.1 years, 29 males). We performed whole brain parcellation into seven functional networks, including visual, somatomotor, dorsal attention, ventral attention, limbic, frontoparietal and default mode networks. We estimated intracranial volume (ICV) and averaged cortical thickness (CT), cortical surface area (CSA) and cortical volume (CV) over each hemisphere as well as for each network. Averaged cortical measures over each hemisphere, especially CT and CV, were significantly lower in older individuals compared to younger ones (one-way ANOVA, p < 0.05, corrected for multiple comparisons). There were negative correlations between age and averaged CT and CV over each hemisphere (p < 0.05, corrected for multiple comparisons) as well as between age and ICV (p = 0.05). Network level analysis showed that age was negatively correlated with CT for all functional networks (p < 0.05, corrected for multiple comparisons), apart from the limbic network. While age was unrelated to CSA, it was negatively correlated with CV across several functional networks (p < 0.05, corrected for multiple comparisons). We also showed positive associations between CV and CT and between CV and CSA for all networks (p < 0.05, corrected for multiple comparisons). We interpret the lack of association between age and CT of the limbic network as evidence that the limbic system may be particularly resistant to age-related declines during this period of life, whereas the significant age-related declines in averaged CT over each hemisphere as well as in all other six networks suggests that CT may serve as a reliable biomarker to capture the effect of normal aging. Due to the simultaneous dependence of CV on CT and CSA, CV was unable to identify such effects of normal aging consistently for the other six networks, but there were negative associations observed between age and averaged CV over each hemisphere as well as between age and ICV. Our findings suggest that the identification of early cortical changes within various functional networks during normal aging might be useful for predicting the effect of aging on the efficiency of functional performance even during early adulthood.

Integration of inputs by cortical neurons provides the basis for the complex information processing performed in the cerebral cortex. Here, we propose a new analytic framework for understanding integration within cortical neuronal receptive fields. Based on the synaptic organization of cortex, we argue that neuronal integration is a systems--level process better studied in terms of local cortical circuitry than at the level of single neurons, and we present a method for constructing self-contained modules which capture (nonlinear) local circuit interactions. In this framework, receptive field elements naturally have dual (rather than the traditional unitary influence since they drive both excitatory and inhibitory cortical neurons. This vector-based analysis, in contrast to scalarsapproaches, greatly simplifies integration by permitting linear summation of inputs from both "classical" and "extraclassical" receptive field regions. We illustrate this by explaining two complex visual cortical phenomena, which are incompatible with scalar notions of neuronal integration.

Orientadores: Iscia Teresinha Lopes Cendes, Fábio Rossi Torres / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T06:33:25Z (GMT). No. of bitstreams: 1 Souza_DanielaAguiar_D.pdf: 4993968 bytes, checksum: b0d9bcf5acf25db217c9dedcd7aa4bbc (MD5) Previous issue date: 2013 / Resumo: As malformações do desenvolvimento cortical (MDC) são distúrbios resultantes de defeitos na embriogênese do córtex cerebral e estão entre as principais causas conhecidas de atraso do desenvolvimento e epilepsia. Dentre os principais tipos de MDC podemos citar a heterotopia nodular periventricular (HNP), o espectro lissencefalia/heterotopia subcortical em banda (LIS/HSB) e a esquizencefalia. Alterações moleculares em genes que atuam em mecanismos que vão desde o controle da divisão celular até a migração neuronal foram identificadas como responsáveis pela etiologia de vários tipos de MDC. Tais descobertas, além de auxiliar na compreensão dos mecanismos envolvidos no desenvolvimento do córtex cerebral e doenças relacionadas, fornecem informações importantes para um melhor diagnóstico e tratamento dos pacientes. Neste contexto, o principal objetivo deste trabalho foi analisar do ponto de vista molecular um grande grupo de pacientes com MDC. A casuística foi composta por um grupo de 107 pacientes: 27 possuem HNP, 33 são afetados por LIS/HSB e 47 possuem esquizencefalia. Em um primeiro momento, foi realizada triagem de mutações de ponto em genes candidatos (FLNA, DCX, LIS1, EMX2, TUBA1A, TUBB2B e TUBA8) por sequenciamento (Sanger). Posteriormente, a técnica de MLPA (Multiplex Ligation-dependent Probe Amplification) foi utilizada para detectar variações estruturais em regiões candidatas, incluindo os genes FLNA, DCX e LIS1. Finalmente, a técnica de SNP-Array foi utilizada para análise das variações no número de cópias alélicas em regiões genômicas de alguns pacientes (copy number variation - CNV). Todas as mutações de ponto encontradas nas sequencias de DNA foram verificadas em um grupo de 200 indivíduos controles. Através do sequenciamento, foram identificadas três alterações patogênicas localizadas nos genes FLNA e DCX, através do MLPA foram encontradas seis alterações estruturais patogênicas nos genes FLNA, DCX e LIS1. Os ensaios de SNP-Array permitiram a identificação de vários CNVs com potencial deletério, incluindo 12 pacientes com 17 novas CNVs ainda não descritas na literatura. Tais CNVs envolvem vários potenciais genes candidatos para as MDC, incluindo os genes TSNARE, DAAM1, ARX, PLXNA1 e HAUS7. Concluindo, nossos resultados mostram uma baixa frequência de mutações em genes candidatos previamente relacionados às MDC, somente 2.8% (n=3/107) dos pacientes possuem variantes deletérias nas sequencias dos genes analisados e 18% (n=6/33 testados) dos pacientes analisados possuem alterações estruturais em regiões candidatas. Porém, através da abordagem genômica para identificação de variações estruturais, foram identificadas vá-rias regiões/genes candidatos potencialmente envolvidos com a etiologia das MDC (12/40= 30%). Nossos dados mostram que as MDC apresentam grande heterogeneidade genética, porém uma proporção significativa dos pacientes possuem variações estruturais que podem ser identificadas pela técnica de SNP-Array / Abstract: Malformations of cortical development (MCD) are disorders resulting from defects in the embryogenesis of the cerebral cortex and are one of the most important causes of developmental delay and epilepsy. The main types of MCDs are periventricular nodular heterotopia (PNH), lissencephaly/subcortical band heterotopia spectrum (LIS/SBH) and schizen-cephaly. Mutations in genes acting in mechanisms ranging from control of cell division to neuronal migration were identified as responsible for several types of MCDs. These advances not only improved our understanding about the mechanisms involved in the development of the cerebral cortex but have also provided relevant information that can be used for better diagnosis and management of patients. In this scenario, the main objective of this study was to access and perform a comprehensive molecular genetics study in a large cohort of patients with MCD. We have studied a total of 107 patients with MCDs divided in the following groups: 27 with PNH, 33 with LIS/SBH and 47 with schizencephaly. We first searched for sequence variations in candidate genes (FNLA, DCX, LIS1, EMX2, TU-BA1A, TUBB2B and TUBA8) using the Sanger sequencing method. Subsequently, we checked for structural variants in FLNA, DCX and LIS1 using Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Finally, we took a genomic approach by using single nucleotide polymorphism (SNP)-array technology to studied copy number variations (CNV) in some patients. All sequence variants found were subsequently verified in a group of 200 control individuals. Our results showed 3 pathogenic sequence variants in FNLA and DCX, as well as 6 pathogenic structural variants detected by MLPA in FLNA, LIS1 and DCX. SNP-array technique detected 17 genomic regions, in 12 patients, containing new CNVs. These CNVs involve a number of potential new candidate genes for MCDs, including: TSNARE, DAAM1, ARX, PLXNA1 and HAUS7. In conclusion, our results show a low frequency of mutations in candidate genes previously associated with MCDs, only 2.8% (n=3/107) of our patients have deleterious sequence variants and 18% (n=6/33) have abnormal structural variants in candidate regions. However, by using a genomic approach to look for CNVs we were able to identify several candidate regions/genes that have the potential to be involved in MCDs (12/40= 30%). Our data show that MCDs are genetic heterogeneous; however, it seems that a significant proportion of patients have structural abnormalities that can be identified by SNP-array technology / Doutorado / Fisiopatologia Médica / Doutora em Ciências

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