Made available in DSpace on 2014-07-29T15:29:05Z (GMT). No. of bitstreams: 1 TESE MARIA CAROLINA.pdf: 402792 bytes, checksum: 8d8bc54ccfec33d3f62e4107f1060beb (MD5) Previous issue date: 2009-08-03 / In the twentieth century, it was believed that the injury cortical was the substrate of cerebral dysfunction neuropathological. Studies of dementia were primarily focused on disorders of the cerebral cortex and sub cortical gray region, which originated the concepts of cortical and subcortical dementia respectively. The report of dementia mainly involving the white brain received less attention. The aim of this study was to achieve a profile of changes in language and cognitive processes involved in changes in the white sub cortical dementia (DSB) and dementia sub cortical gray (DSC) and then compared with the control group and among themselves. Thus 15 patients were evaluated with DSB, 8 with DSC and 14 control subjects. We applied the following tests: Boston for Diagnostic of Aphasia Examination (BDAE), the Boston Naming Test (BNT), Token Test, Verbal fluency - semantic category and board Theft of biscuits. The results showed that the subcortical group showed worse performance with the control group, showing significant differences in the Boston Naming Test and on the evidence of comprehension and oral production and graphics for the Boston Diagnostic Test of Aphasia. The DSB group showed more significant changes when compared with the control group than in the comparison between DSC X control group. Despite the language is related to cortical involvement, our study showed that such changes are found in subcortical dementia and receiving influence of cognitive processes involved in language. Symptoms of changes in language were similar between groups subcortical, but in greater or lesser degree of commitment. The DSB group showed more impairment of comprehension and oral apraxia and DSC group is highlighted by changes in prosody and the presence of hyperkinetic dysarthria. / No século vinte acreditava-se que o prejuízo cortical era o maior substrato neuropatológico da disfunção cerebral. Os estudos de demência foram primeiramente focados nas desordens do córtex cerebral e região subcortical cinzenta, o que originou os conceitos de demência cortical e subcortical respectivamente. O relato de demência principalmente envolvendo substância branca cerebral recebeu menos atenção. O objetivo desse estudo foi traçar um perfil das alterações de linguagem e os processos cognitivos envolvidos nessas alterações com seu substrato neurobiológico na demência subcortical branca (DSB) e demência subcortical cinzenta (DSC) e em seguida estabelecer uma comparação intra e inter grupos. Para tanto foram avaliados 15 pacientes com DSB, 8 com DSC e 14 sujeitos-controle. Foram aplicados os seguintes testes: Teste Boston para Diagnóstico das Afasias (TBDA), Teste de Nomeação de Boston (TNB), Teste Token, Fluência Verbal - categoria semântica e a prancha Roubo dos Biscoitos. Os resultados mostraram que os grupos subcorticais apresentaram pior desempenho com relação ao grupo controle, apresentando diferenças significativas no teste de Nomeação de Boston e nas provas de compreensão e produção oral e gráfica do Teste Boston para Diagnóstico das Afasias. O grupo DSB apresentou mais alterações significativas quando comparado com o grupo controle, do que na comparação entre DSC X grupo controle. Não obstante as alterações de linguagem estarem tradicionalmente relacionadas ao comprometimento cortical, nosso estudo mostrou que tais alterações estão presentes nas demências subcorticais. Os sintomas de alteração de linguagem foram semelhantes entre os grupos subcorticias, porém em maior ou menor grau de comprometimento. O grupo DSB apresentou mais comprometimento de compreensão oral e apraxia buço-facial e o grupo DSC se destacou pela alteração na prosódia e pela presença de disartria hipercinética.

Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) family protein, which is encoded by a gene of identical name present on the X chromosome. CASK may participate in presynaptic scaffolding, gene expression regulation, and cell junction formation. CASK is essential for survival in mammals. Heterozygous mutations in the CASK gene (in females) produce X-linked intellectual disability (XLID) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH, OMIM# 300749). CASK mutations are also frequently associated with optic nerve hypoplasia (ONH) which is the most common cause of childhood blindness in developed countries. Some patients with mutations in CASK have been also diagnosed with optic nerve atrophy (ONA) and glaucoma. We have used floxed CASK (CASKfloxed), CASK heterozygous knockout (CASK(+/-)), CASK neuronal knockout (CASKNKO) and tamoxifen inducible CASK knockout (CASKiKO) mouse models to investigate the mechanism and pathology of CASK-linked ONH. Our observations indicate that ONH occurs with 100% penetrance in CASK(+/-) mice, which also displayed microcephaly and disproportionate cerebellar hypoplasia. Further, we found that CASK-linked ONH is a complex developmental neuropathology with some degenerative components. Cellular pathologies include loss of retinal ganglion cells (RGC), astrogliosis, axonopathy, and synaptopathy. The onset of ONH is late in development, observed only around the early postnatal stage in mice reaching the plateau phase by three weeks of birth. The developmental nature of the disorder is confirmed by deleting CASK after maturity since CASKiKO mice did not produce any obvious optic nerve pathology. Strikingly the CASKfloxed mice expressing ~49% level of CASK did not manifest ONH despite displaying a slightly smaller brain and cerebellar hypoplasia indicating that ONH may not simply be an extension of microcephaly. We discovered that deleting CASK in neurons produced lethality before the onset of adulthood. The CASKNKO mice exhibited delayed myelination of the optic nerve. Overall this work suggests that CASK is critical for neuronal maturation and CASK-linked ONH is a pervasive developmental disorder of the subcortical visual pathway. Finally, in a side project, I also described a new methodology of targeting neurons using receptor-mediated endocytosis which would help target retinal neurons for therapeutic purposes in the future. / Ph. D. / 7 in 10,000 children suffer from childhood blindness, for whom all the visual information from the outside world is completely blocked. Although classified as a rare disease, optic nerve hypoplasia (ONH), or the underdevelopment of optic nerve, is the leading cause of childhood blindness in developed countries, accounting for 15% of childhood blindness. Only a handful of genes have been shown to associate with ONH. The CASK gene, whose protein product calcium/calmodulin-dependent serine protein kinase (CASK) plays a role in presynaptic scaffolding, is one of them. Mutations in the CASK gene not only produce ONH, but also microcephaly and intellectual disability. Investigating the mechanism of CASK-linked ONH will provide critical data to understand the molecular basis of optic nerve formation and maturation. Here we have used the CASK heterozygous knockout mouse model to replicate the ONH and microcephaly seen in female human patients. We discovered that the onset of CASK-linked ONH corresponded to the late third trimester developmental stage in humans, thus ONH is developmental in nature. ONH pathologies include thinning of optic nerves, axonal atrophy, and synaptopathy. In contrast to the postnatal death of constitutive CASK loss of function in mice, CASK ablation in adult mice did not lead to lethality. CASK deletion also delays neuronal myelination. Overall, our results indicate that CASK is critical for postnatal maturation of the central nervous system and mutations of the CASK gene is sufficient to lead to ONH. Early intervention and proper gene therapy may treat CASK-linked ONH.

Huntington's disease (HD) is a genetic, neurodegenerative disorder that is characterized by motor, cognitive and psychiatric disturbances. Anosognosia, or lack of awareness of symptoms, is commonly observed in neurodegenerative disorders, including HD. Most theories suggest that emotion, executive functioning, and memory play important roles in self-awareness. There is limited research of anosognosia in HD and no theoretical model of how it manifests in the disease. The purpose of this study was to examine Metacognitive Knowledge, or overall beliefs about the self, and Online Awareness, or the ability to predict (Anticipatory Awareness) and evaluate (Emergent Awareness) task performance, in HD. Fifty-six symptomatic HD patients and fifty informants completed the study. Results revealed that those with the best executive functioning and lowest apathy were also better able to report on their symptoms. Those with the best executive functioning and memory and lowest apathy were the best at predicting and evaluating their performance on cognitive tasks. Patient self-report of memory was associated with cognitive performance while self-report of executive functioning and apathy was not. Only informant report of apathy and executive functioning was related to cognitive performance. For both Metacognitive Knowledge and Online Awareness, HD patients tended to have a better awareness of memory than executive functioning. These results suggest that awareness in HD is governed by local monitoring systems rather than a single metacognitive mechanism. It is also consistent with literature that suggests that individuals are least able to evaluate performance on tasks for which they are poorest in skill level, as HD patients tend to have impaired executive functioning and increased apathy with relative sparing of memory.

No description available.

Segmentation of sub-cortical Gray Matter (GM) structures in magnetic resonance brain images is crucial in clinic and research for many purposes such as early diagnosis of neurological diseases, guidance of surgical operations and longitudinal volumetric studies. Unfortunately, the algorithms that segment the brain into 3 tissues usually suffer from poor performance in the sub-cortical region. In order to increase the detection of sub-cortical GM structures, an evolutionary hierarchical region merging approach, abbreviated as EHRM, is proposed in this study. Through EHRM, an intensity based region merging is utilized while merging is allowed to proceed among disconnected regions. Texture information is also incorporated into the scheme to prevent the region merging between tissues with similar intensity but different texture properties. The proposed algorithm is tested on real and simulated datasets. The performance is compared with a popular segmentation algorithm, which is also intensity driven: the FAST algorithm [1] in the widely used FSL suite. EHRM is shown to make a significant improvement the detection of sub-cortical GM structures. Average improvements of 10%, 36% and 22% are achieved for caudate, putamen and thalamus respectively. The accuracy of volumetric estimations also increased for GM and WM. Performance of EHRM is robust in presence of bias field. In addition, EHRM operates in O(N) complexity. Furthermore, the algorithm proposed here is simple, because it does not incorporate spatial priors such as an atlas image or intensity priors. With these features, EHRM may become a favorable alternative to the existing brain segmentation tools.

Using neutral and emotional faces as stimuli, the Emotional Continuous Performance Task (EMO-CPT) was designed to measure both “cold” and “hot” executive functions. It was predicted that neutral stimuli would be associated with “cold” circuit functions such as sustained attention and response speed, while emotionally-laden EMO-CPT stimuli would be associated with “hot” circuit functions such as emotional judgement and response inhibition. Twenty-one male and 56 female university students (M = 21.57 years; SD = 3.15) completed the EMO-CPT, Counting Stroop (CS), Balloon Analogue Risk Task (BART), Behaviour Rating Inventory of Executive Function (BRIEF), and a demographic survey. The EMO-CPT consisted of 240 trials counterbalanced into 8 separate blocks of neutral, happy, and angry faces, with 1500ms and 3000ms stimulus intervals. Principle axis factor analysis with orthogonal (varimax) rotation revealed “Sustained/Speed” (SS; Eigenvalue = 4.26) and “Accuracy/Inhibition” (AI; Eigenvalue = 2.49) factors accounting for 48.75% of the total variance. The SS factor was modestly correlated with the BRIEF Metacognitive Index (MI; r=.25), and both the Sustained/Speed factor (r=.27) and the Accuracy/Inhibition factor (r=.25) were modestly correlated with the BRIEF Behavioural Regulation Index (BRI). As predicted, “cold” Counting Stroop reaction time variables were related to the Sustained/Speed factor (r’s .30 to .36), and the “hot” BART adjusted inflations SD were related to the Accuracy/Inhibition factor (r = -.22). Correlated with the CS and BRIEF MI, the Sustained/Speed factor appeared to tap “cold” dorsal circuit functions, while the Accuracy/Inhibition factor appeared to be related to “hot” ventral circuit functions. / Graduate

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22336号 / 医博第4577号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 渡邉 大, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第23340号 / 生博第458号 / 新制||生||61(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 松田 道行, 教授 見学 美根子, 教授 今吉 格 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

When exploring movement production, motor control researchers have been interested in investigating the relative contributions to different types of movement. In a research setting, a startling acoustic stimulus (SAS) can be used as a tool to explore the neural processes that are occurring when preparing and initiating a movement. Additionally, suprathreshold TMS is another tool which can induce a suppression of the cortical region of the brain, resulting in RT delays which provides us with the ability to assess the corticospinal contributions to a particular movement. The aim of the current study was to investigate potential differences in the planning and execution of bimanual versus unimanual wrist extension movements. It was of particular interest as to whether bimanual coupling occurs at the cortical level or in lower parts of the output pathway (reticulospinal). Participants (N=6) were instructed to complete a unimanual or bimanual wrist extension following a control go-signal or a SAS. For subset of trials, in order to explore the level of corticospinal excitability of the movement, suprathreshold TMS was applied over the left M1 during the task to induce a cortical silent period (CSP). Results revealed that theimpact of TMS on response initiation was not significantly different for unimanual task versus a bimanual task. Furthermore, the SP (silent period) only had an impact on the right limb and not the left during the bilateral task. Lastly, SAS did lead to shorter RTs for both the unimanual and bimanual wrist extension task, but the RT delay induced by TMS in the right limb was not shorter in SAS trials compared to control. The findings of the present study suggest that bimanual coupling may be occurring at the cortical level and in lower parts of the output pathway as there may be correlated neural activity in the two hemispheres occurring during bimanual wrist extension movements.