Thesis (Ph. D.)--University of Virginia, 2006. / Includes bibliographical references (leaves 181-233). Also available online through Digital Dissertations.

Introdução: A doença de Huntington (HD) é uma doença neurodegenerativa, autossômica dominante, causada pela expansão CAG que resulta em distúrbios do movimento, prejuízo cognitivo e alterações de personalidade. Muito pouco se sabe sobre a qualidade de vida de pacientes com HD e fatores associados e a influência dos mesmos nos sintomas depressivos dos cuidadores. Objetivo: Avaliar a qualidade de vida de indivíduos portadores da HD bem como suas implicações e, além disso, avaliar presença de sintomas depressivos no seu cuidador de convívio diário. Investigar os fatores que possam estar relacionados com o prejuízo da qualidade de vida do paciente tais como grau de comprometimento funcional, distúrbio motor, cognitivo e comportamental, sintomas de depressão, prejuízo no sono. Metodologia: Trata-se de um estudo quantitativo transversal. A população foi composta por pacientes com HD em acompanhamento no ambulatório de Distúrbios do Movimento e Neurogenética, que possuíam diagnóstico de HD confirmado por teste molecular. As entrevistas foram realizadas com auxilio de ferramentas estruturadas, as quais seguem: SF-36 e HQoLI, para qualidade de vida; UHDRS para avaliação funcional; MoCA para avaliação cognitiva; PSQI para avaliação do sono e BDI para avaliação de sintomas depressivos do paciente e cuidador. Resultados: Foram avaliados 28 pacientes com HD com idade média de 41 ± 9.5 e expansão CAG média de 45 ± 6. A duração da doença apresentou associação com os aspectos físicos da escala SF-36 (p<0.01). AUHDRS apresentou impacto em vários domínios da qualidade de vida, tais como domínios de saúde física e mental. A má qualidade do sono avaliada através da escala PSQI influenciou na QV do paciente nos dois grandes domínios de saúde física e saúde mental com (p<0.05) e (p<0.01) respectivamente. O nível cognitivo apresentado pelos pacientes avaliados pela escala MoCA apresentaram associação com domínio de funcionamento físico da escala SF-36 (p<0.01) Conclusão: As análises dos dados coletados permitem afirmar que se trata de uma doença que impacta de maneira significativa na QV das famílias. O apoio multidisciplinar a família afetada e o tratamento das comorbidades associadas se faz fundamental para amenizar os impactos da doença e melhorar a QV. / Background: The Huntington Disease (HD) is a neurodegenerative autosomal dominant disorder caused by the CAG expansion resulting in movement disorders, cognitive impairment and personality changes. Very little is known about the quality of life in HD patients associated factors and influence on depressive symptoms of caregivers. Objective: To evaluate the quality of life in individuals with HD, as well as its implications, and evaluate their daily caregiver for depressive symptoms. Factors that may be related to harm of patient's quality of life, such as functional impairment; motor, cognitive and behavioral disorder; symptoms of depression; and sleep loss were investigated. Methods: It is a quantitative cross-sectional study. The population was composed of patients with HD from Movement Disorders and Neurogenetics Clinic, who had positive molecular test. The interviews were carried out with support of the structured tools as follow: SF-36 and HQoLI for quality of life, UHDRS for functional evaluation, MoCA for cognitive evaluation, PSQI for sleep evaluation, and BDI for evaluation of depression of patient and caregiver. Results: Twenty-eight HD patients were evaluated with an average age of 41 ± 9.5 and an average CAG expansion of 45 ± 6. The duration of the disease was associated with the physical aspects of the SF-36 scale (p<0.01). UHDRS was associated with impairment in several domains of quality of life including mental and physical domains. It was identified that the bad sleep quality evaluated through the PSQI scale was associated with patient's QL (quality of life). The cognitive level evaluated by the MoCA scale presented association with the Physical functioning domain of SF-36 scale (p<0.01). Conclusion: The analysis of the collected data allows to affirm that HD impacts significantly on the families quality of life. The multidisciplinary support to the affected family is critical to mitigate the impacts of the disease and improve the QL.

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Introdução: A doença de Huntington (HD) é uma doença neurodegenerativa, autossômica dominante, causada pela expansão CAG que resulta em distúrbios do movimento, prejuízo cognitivo e alterações de personalidade. Muito pouco se sabe sobre a qualidade de vida de pacientes com HD e fatores associados e a influência dos mesmos nos sintomas depressivos dos cuidadores. Objetivo: Avaliar a qualidade de vida de indivíduos portadores da HD bem como suas implicações e, além disso, avaliar presença de sintomas depressivos no seu cuidador de convívio diário. Investigar os fatores que possam estar relacionados com o prejuízo da qualidade de vida do paciente tais como grau de comprometimento funcional, distúrbio motor, cognitivo e comportamental, sintomas de depressão, prejuízo no sono. Metodologia: Trata-se de um estudo quantitativo transversal. A população foi composta por pacientes com HD em acompanhamento no ambulatório de Distúrbios do Movimento e Neurogenética, que possuíam diagnóstico de HD confirmado por teste molecular. As entrevistas foram realizadas com auxilio de ferramentas estruturadas, as quais seguem: SF-36 e HQoLI, para qualidade de vida; UHDRS para avaliação funcional; MoCA para avaliação cognitiva; PSQI para avaliação do sono e BDI para avaliação de sintomas depressivos do paciente e cuidador. Resultados: Foram avaliados 28 pacientes com HD com idade média de 41 ± 9.5 e expansão CAG média de 45 ± 6. A duração da doença apresentou associação com os aspectos físicos da escala SF-36 (p<0.01). AUHDRS apresentou impacto em vários domínios da qualidade de vida, tais como domínios de saúde física e mental. A má qualidade do sono avaliada através da escala PSQI influenciou na QV do paciente nos dois grandes domínios de saúde física e saúde mental com (p<0.05) e (p<0.01) respectivamente. O nível cognitivo apresentado pelos pacientes avaliados pela escala MoCA apresentaram associação com domínio de funcionamento físico da escala SF-36 (p<0.01) Conclusão: As análises dos dados coletados permitem afirmar que se trata de uma doença que impacta de maneira significativa na QV das famílias. O apoio multidisciplinar a família afetada e o tratamento das comorbidades associadas se faz fundamental para amenizar os impactos da doença e melhorar a QV. / Background: The Huntington Disease (HD) is a neurodegenerative autosomal dominant disorder caused by the CAG expansion resulting in movement disorders, cognitive impairment and personality changes. Very little is known about the quality of life in HD patients associated factors and influence on depressive symptoms of caregivers. Objective: To evaluate the quality of life in individuals with HD, as well as its implications, and evaluate their daily caregiver for depressive symptoms. Factors that may be related to harm of patient's quality of life, such as functional impairment; motor, cognitive and behavioral disorder; symptoms of depression; and sleep loss were investigated. Methods: It is a quantitative cross-sectional study. The population was composed of patients with HD from Movement Disorders and Neurogenetics Clinic, who had positive molecular test. The interviews were carried out with support of the structured tools as follow: SF-36 and HQoLI for quality of life, UHDRS for functional evaluation, MoCA for cognitive evaluation, PSQI for sleep evaluation, and BDI for evaluation of depression of patient and caregiver. Results: Twenty-eight HD patients were evaluated with an average age of 41 ± 9.5 and an average CAG expansion of 45 ± 6. The duration of the disease was associated with the physical aspects of the SF-36 scale (p<0.01). UHDRS was associated with impairment in several domains of quality of life including mental and physical domains. It was identified that the bad sleep quality evaluated through the PSQI scale was associated with patient's QL (quality of life). The cognitive level evaluated by the MoCA scale presented association with the Physical functioning domain of SF-36 scale (p<0.01). Conclusion: The analysis of the collected data allows to affirm that HD impacts significantly on the families quality of life. The multidisciplinary support to the affected family is critical to mitigate the impacts of the disease and improve the QL.

Introdução: A doença de Huntington (HD) é uma doença neurodegenerativa, autossômica dominante, causada pela expansão CAG que resulta em distúrbios do movimento, prejuízo cognitivo e alterações de personalidade. Muito pouco se sabe sobre a qualidade de vida de pacientes com HD e fatores associados e a influência dos mesmos nos sintomas depressivos dos cuidadores. Objetivo: Avaliar a qualidade de vida de indivíduos portadores da HD bem como suas implicações e, além disso, avaliar presença de sintomas depressivos no seu cuidador de convívio diário. Investigar os fatores que possam estar relacionados com o prejuízo da qualidade de vida do paciente tais como grau de comprometimento funcional, distúrbio motor, cognitivo e comportamental, sintomas de depressão, prejuízo no sono. Metodologia: Trata-se de um estudo quantitativo transversal. A população foi composta por pacientes com HD em acompanhamento no ambulatório de Distúrbios do Movimento e Neurogenética, que possuíam diagnóstico de HD confirmado por teste molecular. As entrevistas foram realizadas com auxilio de ferramentas estruturadas, as quais seguem: SF-36 e HQoLI, para qualidade de vida; UHDRS para avaliação funcional; MoCA para avaliação cognitiva; PSQI para avaliação do sono e BDI para avaliação de sintomas depressivos do paciente e cuidador. Resultados: Foram avaliados 28 pacientes com HD com idade média de 41 ± 9.5 e expansão CAG média de 45 ± 6. A duração da doença apresentou associação com os aspectos físicos da escala SF-36 (p<0.01). AUHDRS apresentou impacto em vários domínios da qualidade de vida, tais como domínios de saúde física e mental. A má qualidade do sono avaliada através da escala PSQI influenciou na QV do paciente nos dois grandes domínios de saúde física e saúde mental com (p<0.05) e (p<0.01) respectivamente. O nível cognitivo apresentado pelos pacientes avaliados pela escala MoCA apresentaram associação com domínio de funcionamento físico da escala SF-36 (p<0.01) Conclusão: As análises dos dados coletados permitem afirmar que se trata de uma doença que impacta de maneira significativa na QV das famílias. O apoio multidisciplinar a família afetada e o tratamento das comorbidades associadas se faz fundamental para amenizar os impactos da doença e melhorar a QV. / Background: The Huntington Disease (HD) is a neurodegenerative autosomal dominant disorder caused by the CAG expansion resulting in movement disorders, cognitive impairment and personality changes. Very little is known about the quality of life in HD patients associated factors and influence on depressive symptoms of caregivers. Objective: To evaluate the quality of life in individuals with HD, as well as its implications, and evaluate their daily caregiver for depressive symptoms. Factors that may be related to harm of patient's quality of life, such as functional impairment; motor, cognitive and behavioral disorder; symptoms of depression; and sleep loss were investigated. Methods: It is a quantitative cross-sectional study. The population was composed of patients with HD from Movement Disorders and Neurogenetics Clinic, who had positive molecular test. The interviews were carried out with support of the structured tools as follow: SF-36 and HQoLI for quality of life, UHDRS for functional evaluation, MoCA for cognitive evaluation, PSQI for sleep evaluation, and BDI for evaluation of depression of patient and caregiver. Results: Twenty-eight HD patients were evaluated with an average age of 41 ± 9.5 and an average CAG expansion of 45 ± 6. The duration of the disease was associated with the physical aspects of the SF-36 scale (p<0.01). UHDRS was associated with impairment in several domains of quality of life including mental and physical domains. It was identified that the bad sleep quality evaluated through the PSQI scale was associated with patient's QL (quality of life). The cognitive level evaluated by the MoCA scale presented association with the Physical functioning domain of SF-36 scale (p<0.01). Conclusion: The analysis of the collected data allows to affirm that HD impacts significantly on the families quality of life. The multidisciplinary support to the affected family is critical to mitigate the impacts of the disease and improve the QL.

O objetivo deste trabalho foi caracterizar as alterações de linguagem na doença de Huntington e correlacioná-las com os transtornos motores, cognitivos, psiquiátricos e, também, com o tempo de doença. Foram estudados 26 indivíduos, divididos em grupo leve (11 doentes) e moderado (15 doentes), comparados com dois grupos controle. Foram encontradas alterações em provas de compreensão e expressão da linguagem oral e gráfica para os dois grupos de doentes. Evidências sugerem que não há prejuízo nas representações semânticas, e que as dificuldades de linguagem estão relacionadas com o declínio cognitivo global e, especialmente, com o prejuízo das funções executivas. As alterações de linguagem se correlacionaram com o desempenho em tarefas cognitivas, mas não com as alterações motoras ou psiquiátricas da doença. Também não foi encontrada correlação entre o desempenho de linguagem e o tempo de doença / The objective of this study was to characterize the language alterations in Huntington's disease and how they relate to severity of motor, cognitive, psychiatric disturbances and also with the disease duration. Twenty-six (26) individuals were divided into groups characterized as lightly (11) and moderately ill (15) and compared with two control groups. Alterations in exams of language comprehension and expression were noticed for both groups of sick individuals. The result indicates no evident loss in semantic representation. The language difficulties are related to a global cognitive decline and, principally, to loss of executive functions. The language alterations were significantly correlated to performance in cognitive tasks, but not to the motor or psychiatric alterations of the disease. There was also no correlation observed between the language performance and duration of illness

Huntington disease (HD) is a genetically transmitted fatal neurodegenerative condition that currently has no cure. The symptoms of HD are manifested as cognitive declines, neuropsychiatric disturbances, and motor dysfunction. An autosomal dominant genetic defect is responsible for the onset of HD, which means that the children of an affected parent have a 50% chance of inheriting the disease. Predictive genetic testing for HD has been available since 1993, and a positive test result means that a person will develop HD with 100% certainty. People who have the HD-gene expansion, but have not yet manifested unequivocal motor signs, are said to be in the prodromal phase of HD. A number of studies have examined concerns about the utility of genetic testing and its negative psychological consequences for gene-expanded and non-expanded individuals (e.g., traumatization, suicidal ideation). Although research has understandably focused on the potential for distress, there has been some evidence suggesting that individuals may actually experience psychological growth related to a receiving a genetic test result (e.g., improved relationships, pursuing new opportunities). The aim of the present study was to understand the relationship between genetic testing, prodromal HD symptoms, and posttraumatic growth (PTG). Participants were recruited through the multinational PREDICT-HD study (Jane Paulsen, PI) and they completed the Posttraumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996) to assess permanent positive psychological change as a result of learning about their HD-gene status. The Symbol Digit Modalities Test (Smith, 1991), Unified Huntington's Disease Rating Scale Motor Exam (Huntington's Study Group, 1996), and the SCl-90-R Depression subscale (Derogatis, 1994) were also completed. A total of 82 gene-expanded patients and 37 non-expanded patients took part in this study. Results revealed that gene-expanded and non-expanded individuals reported experiencing PTG, particularly in their appreciation for life and ability to relate to others. Gene-expanded and non-expanded participants did not differ in the amount of growth they reported, which indicated that the outcome of genetic testing was not related to how much growth people experienced. Age and gender were associated with PTG, with younger participants and women reporting the most growth. The amount of time elapsed since genetic testing, estimated proximity to a diagnosis of HD, and the clinical characteristics of prodromal HD were not related to PTG. In conclusion, people experience positive psychological change as result of genetic testing for HD. The findings of this study have important implications for future research and for mental health professionals assisting people through the genetic counseling process.

La maladie de Huntington (MH) est une maladie neurodégénérative avec une transmission dominante, qui entraîne la mort dans les 15 à 20 ans suivant les premiers signes pathologiques. Le gène muté dans la MH contient une répétition de trinucléotide CAG instable qui code pour une expansion de polyglutamine (polyQ) dans la protéine huntingtine (HTT). Lorsque le gène code pour une protéine avec plus de 35 glutamines, il déclenche un dysfonction puis une mort neuronale notamment dans le striatum et le cortex, entrainant l'apparition de symptômes cognitifs, psychiatriques et moteurs. HTT est exprimée dans de nombreux tissus et est impliquée dans diverses fonctions cellulaires. Il est admis que dans la MH, l'expansion polyQ conduit à un gain de nouvelles fonctions toxiques, mais également à une perte des fonctions neuroprotectrices de HTT sauvage. Avant même l'apparition des premiers symptômes, des dysfonctions existent au sein du réseau neuronal corticostriatal. Cependant, les études in vivo des dysfonctions précoces au sein de ce réseau sont techniquement difficiles à l’échelle cellulaire.Le premier enjeu de ma thèse a été de reconstituer et de caractériser in vitro le réseau corticostriatal. Pour cela nous avons utilisé une plateforme microfluidique, compatible avec de la vidéomicroscopie haute résolution, dans laquelle chaque compartiment est identifié et où la progression de la croissance axonale à la formation des synapses est régulée. Nous avons observé des défauts majeurs au sein des différents compartiments du réseau corticostriatal, de la dynamique présynaptique à des défauts de structure et de transmission synaptiques, ainsi que des dysfonctions du trafic et des voies de signalisation post-synaptique. De manière intéressante, nous avons montré que le statut génétique du compartiment présynaptique était nécessaire et suffisant pour altérer ou restaurer le réseau corticostriatal.Le second aspect de ma thèse a été d’étudier la dynamique intracellulaire, depuis le réticulum endoplasmique jusqu’au compartiment final, au sein de cellules modèles de la MH. Pour cela nous avons utilisés le système RUSH (Retention Using Selective Hooks) couplé à une molécule utilisant la voie standard de biosynthèse des protéines. Au sein de cellules modèles de la MH, la dynamique intracellulaire est perturbée. L’utilisation de molécules inhibitrices d’une classe d’enzyme au sein de cellules modèles de la MH, est capable de restaurer une dynamique intracellulaire. En particulier, grâce au système microfluidique, nous avons montré qu’une molécule a la capacité de restaurer un réseau corticostriatal sauvage. Les études pharmacologiques de passage ont montré que cette molécule a un haut pouvoir de passage de la barrière hémato encéphalique. Le traitement pendant un mois de souris modèles de la MH et l’analyse de leur coordination motrice et de leur état anxiodépressif suggère que cette molécule est capable d’améliorer les symptômes chez les souris MH.Ces travaux ont permis de mettre en évidence 1/ l’importance du cortex comme région d’intérêt thérapeutique dans la MH, et 2/ le trafic de protéines comme une nouvelle cible thérapeutique. / Huntington Disease (HD) is a mid-life onset inherited neurodegenerative disorder that leads to death within 15 to 20 years after appearance of the first symptoms. The defective gene in HD contains an unstable trinuocleotide CAG repeat which encodes for a polyglutamine stretch (polyQ) in the huntingtin (HTT) protein. When the number of glutamines coded by the gene exceeds 35 repeats, it triggers neuronal dysfunction and death, affecting in particular the striatum and the cortex, causing cognitive, psychiatric, and motor symptoms. HTT is widely expressed and it is involved in numerous functions. In HD, it is accepted that, the polyQ strech leads to a gain of toxic functions, and converselyto a loss of neuroprotective functions of wild-type HTT. Long before the appearance of the first symptoms, dysfunctions exist within the corticostriatal neuronal network. However, in vivo studies of early cell dysfunction in this network are technically difficult, especially at the subcellular resolution.The first objective of my thesis was to reconstitute and characterize the corticostriatal network in vitro. We used a microfluidic device in which each neuronal compartment is identified and in which the progression from axonal growth to synapse regulation is controlled. We observed major defects in the different compartments of the corticostriatal circuit, from presynaptic dynamics to synaptic structure and transmission and to postsynaptic traffic and signaling. Importantly, the genetic status of the presynaptic compartment was necessary and sufficient to alter or restore the circuit.The second aspect of my thesis was to study the intracellular dynamics, from the endoplasmic reticulum to the final compartment, in cellular models of HD. For this we used the RUSH system (Retention Using Selective Hooks) coupled to a molecule using the standard pathway of protein biosynthesis. In cellular models of HD, intracellular dynamics are disrupted. We found that molecules targeting enzyme protein trafficking restore intracellular dynamics in HD cells. In particular, thanks to the microfluidic system, we showed that a given molecule has the capacity to restore a HD mutant corticostriatal network. Pharmacological studies showed that this molecule has a high power of passage of the blood brain barrier. One month treatment of HD mouse models and their behavioral tests for motor and anxiety-depressive symptoms suggest that the molecule is able to ameliorate symptoms.These studies made it possible to highlight 1 / the importance of the cortex as a key region of therapeutic interest in HD, and 2 / protein trafficking as a new therapeutic target in HD.

Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so-called priming processes (i.e., production of receptor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co-dependently govern behavioral ontogeny and outcome. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences.

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