Degeneration of the striatum and striatal-frontal circuits are generally thought to cause most of the neuropsychological symptoms experienced in Huntington‘s Disease (HD). Advances in cortical thickness mapping (an automated MRI method for precisely measuring the cortical thickness across the entire cortex) provide a new technique for examining changes in the brain in HD. Recent studies using this technology have reported provocative results. They found significant cortical thinning in participants with early HD (Rosas et al., 2002; Rosas et al., 2008) and even in presymptomatic HD (Rosas et al., 2005). Moreover, cortical thinning was most prominent in posterior regions of the brain, with relative preservation of the anterior frontal regions. The present study replicated Rosas et al.‘s (2005) study but used a larger sample of presymptomatic HD participants (n = 19) and a control group matched for age, gender and education (n = 19). Presymptomatic HD participants were divided into two groups, PreHDclose and PreHDfar, based on their estimated proximity to clinical onset. The distribution of cortical thinning was assessed using an identical MRI method to previous cortical thinning studies with HD participants. Specific neuropsychological tests were used to assess cognitive and mood changes that may be associated with cortical thinning. It was hypothesised that cortical thinning would be more evident in posterior than frontal cortical regions. It was also hypothesised that presymptomatic HD participants would perform more poorly than controls on tests that are subserved primarily by specific posterior cortical regions, but not on tests that are subserved by anterior cortical regions. Lastly, it was predicted that poorer performance in the neuropsychological measures would be associated with greater thinning in cortical regions that are important during performance of these tasks. Consistent with predictions, the presymptomatic HD group showed regionally-specific cortical thinning which was most prominent in the posterior cortices, particularly around the right parieto-temporal-occipital (PTO) junction. Thinning occurred in people up to 15 years before clinical onset, with little to no thinning before that. The presymptomatic HD group, and particularly the PreHDclose participants, performed significantly worse than controls in 2 of the 6 cognitive tests that are subserved primarily by posterior cortical regions (the Judgment of Line iii Orientation test and modified Roadmap Test), but not in tests that are subserved primarily by frontal cortical regions. Correlational analyses showed a number of regionally-specific relationships between thinning and cognitive performance, although the distribution of these relationships did not generally support our region-of-interest predictions. The results contribute to a better characterisation of the cortical and neuropsychological changes that occur early in the development of HD, and provide tentative support for cortical thickness mapping as a valid and sensitive measure for assessing cortical changes in presymptomatic HD.

Degeneration of the striatum and striatal-frontal circuits are generally thought to cause most of the neuropsychological symptoms experienced in Huntington‘s Disease (HD). Advances in cortical thickness mapping (an automated MRI method for precisely measuring the cortical thickness across the entire cortex) provide a new technique for examining changes in the brain in HD. Recent studies using this technology have reported provocative results. They found significant cortical thinning in participants with early HD (Rosas et al., 2002; Rosas et al., 2008) and even in presymptomatic HD (Rosas et al., 2005). Moreover, cortical thinning was most prominent in posterior regions of the brain, with relative preservation of the anterior frontal regions. The present study replicated Rosas et al.‘s (2005) study but used a larger sample of presymptomatic HD participants (n = 19) and a control group matched for age, gender and education (n = 19). Presymptomatic HD participants were divided into two groups, PreHDclose and PreHDfar, based on their estimated proximity to clinical onset. The distribution of cortical thinning was assessed using an identical MRI method to previous cortical thinning studies with HD participants. Specific neuropsychological tests were used to assess cognitive and mood changes that may be associated with cortical thinning. It was hypothesised that cortical thinning would be more evident in posterior than frontal cortical regions. It was also hypothesised that presymptomatic HD participants would perform more poorly than controls on tests that are subserved primarily by specific posterior cortical regions, but not on tests that are subserved by anterior cortical regions. Lastly, it was predicted that poorer performance in the neuropsychological measures would be associated with greater thinning in cortical regions that are important during performance of these tasks. Consistent with predictions, the presymptomatic HD group showed regionally-specific cortical thinning which was most prominent in the posterior cortices, particularly around the right parieto-temporal-occipital (PTO) junction. Thinning occurred in people up to 15 years before clinical onset, with little to no thinning before that. The presymptomatic HD group, and particularly the PreHDclose participants, performed significantly worse than controls in 2 of the 6 cognitive tests that are subserved primarily by posterior cortical regions (the Judgment of Line iii Orientation test and modified Roadmap Test), but not in tests that are subserved primarily by frontal cortical regions. Correlational analyses showed a number of regionally-specific relationships between thinning and cognitive performance, although the distribution of these relationships did not generally support our region-of-interest predictions. The results contribute to a better characterisation of the cortical and neuropsychological changes that occur early in the development of HD, and provide tentative support for cortical thickness mapping as a valid and sensitive measure for assessing cortical changes in presymptomatic HD.

Thesis (Ph. D.)--University of Lund, 1994. / Published dissertation. Includes bibliographical references.

Thesis (Ph. D.)--University of Lund, 1994. / Published dissertation. Includes bibliographical references.

La combinaison de biomatériaux et cellules souches, a pour but de protéger des cellules endommagées et de ralentir la progression des maladies neurodégénératives, comme la maladie de Huntington (MH). Les cellules souches mésenchymateuses et particulièrement une sous-population, les cellules MIAMI, ont déjà démontré leur efficacité dans la maladie de Parkinson. Il est cependant essentiel d’améliorer leur différenciation neuronale, leur survie et évaluer leur sécrétome. L’objectif principal de ce travail fut de proposer une stratégie innovante de médecine régénératrice pour la MH associant cellules souches, nano et micro médecines. Pour l’évaluer, un nouveau modèle animale ex vivo de la MH a été mis en place. Nous avons ensuite développé et optimisé deux nano-vecteurs, des nanocapsules lipidiques et des nanoparticules solides de SPAN, et les avons associés à un inhibiteur de REST qui est un facteur de transcription qui empêche la différenciation neuronale. La transfection de ce siREST a montré une amélioration du phénotype neuronal. Ces cellules ainsi modifiées furent ensuite induites vers un phénotype GABAergic grâce à des facteurs de croissance. Puis elles ont été associées à un support 3D, les microcarriers pharmacologiquement actif (MPA) permettant une meilleure intégration des cellules après greffe. Les MPA sont des microsphères ayant une surface biomimétique de laminine et libérant de façon contrôlée un facteur trophique le « brain derived neurotrophic factor » (inducteur d’un phénotype neuronal et neuro-protecteur). Des résultats prometteurs ont été obtenus, encourageant à continuer l’évaluation de cette stratégie in vivo dans des modèles génétiques de la MH. / The combination of biomaterials and stem cells aims to protect damaged cells and slow the progression of neurodegenerative diseases such as Huntington's disease(HD). Mesenchymal stem cells, particularly a subpopulation known as MIAMI cells, have already demonstrated their effectiveness in Parkinson's disease. However, it is essential to improve their neuronal differentiation, survival, and to assess their secretome. The main objective of this work was to propose an innovative regenerative medicine strategy for HD by combining stemcells, micro and nano medicines. To perform this assessment, a new ex vivo animal model of HD has been set up. We then developed and optimized two nanovectors,lipid nanocapsules and solid SPAN nanoparticles,carrying an inhibitor of REST a transcription factor, which prevents neuronal differentiation. The transfection of this siREST showed an improvement in the neuronal phenotype. These modified cells were then induced into a GABAergic phenotype through growth factors. They were then associated with a 3D support, the pharmacologically active microcarriers (PAM) allowing a high rate of engraftment. The PAM are microspheres which have a biomimetic surface of laminin and release a trophic factor BDNF, brain derived neurotrophic factor (inducer of a neural phenotype and neuroprotective) in a controlled manner. Promising results were obtained, further encouraging continuing the evaluation of this strategy in vivo in genetic models of HD.

Huntington's disease (HD) is an autosomal dominant inherited neuro-psychiatric disease with usual onset in the middle age. The mutation, located on the short shoulder of chromosome 4, is an expansion of a nucleotide triplet, containing cytosine, adenine, guanine (CAG), with critical limit of 40+ repetitions. The principal symptoms include motor symptoms (chorea, dystonia, disorders of voluntary movements), progressive cognitive deterioration and neuropsychiatric symptoms (behaviour disorders, affective symptoms and so on). The clinical diagnosis is confirmed by a genetic test, which may also be carried out presymptomatically in offsprings of the diseased person. The objective of the 1st study consisted in the characterization of differences in psychiatric examination and neuropsychological testing among the people at risk (PAR), in whom it was recommended to delay the test, and people at risk, who were recommended to continue in the so-called predictive protocol. The total of 52 people have been examined (32 females, 20 males). In addition to the common psychiatric examination we have also administered the Eysenck Personality Questionnaire (EPQ-A), self-rating scale of general psychopathology (SCL- 90), three short cognitive tests - Trail making test, test of Verbal fluency and...

This diploma thesis explores problematic areas of patients with Huntington's disease in their performance during activities of daily living (ADLs) from the perspective of patients and their caregivers. The aim of the research was also to assess a possible correlation between cognitive impairment and the patient's performance in ADL. Twenty-five patients with their caregivers met the selection criteria for the research. There were used standardized assessment methods available in Czech: the Montreal Cognitive Assessment (MoCA), the Canadian Occupational Performance Measure (COPM) and the questionnaire for caregivers called Bristol Activities of Daily Living Scale (BADLS-CZ). The statistical analyses consisted of methods of the nonparametric statistics, qualitative analysis was processed by data categorizing. Caregivers reported more problematic areas in ADLs which was significantly confirmed in the statistical hypothesis testing (p <0,05). A significant correlation was seen between the results of the questionnaire and the results of the MoCA assessment (rSp = -0,620; p <0,05). For various reasons, patients with Huntington's disease did not mention as many problematic areas in performing ADL as their caregivers. Therefore, it is appropriate in clinical practice to supplement the assessment of the patient's...

As doenças neurodegenerativas (DN) estão entre as principais causas de mortalidade e morbidade nos países ocidentais. Não há ainda um tratamento definitivo para estas neuropatias, mas estudos têm indicado mecanismos comuns de toxicidade que incluem disfunção mitocondrial, estresse oxidativo, apoptose e neuroinflamação. Adicionalmente, o efeito benéfico da neuroplasticidade induzida por fatores neurotróficos no retardamento ou inibição do processo neurodegenerativo também tem sido sugerido por muitos estudos. O beta-cariofileno é um sesquiterpeno bi-cíclico encontrado no óleo essencial de algumas plantas, e que possui efeito anti-inflamatório e antioxidante. Assim, este composto possui características e é capaz de induzir efeitos que o tornam um potencial candidato ao tratamento/prevenção dos processos envolvidos na neurodegeneração. Apesar disso, pouco se sabe sobre os efeitos e os mecanismos de ação do beta-cariofileno no processo de degeneração neuronal. Então, neste estudo, avaliou-se o efeito do beta-cariofileno em modelos celulares (PC 12) de neurotoxicidade que mimetizam in vitro os mecanismos moleculares envolvidos nas doenças de Parkinson, Huntington e Alzheimer, os quais, para efeitos práticos, denominaremos de \"modelos celulares de Parkinson, Huntington e Alzheimer\". Estes modelos são induzidos experimentalmente pela neurotoxina dopaminérgica iodeto de 1-metil 4-fenil piridina (MPP+), pela neurotoxina mitocondrial ácido 3-nitropropiônico (3NP) e pelo peptídeo neurotóxico B-amiloide (AB42), respectivamente. O beta-cariofileno apresentou efeitos benéficos nestes três modelos de neurotoxicidade, e adicionalmente induziu neuritogênese e a expressão de proteínas neurotípicas no modelo neuronal. Este é o primeiro estudo a demonstrar tais efeitos do beta-cariofileno. / Neurodegenerative diseases (ND) are among the leading causes of mortality and morbidity in Western countries. There is not a definitive treatment for these neuropathies, but studies have indicated common mechanisms of toxicity that include mitochondrial dysfunction, oxidative stress, neuroinflammation and apoptosis. Additionally, the beneficial effect of the neuroplasticity induced by neurotrophic factors on the retardation or inhibition of neurodegeneration has also been suggested by several studies. Beta-caryophyllene is a bicyclic sesquiterpene found in essential oils of some plants, and possesses anti-inflammatory and antioxidant effects. Thus, this compound has characteristics and is capable of inducing effects that make it a potential candidate for treatment / prevention of the processes involved in neurodegeneration. Despite this, little is known about the effects and mechanisms of action of beta-caryophyllene in the neuronal degeneration process. Then, this study evaluated the effect of beta-caryophyllene in cellular models of neurotoxicity (PC 12) that mimic in vitro the molecular mechanisms involved in Parkinson\'s, Huntington\'s and Alzheimer\'s diseases, which, for practical purposes, we will denominate \"Cellular models of Parkinson\'s, Huntington\'s and Alzheimer\'s diseases.\" These models are experimentally induced by the dopaminergic neurotoxin 1-methyl iodide, 4-phenyl pyridine (MPP+), by the mitochondrial neurotoxin 3-nitropropionic acid (3NP) and the neurotoxic peptide B-amyloid (AB42), respectively. Beta-caryophyllene showed beneficial effects on these three models of neurotoxicity, and additionally induced neuritogenesis and the expression of neurotypic proteins in the neuronal model. This is the first study to demonstrate such effects of beta-caryophyllene.

A doença de Huntington (DH) é um distúrbio neurodegenerativo hereditário e autossômico dominante e tem como características alterações motoras e mentais progressivas. Recentemente, além das alterações verificadas no sistema nervoso central, também têm sido descritas alterações em órgãos periféricos, tais como osteoporose, atrofia muscular, problemas intestinais, alterações cardíacas e, sobretudo, alterações no sistema nervoso autônomo. São evidentes as alterações autonômicas do coração nos portadores da DH, as quais, são, sobretudo, um risco potencial, tornando os pacientes suscetíveis a problemas cardiovasculares. No entanto, os mecanismos pelos quais a doença afeta os componentes autonômicos do coração não são totalmente conhecidos, por isso a importância de se estudar os componentes da inervação cardíaca, sobretudo o gânglio estrelado (GE). A DH pode ser induzida através do ácido 3-nitropropiônico (3-NP), pois essa substância produz efeitos neurotóxicos inibindo a succinato desidrogenase. Esta pesquisa objetiva analisar, por meio da indução através do 3-NP, os efeitos da DH no GE, identificando possíveis alterações morfoquantitativas dos neurônios ganglionares, com uso de técnicas baseadas em delineamento estereológico 3D e de bioimagem associadas à teste comportamental e perfil hemodinâmico, a fim de contribuir para o entendimento de como a doença age na inervação do coração. Para isso foram utilizados 14 camundongos C57BL-6 machos que foram alocados em dois grupos: Grupo Controle com 7 animais induzidos com solução salina (0,9%); Grupo 3NP com 7 animais induzidos com doses subagudas de 60 mg.kg-1dia-1 de 3-NP. Foram realizados o teste comportamental, a avaliação cardíaca e a análise estereológica. Os principais achados dessa pesquisa foram: (I) diminuição da atividade exploratória dos animais; (II) prejuízo da função sistólica; (III) aumento de 76% no volume ganglionar; (IV) aumento de 70% no volume médio dos neurônios, concluindo-se que o 3-NP produz efeitos na função cardíaca, ocasionando hipertrofia do gânglio / Huntington\'s disease (HD) is a hereditary and autosomal dominant neurodegenerative disorder and is characterized by progressive motor and mental changes. Recently, in addition to changes in the central nervous system, alterations in peripheral organs such as osteoporosis, muscular atrophy, intestinal problems, cardiac alterations and, above all, changes in the autonomic nervous system have also been described. Autonomic heart alterations in DH patients are evident, which are a potential risk, making patients susceptible to cardiovascular problems. However, the mechanisms by which the disease affects the autonomic components of the heart are not fully understood, therefore, the importance of studying the components of cardiac innervation, especially the stellate ganglion (SG). HD can be induced through 3-nitropropionic acid (3-NP), as this substance produces neurotoxic effects inhibiting succinate dehydrogenase. The aim of this research was to analyze the effects of HD on the SG by means of 3-NP induction, identifying possible morpho-quantitative changes in ganglion neurons, using techniques based on 3D stereological and bioimaging techniques associated with behavioral and hemodynamic profile, In order to contribute to the understanding of how the disease acts in the heart innervation. For this, 14 male C57BL-6 mice were used, which were allocated in two groups: Control Group with 7 animals induced with saline solution (0.9%); Group 3NP with 7 animals induced with subacute doses of 60 mg.kg-1day-1 of 3-NP. Behavioral test, cardiac evaluation and stereological analysis were performed. The main findings of this research were: (I) decrease in the exploratory activity of the animals; (II) impairment of systolic function; (III) 76% increase in ganglion volume; (IV) increase of 70% in the mean volume of the neurons, concluding that 3-NP produces effects on cardiac function, causing hypertrophy of the ganglion

La maladie de Huntington est une maladie neurodégénérative héréditaire qui est devenue un modèle d'étude pour comprendre la physiopathologie des maladies du cerveau associées à la production de protéines mal conformées et à la neurodégénérescence. Bien que plusieurs mécanismes aient été mis en avant pour cette maladie, dont plusieurs seraient aussi impliqués dans des pathologies plus fréquentes comme la maladie d’Alzheimer ou la maladie de Parkinson, nous ne savons toujours pas quels sont les mécanismes ou les profils moléculaires qui déterminent fondamentalement la dynamique des processus de dysfonction et de dégénérescence neuronale dans cette maladie. De même, nous ne savons toujours pas comment le cerveau peut résister aussi longtemps à la production de protéines mal conformées, ce qui suggère en fait que ces protéines ne présentent qu’une toxicité modérée ou que le cerveau dispose d'une capacité de compensation et de résilience considérable. L'hypothèse de mon travail de thèse est que l'intégration de données génomiques et transcriptomiques au travers des modèles qui récapitulent différentes phases biologiques de la maladie de Huntington peut permettre de répondre à ces questions. Dans cette optique, l'utilisation des réseaux de gènes et la mise en application de concepts issus de la théorie des graphes sont particulièrement bien adaptés à l'intégration de données hétérogènes, au travers des modèles et au travers des espèces. Les résultats de mon travail suggèrent que l'altération précoce (avant les symptômes, avant la mort cellulaire) et éventuellement dès le développement cérébral) des grandes voies de développement et de maintenance neuronale, puis la persistance voire l'aggravation de ces effets, sont à la base des processus physiopathologiques qui conduisent à la dysfonction puis à la mort neuronale. Ces résultats permettent aussi de prioriser des gènes et de générer des hypothèses fortes sur les cibles thérapeutiques les plus intéressantes à étudier d'un point de vue expérimental. En conclusion, mes recherches ont un impact à la fois fondamental et translationnel sur l'étude de la maladie de Huntington, permettant de dégager des méthodes d'analyse et des hypothèses qui pourraient avoir valeur thérapeutique pour les maladies neurodégénératives en général. / Huntington’s disease is a hereditary neurodegenerative disease that has become a model to understand physiopathological mechanisms associated to misfolded proteins that ocurs in brain diseases. Despite exciting findings that have uncover pathological mechanisms occurring in this disease and that might also be relevant to Alzheimer’s disease and Parkinson’s disease, we still do not know yet which are the mechanisms and molecular profiles that rule the dynamic of neurodegenerative processes in Huntington’s disease. Also, we do not understand clearly how the brain resist over such a long time to misfolded proteins, which suggest that the toxicity of these proteins is mild, and that the brain have exceptional compensation capacities. My work is based on the hypothesis that integration of ‘omics’ data from models that depicts various stages of the disease might be able to give us clues to answer these questions. Within this framework, the use of network biology and graph theory concepts seems particularly well suited to help us integrate heterogeneous data across models and species. So far, the outcome of my work suggest that early, pre-symptomatic alterations of signaling pathways and cellular maintenance processes, and persistency and worthening of these phenomenon are at the basis of physiopathological processes that lead to neuronal dysfunction and death. These results might allow to prioritize targets and formulate new hypotheses that are interesting to further study and test experimentally. To conclude, this work shall have a fundamental and translational impact to the field of Huntington’s disease, by pinpointing methods and hypotheses that could be valuable in a therapeutic perspective.