Human to computer interaction only using thoughts is no longer a science fiction topic and recent progress made in this field are astounding. This work shows the creation of a novel upper limb pointing movement performance quantification platform (eCAM test) and its validation on a group of healthy subjects. After that, it shows that functional electrical stimulation (FES) enhances these upper limbs movements performance. Furthermore, this work shows that anodal transcranial direct current stimulation (atDCS) of the cerebellum impacts brain rhythms as well as postural tremor on a patient. Also, the MRI data gathered during this work will allow to better understand the underlying mechanisms of tDCS. Following that, it has been shown that the frequency and complexity of a tapping task increase the postural tremor of the contralateral limb. The same effect has been witnessed for neuromuscular fatigue. All these advances allowed us to place the foundations of a multimodal brain computer interface (BCI) based on sensors fusion. A development phase is now required to create this interface and test it on healthy and sick subjects. / Communiquer avec un ordinateur par le biais de la pensée n'est plus un sujet de science-fiction et les progrès effectués dans le domaine sont ahurissants. Ce travail montre la création d'une nouvelle plateforme de mesure de la performance des mouvements de pointage verticaux (eCAM test) ainsi que sa validation sur une cohorte de sujets sains. Suite à cela, il montre que la stimulation électrique fonctionnelle (FES) améliore la performance de ces mouvements des membres supérieurs. En plus il démontre que la stimulation anodale trancranienne en courant continu (atDCS) du cervelet a un effet sur les rythmes des signaux cérébraux ainsi que sur le tremblement postural d'un patient. De plus des données IRM recueillies durant ce travail permettront de mieux cerner les mécanismes d'action de la stimulation tDCS. Suite à cela, il a été montré que la fréquence et la complexité d'une tâche de tapping augmentent le tremblement postural du membre controlatéral. Le même effet est constaté pour la fatigue musculaire. Toutes ces avancées installent les fondements à la création d'une interface cerveau-machine multimodale basée sur la fusion de senseurs. Une phase de développement est maintenant nécessaire pour établir cette interface et la tester sur des sujets sains et malades. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

With cardiovascular disease, diabetes mellitus, and neurodegenerative conditions on the rise, understanding their pathogenesis is paramount to tackling this public health crisis. Current research indicates that the primary cause of these diseases is mitochondrial dysfunction in the affected patients. While genetics plays a role in these conditions, lifestyle choices and exposure to toxins also significantly contribute to their development. Unfortunately, early-stage diagnosis can be difficult due to overlapping symptoms with other diseases. Developing innovative therapies that can prevent or reverse the deterioration of metabolic dysfunctions is critical to establishing early intervention. My research focused on investigating molecular targets linked with Friedrich's Ataxia, an inherited metabolic disorder, through conducting functional in-vitro studies using human-derived cell samples, as well as developing inventive animal models created via Xenopus laevis tadpoles to evaluate the effects of environmental stressors. My investigations have uncovered promising treatment options that improve mitochondrial function, mitigate oxidative stress, and elucidate critical mechanisms involved in environmentally induced disruptions to mitochondria. / Doctor of Philosophy / Metabolic dysfunction is a widespread health issue that affects millions of individuals each day. Its associated disorders, such as cardiovascular disease, diabetes, and neurodegenerative conditions, are rising due to various factors ranging from genetic predispositions to environmental and lifestyle-related risks. Therefore, there's an urgent need to identify this disorder early on and develop innovative treatment options. Considering this growing public health concern, it has become imperative to establish new methods for detecting metabolic dysfunction at its nascent stage while also exploring potential therapeutic interventions. Our research utilized cells derived from affected patients and animal models in devising novel approaches toward understanding the molecular mechanisms underpinning metabolic dysfunction. Our findings revealed several pathways and molecular targets contributing significantly to this condition, which could effectively be leveraged to develop targeted therapeutic strategies to combat its effects. Expanding our knowledge base will enable us to stay updated with emerging insights on treating metabolic dysfunction effectively while substantially improving patient outcomes.

No description available.

Neurodegenerative disorders are among the most devastating human illnesses. They present a significant source of morbidity and mortality, and given an aging population, an impending public health crisis. Disease-modifying treatments remain sparse, with most current therapies focused on reducing symptom burden. The cellular stress response is intimately linked to energy management and has frequently been posited as playing a central role in neurodegeneration. Using two distinct neurodegenerative diseases as ‘case studies’, aberrant cellular stress and energy management are demonstrated as potential pathways contributing to neurodegeneration. First, the Huntington’s disease protein, huntingtin, is observed to rapidly localize to early endosomes, where it is associated with arrest in early-to-late and early-to-recycling endocytic trafficking. Given the energy-dependent nature of vesicular trafficking, this arrest is postulated to free substantial energy within the cell, which may subsequently be diverted to pathways that are critical for the initiation of longer-duration stress responses, such as the unfolded protein response. In the context of Huntington’s disease, impaired recovery from this stress response is observed, suggesting deficits in intracellular vesicular trafficking and energy regulation exist in disease states. In the second ‘case study’, a novel spinocerebellar ataxia variant is characterized, occurring as a result of point mutations within two genes: ATXN7 and TOP1MT, which encode ataxin-7 and the type I mitochondrial topoisomerase (top1mt), respectively. Ataxin-7 has previously been implicated in spinocerebellar ataxia type 7, which occurs as a result of a polyglutamine expansion in the first exon of the protein. Patient cells are noted to have substantially lower mitochondrial respiratory function in comparison to healthy controls and decreased levels of mitochondrial DNA, and ataxin-7 subcellular localization is observed to be abnormal. This suggests that there is important interplay between the mitochondria and proteins implicated in neurodegeneration and provides further support for aberrant cellular bioenergetics as a unifying pathway to neurodegeneration. In the concluding chapters, the nuclear localization signal of ataxin-7 is characterized, and there is analysis comparing conical ‘atraumatic’ lumbar puncture needles with bevel-tipped ‘conventional’ needles. Atraumatic needles are noted to be associated with significantly less patient complications and require fewer return visits to hospital. Moreover, atraumatic needles are demonstrated to have similar rates of success and failure when controlling for important variables like clinician specialty, dispelling common misconceptions surrounding their ease-of-use. As lumbar puncture is ubiquitous within the clinical neurosciences and is important for diagnosis, monitoring, and treatment of disease, as well as clinical trials, this work has far-reaching implications for patient care and future research. / Thesis / Doctor of Philosophy (PhD)

Background. People with spinocerebellar ataxia (SCA) have symptoms that impact balance, gait, motor learning and control. Independently, balance training (BT) and aerobic exercise (AE) have improved motor function for people with SCA. Studies in stroke and Parkinson disease have evaluated the use of AE prior to BT as a form of motor priming to enhance motor learning. Motor priming has not been explored in SCA. Introduction & Purpose. This was a pilot randomized controlled trial aimed to 1) determine the feasibility and efficacy of an 8-week telehealth intervention of high intensity AE prior to BT (HIBT) compared to low intensity exercise prior to BT (LIBT) on disease specific motor and cognitive outcomes, and 2) explore changes in patient reported outcomes as well as functional outcomes post exercise intervention in people with SCA. Methods. Participants (n=20) were randomized to receive either HIBT, or LIBT, for 60 minutes, twice weekly, for 8-weeks over telehealth. The HIBT group underwent 30 minutes of High Intensity Interval Training (HIIT) prior to 30 minutes of BT, while the LIBT group underwent 30 minutes of low intensity warm up type exercises prior to 30 minutes of BT. Outcomes were assessed at baseline, mid- and post-intervention and included: disease specific measures (e.g., Cerebellar Cognitive Affective Scale (CCAS), Scale for Assessment and Rating of Ataxia at Home (SARAHome), functional measures of balance and gait (e.g., Timed Up and Go test (TUG), 30 second Sit to Stand Test (30secSTS)), patient reported measures (e.g., fatigue severity scale (FSS-49)) and metrics of feasibility. Data for disease specific, and functional outcomes were not normally distributed. Data for patient reported outcomes was normally distributed. Statistical significance of findings are reported as p-value. Results. A total of 93 people were referred to this intervention, and 20 were enrolled (21.5% enrollment). Eighteen participants completed the intervention and post-intervention outcome assessments (90% retention). Both the HIBT and LIBT interventions had high acceptance from on the post-intervention questionnaire. Enrolled participants had a mean (SD) age of 58.1(13.5) yrs; 6M/14F. Diagnoses were early-mid stage SCA types 1, 2, 3, and 6. Participants showed 100% adherence to the intervention, with 1 adverse event of low back pain exacerbation which resolved. Both groups improved on disease specific measures of the CCAS, and SARAHome where outcomes for the SARAHome surpassed the established group minimal detectable change score of 0.3 points. At post-intervention however, there were no between group differences identified on the SARAHome (p > .05), however for the CCAS the LIBT group demonstrated significant improvements at post intervention over the HIBT group (p < .01). There were no differences observed at post-intervention between groups for functional measures such as the TUG test, 30secSTS test, or in any static stance position. The LIBT group showed greater changes in fatigue post-intervention, (p < .05). The HIBT group showed no significant change in fatigue, however they displayed decreased tolerability to engage in BT after engagement in AE. The HIBT group managing to complete an average of only 8.50 BT exercises per session while LIBT completed 10.04. Conclusions. Results from this pilot randomized controlled trial support a telehealth-delivered exercise intervention for people with SCA 1, 2, 3, and 6, with low overall attrition, and high rates of intervention adherence, and acceptability. However, effect estimates do not support the hypothesis of motor priming in people with SCA. Fatigue after engagement in AE limited intervention tolerability for BT in the HIBT group, and this suggests that fatigue may stand as a potential barrier for not only exercise engagement and functional improvement, but also neuroplastic growth and motor learning potential. Future research should aim to optimize exercise prescription to mitigate fatigue in this population.

Diploma the 'is deals wi th the research of effect of biofeedback in the form of electrotactile stimulation of tongue in the patients with balance disorders eaused by the cerebellar lesion. For the therapeutic program 4 patients with cerebellar ataxia at the age of38 - 74 years were chosen. Subjects have partieipated in the therapeutic program with the application of biofeedback, they were training postural stability while visual control was excluded and they were using electrotacti le signal on the tongue for orientation. I used neurological tests BESTest and Dynamic Oait Index, questionnaire The Activities- Specific Balance Confidence (ABC) Scale, Dizziness I Tandicap Inventory (D ll) a Visual Analogue Scale (VAS), and examination by stati posturography for evaluation of postural stability in the patients. I supposed that therapy by biofeedback in the form of electrotactile stimulation of tongue improves postural stability in the patients with balance disorders caused by cerebellar lesion. Powered by TCPDF (www.tcpdf.org)

A hipomielinização ou leucodistrofia hipomielinizante caracteriza-se por diminuição da produção de mielina e consequente redução significativa e permanente de seu depósito na substância branca cerebral. A ressonância magnética (RM) de encéfalo é essencial para o diagnóstico e revela hipersinal leve a moderado na imagem pesada em T2 e sinal variável na imagem pesada em T1, na dependência da quantidade de mielina formada. Para crianças abaixo de 2 anos de idade, mais de um estudo por RM pode ser necessário para confirmar a ausência de mielinização. As leucodistrofias hipomielinizantes clássicas são: a doença de Pelizaeus-Merzbacher (PMD), a doença de Pelizaeus-Merzbacher símile (PMLD), a síndrome de Cockayne, a síndrome 18q-, e mais recentemente descritas, a hipomielinização com catarata congênita (HCC), a hipomielinização com atrofia dos núcleos da base e cerebelo e a hipomielinização com hipodontia e hipogonadismo hipogonadotrófico (síndrome 4H). O objetivo desta tese foi descrever aspectos clínicos, eletrofisiológicos e de neuroimagem em pacientes com hipomielinização. Vinte e cinco pacientes foram incluídos no estudo, apresentando os seguintes diagnósticos: PMD (5), PMLD (5), HCC (1), síndrome de Cockayne (4), síndrome 18q- (1) e leucodistrofias hipomielinizantes não classificadas (4). A avaliação clínica e por RM foi realizada em todos os pacientes e a maioria destes foram submetidos aos estudos eletrofisiológicos com eletroencefalograma (88%), estudo de neurocondução (84%) e potenciais evocados (84%). Vinte e duas famílias foram envolvidas, com consanguinidade reconhecida em quatro delas. A idade variou de 5-21 anos e o sexo masculino representou 56% da amostra. O quadro neurológico teve início até os 3 anos, habitualmente com nistagmo ou ataxia. Manifestações inespecíficas comumente encontradas foram: curso clínico estático ou lentamente progressivo, atraso do desenvolvimento neuropsicomotor, comprometimento antropométrico, deficiência mental, ataxia, sinais de liberação piramidal, nistagmo e alterações da movimentação ocular. Crises epilépticas e manifestações extrapiramidais foram verificadas com menor frequência. Achados discriminatórios foram: o curso clínico progressivo na síndrome de Cockayne, a piora episódica na síndrome 4H, o nistagmo pendular e o tremor cefálico em PMD e PMLD, os dismorfismos nas síndromes de Cockayne e 18q -, a fotossensibilidade na síndrome de Cockayne, as alterações da dentição e o envolvimento endocrinológico na síndrome 4H. O eletroencefalograma exibiu desorganização difusa da atividade elétrica cerebral em 95% dos pacientes, frequentemente associada à assincronia dos elementos fisiológicos do sono, com ou sem paroxismos epileptiformes. O estudo de neurocondução revelou neuropatia periférica desmielinizante, sensitivo-motora ou puramente motora, em 33% da amostra, incluindo pacientes com HCC, síndrome de Cockayne, síndrome 4H e hipomielinização não classificada. Os potenciais evocados evidenciaram disfunção central das vias visuais (29%), auditivas (57%) e somatossensitivas (67%), sem diferenças entre os grupos. O padrão neurorradiológico de hipomielinização, constante entre os grupos, caracterizou-se por alteração simétrica, difusa, extensa e homogênea da substância branca, com hipersinal em T2 e sinal variável em T1. No entanto, algumas particularidades foram observadas em alguns grupos como: maior mielinização da base em relação ao tegmento da ponte em PMD, em HCC e na síndrome 18q-; maior mielinização do tegmento em relação à base em PMLD; predomínio de mielinização no terço médio ou no esplênio do corpo caloso na síndrome 4H; preservação relativa dos tratos piramidais em PMD e na síndrome 4H; mielinização próxima ao normal no núcleo anterolateral do tálamo em PMD, PMLD e na síndrome 4H; focos de mielinização preservada na síndrome 4H; atrofia moderada a grave no corpo caloso em PMD e PMLD ou em cerebelo e corpo caloso na síndrome 4H; atrofia global acentuada na síndrome de Cockayne e ausência de atrofia na síndrome 18q-. Desta forma, confirmamos a heterogeneidade clínica, eletrofisiológica e de neuroimagem da hipomielinização, com resultados muito similares às descrições originais de cada doença, além de reconhecer padrões clínicos e de neuroimagem específicos para algumas doenças. As principais limitações deste estudo foram o tamanho reduzido da nossa amostra e a ausência de confirmação diagnóstica molecular de alguns pacientes. Com o crescente reconhecimento das leucodistrofias hipomielinizantes, torna-se fundamental a melhor compreensão de sua ampla diversidade etiológica, bem como, de suas diferenças sutis / Hypomyelination or hypomyelinating leukodystrophy is characterized by reduced myelin production, leading to significant and permanent decrease on the amount of myelin on the brain white matter. Brain magnetic resonance imaging (MRI) is essential for its diagnosis and discloses a mild to moderate T2W hypersignal and variable T1W signal, which is dependent on the amount of myelin formed. For children bellow 2 years of age, more than one MRI study might be necessary in order to confirm lack of myelination. Classical hypomyelinating leukodystrophies are: Pelizaeus-Merzbacher disease (PMD), Pelizaeus-Merzbacher-like disease (PMLD), Cockayne syndrome, 18q- syndrome, and the more recently described, hypomyelination and congenital cataract (HCC), hypomyelination with atrophy of the basal ganglia and cerebellum, and hypomyelination with hypodontia and hypogonadotrophic hypogonadism (4H syndrome). The aim of this thesis was to describe clinical, electrophysiological and neuroimaging characteristics of patients with hypomyelination. Twenty-five subjects were included in this study and they presented with the following diagnosis: PMD (5), PMLD (5), HCC (1), Cockayne syndrome (4), 18q- syndrome (1) and unclassified hypomyelinating leukodystrophy (4). Clinical and MRI evaluation were performed in all subjects and most of them were submitted to electrophysiological studies with electroencephalogram (88%), nerve conduction study (84%) and multimodel evoked potentials (84%). Twenty- two families were enrolled and imbreeding was recognized in four of them. The age range was 5 to 21 years and males represented 56% of the sample. The age of onset of neurological symptoms was before 3 years old and was characterized mainly by nystagmus and ataxia. Inespecific manifestations commonly seen were: static or slowly progressive clinical course, neurodevelopmental delay, failure to thrive, mental retardation, ataxia, pyramidal signs, nystagmus and other eye movements abnormalities. Epilepsy and extrapyramidal signs were seldom noticed. Discriminant findings were: progressive clinical decline in Cockayne syndrome, episodic deterioration in 4H syndrome, pendular nystagmus and cephalic tremor in PMD and PMLD, dysmorphisms in Cockayne and 18q- syndromes, photosensitivity in Cockayne syndrome, dentition abnormalities and endocrine involvement in 4H syndrome. Electroencephalogram displayed diffuse disorganization of brain electrical activity in 95% of the patients, frequently associated with asynchrony of sleep physiological elements, with or without epileptiform paroxysms. Nerve conduction study disclosed sensory-motor or purely motor demyelinating peripheral neuropathy in 33% of the sample, including patients with HCC, Cockayne syndrome, 4H syndrome and unclassified hypomyelinating leukodystrophy. Evoked potentials demonstrated central dysfunction of the visual (29%), auditory (57%) and somatosensory (67%) pathways, without discrimination among the groups. Hypomyelination pattern on brain MRI was constant among the groups and was characterized by symmetrical, diffuse, extensive and homogeneous abnormal white matter, displayed by T2W hypersignal and variable T1W signal. Nevertheless, some particular findings were observed in some groups: increased myelination of basilar portion of pons compared to the tegmental region in PMD, HCC and 18q- syndrome; increased tegmental myelination compared to the basilar portion of pons in PMLD; predominant myelination of corpus callosum truncus and splenium in 4H syndrome; relative sparing of pyramidal tract in PMD and 4H syndrome; close to normal myelination in anterolateral nucleus of the thalamus in PMD, PMLD and 4H syndrome; focal areas of preserved myelination in 4H syndrome; moderate to severe atrophy of corpus callosum in PMD and PMLD, and of cerebellum and corpus callosum in 4H syndrome; global and pronounced brain atrophy in Cockayne syndrome, and no brain atrophy in 18q- syndrome. We were able to confirm the clinical, electrophysiological and neuroimaging heterogeneity in hypomyelination, with findings similar to those of the original descriptions, and to recognize specific clinical and neuroimaging patterns in some conditions. The main limitations of this study were the small size of our sample and the absence of molecular confirmation of diagnosis in some of the patients. As hypomyelinating leukodystrophy is being recognized with increasing frequency, it is imperative to have a better understanding of their broad etiologic diversity and their subtle differences

A mutação espontânea tremor (tr) , autossômica recessiva, foi identificada na colônia de camundongos Swiss no Biotério do Departamento de Patologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo. Os mutantes apresentaram como principais características fenotípicas tremores, ataxia e convulsões tônicas audiogênicas. Por meio de dez retrocruzamentos essa mutação foi transferida para a linhagem congênica C57BL/6 (N10). O mapeamento genético com marcadores microssatélites distribuídos pelo genoma do camundongo indicou que a mutação tr encontra-se no cromossomo 14, na região entre 33,21 e 38,21 cM, tendo como possível candidato o gene Egr3 (Early Growth Response 3). O presente estudo teve como objetivo caracterizar o fenótipo comportamental do camundongo mutante tremor. A caracterização do fenótipo dos camundongos mutantes Swiss foi realizada a partir do nascimento até a idade adulta. Os parâmetros do desenvolvimento físico analisados foram: desdobramento das orelhas, erupção dos dentes incisivos, abertura dos olhos, surgimento da pelagem completa, ganho de peso e comprimento dos filhotes e desenvolvimento sexual. No desenvolvimento reflexológico foram analisados: preensão palmar, geotaxia negativa, endireitamento de postura e sobressalto. No 21&ordem; dia de vida foi realizado o teste de campo aberto para analisar a atividade geral dos animais, e no 60&ordem; dia esse teste foi repetido, juntamente com testes para analisar parâmetros comportamentais. Os testes realizados em campo aberto foram ordenados por parâmetro avaliado; 1) atividade geral dos animais e sistema sensorial: frêmito vocal, irritabilidade, reflexo auricular, aperto de cauda, reflexo corneal e resposta ao toque; 2) testes psicomotores: trem posterior, reflexo de endireitamento, tônus corporal e força de agarrar; 3) avaliação do sistema nervoso central: tremores, cauda em pé, micção e defecação. Demais testes realizados analisaram: comportamento em labirinto em cruz elevada, coordenação motora em trave elevada, memória espacial no labirinto em T, e respostas comportamentais nos testes de natação forçada e de suspensão pela cauda. Exceto pelo menor peso no desmame, os parâmetros de desenvolvimento analisados não apresentaram diferenças significativas entre os mutantes e controles, o que confirmou a hipótese de que as alterações fenotípicas somente são perceptíveis a partir de 3 semanas de vida. A caracterização comportamental do fenótipo também foi realizada nos mutantes em fundo genético C57BL/6, de ambos os sexos, com 8 semanas de idade. Em relação aos camundongos controle, nos mutantes houve aumento da presença de cauda em pé, da ataxia e do tremor; menor frequência de levantar e de limpeza do corpo (grooming); redução da coordenação motora, indicando evidente prejuízo motor. Também foram observadas respostas negativas à ansiedade e hiperatividade, mas não houve alteração na memória espacial dos mutantes. Os resultados indicaram que o mutante tremor apresentou prejuízos de origem no sistema nervoso central; demostraram também que o fenótipo observado coincide com as alterações descritas na literatura, sugerindo o gene Egr3 como possível candidato para a mutação. A caracterização fenotípica desse animal é importante no entendimento das alterações causadas pela mutação e se essa apresenta potencial como modelo para doenças neurológicas. / The autosomal recessive spontaneous mutation tremor (tr) was identified in the Swiss mice colony of the laboratory animal facility of the Department of Pathology, from Faculdade de Medicina Veterinária e Zootecnia - Universidade de São Paulo. The mutants presented tremors, ataxia and audiogenic tonic convulsions as the main expressive characteristics. This mutation was moved from Swiss onto C57BL/6 by ten backcrosses (N10). Genetic mapping with microsatellite markers distributed through the mouse genome showed that the mutation is on 14 chromosome, between 33.21 and 38.21 cM, making Egr3 (Early Growth Response 3) a candidate gene. This study aimed to characterize the behavior phenotype of the tremor mice. Phenotypic characterization of the Swiss mutant mice was performed from birth to adulthood. The physical development points analyzed were: unfolding of the ears, eruption of the incisor teeth, opening the eyes, complete fur, weight gain and length, and sexual development. The reflexology development ones were: palmar grip, negative geotaxia, posture straightening and reaction to sound. On the 21day-old the open field test was performed to analyze the activity of the animals, and on the 60-day-old this task was repeated along with tests to analyze behavioral parameters. The tests performed in the open field were evaluated by parameters; 1) general activity and sensory system: vocalization, irritability, auricular reflex, tail flick, corneal reflex and response to touch; 2) psychomotor tests: hindquarter fall, surface-rightingreflex, body tone and grasping strength; 3) evaluation of the central nervous system: tremors, straub tail, micturitionand defecation. Other tests analyzed: behavior in elevated plus maze, motor coordination in balance beam test, spatial memory in T maze alternation test, and behavioral responses in forced swing and tail suspension tests. Except for the lower weight at weaning, the development parameters analyzed did not show significant differences between the mutants and controls, which confirmed the hypothesis that phenotypic changes are only perceptible after 3weeks-old. The behavioral characterization of the phenotype was also performed on 8-week-old C57BL/6 mutants of both sexes. In comparison to the control mice, in the mutants there were an increase in the presence of straub tail, ataxia and tremor; less frequent rearing and grooming; less motor coordination, indicating evident motor impairment. Negative responses to anxiety and hyperactivity were also observed, but there was no change in the spatial memory of the mutants. The results indicated that the tremor mutant presented damages in the central nervous system; also showed that the phenotype coincides with the changes described in the literature, suggesting the Egr3 gene as a possible candidate for the mutation. The phenotypic characterization of this animal is important to clarify impairments caused by the genetic mutation, and also identify if this potential model could be useful to study neurological diseases.

A mutação espontânea tremor (tr) , autossômica recessiva, foi identificada na colônia de camundongos Swiss no Biotério do Departamento de Patologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo. Os mutantes apresentaram como principais características fenotípicas tremores, ataxia e convulsões tônicas audiogênicas. Por meio de dez retrocruzamentos essa mutação foi transferida para a linhagem congênica C57BL/6 (N10). O mapeamento genético com marcadores microssatélites distribuídos pelo genoma do camundongo indicou que a mutação tr encontra-se no cromossomo 14, na região entre 33,21 e 38,21 cM, tendo como possível candidato o gene Egr3 (Early Growth Response 3). O presente estudo teve como objetivo caracterizar o fenótipo comportamental do camundongo mutante tremor. A caracterização do fenótipo dos camundongos mutantes Swiss foi realizada a partir do nascimento até a idade adulta. Os parâmetros do desenvolvimento físico analisados foram: desdobramento das orelhas, erupção dos dentes incisivos, abertura dos olhos, surgimento da pelagem completa, ganho de peso e comprimento dos filhotes e desenvolvimento sexual. No desenvolvimento reflexológico foram analisados: preensão palmar, geotaxia negativa, endireitamento de postura e sobressalto. No 21&ordem; dia de vida foi realizado o teste de campo aberto para analisar a atividade geral dos animais, e no 60&ordem; dia esse teste foi repetido, juntamente com testes para analisar parâmetros comportamentais. Os testes realizados em campo aberto foram ordenados por parâmetro avaliado; 1) atividade geral dos animais e sistema sensorial: frêmito vocal, irritabilidade, reflexo auricular, aperto de cauda, reflexo corneal e resposta ao toque; 2) testes psicomotores: trem posterior, reflexo de endireitamento, tônus corporal e força de agarrar; 3) avaliação do sistema nervoso central: tremores, cauda em pé, micção e defecação. Demais testes realizados analisaram: comportamento em labirinto em cruz elevada, coordenação motora em trave elevada, memória espacial no labirinto em T, e respostas comportamentais nos testes de natação forçada e de suspensão pela cauda. Exceto pelo menor peso no desmame, os parâmetros de desenvolvimento analisados não apresentaram diferenças significativas entre os mutantes e controles, o que confirmou a hipótese de que as alterações fenotípicas somente são perceptíveis a partir de 3 semanas de vida. A caracterização comportamental do fenótipo também foi realizada nos mutantes em fundo genético C57BL/6, de ambos os sexos, com 8 semanas de idade. Em relação aos camundongos controle, nos mutantes houve aumento da presença de cauda em pé, da ataxia e do tremor; menor frequência de levantar e de limpeza do corpo (grooming); redução da coordenação motora, indicando evidente prejuízo motor. Também foram observadas respostas negativas à ansiedade e hiperatividade, mas não houve alteração na memória espacial dos mutantes. Os resultados indicaram que o mutante tremor apresentou prejuízos de origem no sistema nervoso central; demostraram também que o fenótipo observado coincide com as alterações descritas na literatura, sugerindo o gene Egr3 como possível candidato para a mutação. A caracterização fenotípica desse animal é importante no entendimento das alterações causadas pela mutação e se essa apresenta potencial como modelo para doenças neurológicas. / The autosomal recessive spontaneous mutation tremor (tr) was identified in the Swiss mice colony of the laboratory animal facility of the Department of Pathology, from Faculdade de Medicina Veterinária e Zootecnia - Universidade de São Paulo. The mutants presented tremors, ataxia and audiogenic tonic convulsions as the main expressive characteristics. This mutation was moved from Swiss onto C57BL/6 by ten backcrosses (N10). Genetic mapping with microsatellite markers distributed through the mouse genome showed that the mutation is on 14 chromosome, between 33.21 and 38.21 cM, making Egr3 (Early Growth Response 3) a candidate gene. This study aimed to characterize the behavior phenotype of the tremor mice. Phenotypic characterization of the Swiss mutant mice was performed from birth to adulthood. The physical development points analyzed were: unfolding of the ears, eruption of the incisor teeth, opening the eyes, complete fur, weight gain and length, and sexual development. The reflexology development ones were: palmar grip, negative geotaxia, posture straightening and reaction to sound. On the 21day-old the open field test was performed to analyze the activity of the animals, and on the 60-day-old this task was repeated along with tests to analyze behavioral parameters. The tests performed in the open field were evaluated by parameters; 1) general activity and sensory system: vocalization, irritability, auricular reflex, tail flick, corneal reflex and response to touch; 2) psychomotor tests: hindquarter fall, surface-rightingreflex, body tone and grasping strength; 3) evaluation of the central nervous system: tremors, straub tail, micturitionand defecation. Other tests analyzed: behavior in elevated plus maze, motor coordination in balance beam test, spatial memory in T maze alternation test, and behavioral responses in forced swing and tail suspension tests. Except for the lower weight at weaning, the development parameters analyzed did not show significant differences between the mutants and controls, which confirmed the hypothesis that phenotypic changes are only perceptible after 3weeks-old. The behavioral characterization of the phenotype was also performed on 8-week-old C57BL/6 mutants of both sexes. In comparison to the control mice, in the mutants there were an increase in the presence of straub tail, ataxia and tremor; less frequent rearing and grooming; less motor coordination, indicating evident motor impairment. Negative responses to anxiety and hyperactivity were also observed, but there was no change in the spatial memory of the mutants. The results indicated that the tremor mutant presented damages in the central nervous system; also showed that the phenotype coincides with the changes described in the literature, suggesting the Egr3 gene as a possible candidate for the mutation. The phenotypic characterization of this animal is important to clarify impairments caused by the genetic mutation, and also identify if this potential model could be useful to study neurological diseases.

Friedreich's Ataxia (FA) is an autosomal-recessive, neurodegenerative disease characterized by progressive lower extremity muscle weakness and sensory loss, balance deficits, limb and gait ataxia, and dysarthria. FA is considered a sensory ataxia because the dorsal root ganglia and spinal cord dorsal columns are involved early in the disease, whereas the cerebellum is affected later. Balance deficits and gait ataxia are often evaluated clinically and in research using clinical rating scales. Recently, quantitative tools such as the Biodex Balance System SD and the GAITRite Walkway System have become available to objectively assess balance and gait, respectively. However, there are limited studies using instrumented measures to quantitatively assess and characterize balance and gait disturbances in FA, and longitudinal, quantitative analyses of both balance and gait have not been investigated in this patient cohort. The purpose of the present study was to characterize gait patterns of adults with FA and to identify changes in gait and balance over time using clinical rating scales and quantitative measures. Additionally, this study investigated the relationship between disease duration, clinical rating scale scores and objective measures of gait and balance. This study used a longitudinal research design to investigate changes in balance and gait in 8 adults with genetically confirmed FA and 8 healthy controls matched for gender, age, height, and weight. Subjects with FA were evaluated using the Berg Balance Scale (BBS), the Friedreich's Ataxia Rating Scale (FARS) and instrumented gait and balance measures at baseline, 6 months, 12 months and 24 months. Controls underwent the same tests at baseline and 12 months. Gait parameters were measured utilizing the GAITRite Walkway system with a focus on gait velocity, cadence, step and stride lengths, step and stride length variability and percent of the gait cycle in swing, stance and double limb support. Balance was assessed using the BBS and the Biodex Balance System; the latter included tests of postural stability and limits of stability. At baseline, there were significant differences in gait and balance parameters, BBS scores and FARS total scores between FA subjects and controls as determined using paired t-tests (p This is the first longitudinal study to demonstrate changes over time in gait and balance of adults with FA using both quantitative measures and clinical rating scales. This study provided a detailed characterization of the gait pattern and balance of adults with FA. The GAITRite Walkway system proved to be a sensitive measure, and able to detect subtle changes in gait parameters over time in adults with FA. In addition, the BBS was an appropriate and sensitive assessment to detect changes in static and dynamic balance in this patient cohort. Finally, results revealed a strong and consistent relationship between clinical rating scale scores, postural stability indices, limits of stability scores, and step and stride length variability in individuals with FA.