|
|
Functional and Pathophysiological-morphological Correlates of Neurodegenerative Diseases
Dušek, Pavel ; Roth, Jan (advisor) ; Baláž, Marek (referee) ; Menšíková, Kateřina (referee)
This doctoral thesis pictures neurodegenerative diseases as a multilevel process, describes various correlates on each pathophysiological level, and presents selected correlates in Huntington's disease and mitochondrial membrane protein-associated neurodegeneration (MPAN). It uses various methodological approaches such as basic laboratory research, clinical work, imaging, database formation, and database summary. Changes in the amount of respiratory chain complex I and respiratory chain complex IV in buccal ep- ithelial cells of Huntington's disease patients are described. The insufficient power of optical coherence tomography as a biomarker in Huntington's disease is demonstrated. Various phenotypes of MPAN are summarized, and an association between C19orf12 mutation and visual impairment is confirmed. A phenotype of a well-documented case of MPAN is presented. Keywords: C19orf12 mutation; color discrimination; contrast sensitivity; huntingtin; Huntington's disease; iron accumulation; mitochondrial membrane-protein associated neurodegeneration; multilevel process; neurodegeneration; optical coherence tomogra- phy; parkinsonism; respiratory chain complex; retinal nerve fiber layer thickness
|
|
|
Vestibular and postural biomarkers in spinocerebellar ataxias and peripheral vestibular lesions
Danková, Michaela ; Jeřábek, Jaroslav (advisor) ; Roth, Jan (referee) ; Sivák, Štefan (referee)
Vestibular and postural biomarkers in spinocerebellar ataxias and peripheral vestibular lesions Abstract Vestibular dysfunction can be a part of clinical impairment in spinocerebellar ataxias. Together with cerebellar symptoms, it can lead to imbalance and also to impairment of dynamic visual acuity (DVA) in these patients. The aim of the work was to objectify the involvement of the vestibulo-ocular reflex in patients with SCA using modern diagnostic methods. At first the innovative method of video head impulse test (vHIT) was introduced in patients after vestibular schwannoma surgery, in whom a clearly defined vestibular impairment is present. We investigated DVA in SCA patients, the degree of the DVA impairment correlated proportionally with the impairment of vestibular function measured by vHIT. The best predictive values for DVA impairment were obtained by using a model that combined impairment of vestibulo-ocular reflex measured by vHIT and degree of cerebellar dysfunction according to SARA (scale for assessment and rating of ataxia). The research also aimed at the verification of postural stability disorders in patients with SCA using posturography. Standard posturographic parameters (area, sway path and mean velocity of Centre of foot Pressure - CoP) did not allow to distinguish between individual...
|
|
|
DNA damage response in Huntington disease
Vachová, Veronika ; Šolc, Petr (advisor) ; Roth, Jan (referee)
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, which leads to loss of striatal neurons in basal ganglias. It is characterized by involuntary movements and progressive cognitive impairment. HD is a relatively rare disease and the prevalence is approximately 0,01 % of the population of Western European. HD is caused by a CAG repeat expansion in the huntingtin gene (HTT). This mutation results in an elongated stretch of glutamin. Mutant huntingtin (mHTT) expression leads to accumulation of DNA double-strand breaks (DSB) due to reduced ability of effective reparation, which contributes to the pathogenesis of HD, however this mechanism is not fully understood. There are several angles of view how mHTT impaires DNA damage response (DDR). Some studies say that the expression of the mHTT initiates excessive activation of the DDR including p53 signaling pathway leading to apoptosis. Other studies represent results for dysfunction of non-homologous end joining after recognition of DSB or that the cell is not able to recognize DSB. All theories would explain cell death as a consequence of high level of unrepaired DNA damage. The understanding of these mechanisms is important for the development of therapeutical strategies. Key words: Huntington's disease, huntingtin, DNA...
|
|
| |
|
|
Huntington's disease modeling and stem cell therapy in spinal cord disorders and injury
Hruška-Plocháň, Marián ; Motlík, Jan (advisor) ; Bjarkam, Carsten (referee) ; Roth, Jan (referee)
Neurological disorders affect more than 14% of the population worldwide and together with traumatic brain and spinal cord injuries represent major health, public and economic burden of the society. Incidence of inherited and idiopathic neurodegenerative disorders and acute CNS injuries is growing globally while neuroscience society is being challenged by numerous unanswered questions. Therefore, research of the CNS disorders is essential. Since animal models of the CNS diseases and injuries represent the key step in the conversion of the basic research to the clinics, we focused our work on generation of new animal models and on their use in pre-clinical research. We generated and characterized transgenic minipig model of Huntington's disease (HD) which represents the only successful establishment of a transgenic model of HD in minipig which should be valuable for testing of long term safety of HD therapeutics. Next, we crossed the well characterized R6/2 mouse HD model with the gad mouse model which lacks the expression of UCHL1 which led to results that support the theory of "protective" role of mutant huntingtin aggregates and suggest that UCHL1 function(s) may be affected in HD disturbing certain branches of Ubiquitin Proteasome System. Traumatic spinal cord injury and Amyotrophic Lateral...
|
|
|
The Utility of Spatial Navigation and Metabolic Biomarkers in Early and Differential Diagnosis of Neurodegenerative Diseases
Cerman, Jiří ; Laczó, Jan (advisor) ; Roth, Jan (referee) ; Kopeček, Miloslav (referee)
Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia and represents a significant socio-economic problem. Currently, only symptomatic treatment of AD is possible and the development of new causal therapy faces a number of difficulties, which are inter alia related to identifying early stages and the possibilities of differential diagnosis of specific neurodegenerative diseases. Therefore, in recent years, methods that are easily available and able to reliably identify individuals at risk of developing AD already at preclinical and prodromal stages are of particular interest. The work presents a basic overview of the current knowledge about neurodegenerative diseases and especially AD and extends the knowledge in this area. The main goals of the thesis are to map out the potential contribution of spatial navigation testing as a new experimental method, which is suitable for early diagnosis and differential diagnosis of advanced stages of neurodegenerative diseases, and to evaluate the benefits of metabolic biomarker testing in clinical practice. In the early stages of neurodegenerative diseases, the work focuses primarily on the evaluation of impairment of a specific type of spatial navigation - path integration in patients with AD and also on subjective spatial...
|
|
| |
|
|
Phenotypic study Huntington's disease TgHD minipigs: Appearance and progress of reproductive and biochemical changes
Bohuslavová, Božena ; Motlík, Jan (advisor) ; Roth, Jan (referee) ; Petr, Jaroslav (referee) ; Krylov, Vladimír (referee)
Huntington's disease (HD) is one of the incurable and fatal diseases. HD belongs to the monogenic neurodegenerative diseases. According to the number of the CAG repetitions in the gene coding huntingtin, the onset of the disease is in childhood (5%), in the middle age, which is the most common (90%) and in the older age (5%). Beginning of the disease is manifested by changes in behavior; including problems with coordination and movement. Later, there is a psychological change. The disease leads to death. Until now, there is no effective curative treatment. In 2009, we created a model of the transgenic minipigs (TgHD) carrying the N - terminal part of the human mutant huntingtin (mtHtt) at our Institute in Liběchov. The number of offsprings and the resemblance in physiology and morphology between the pig (Sus scrofa) and humans (Homo sapiens) give us opportunities not only to study changes not only in central nerve organs, but also in peripheral tissues. The reproductive problems of TgHD boars were observed as the first phenotypic changes. Therefore, my work focuses at first on a study of the reproduction parameters of TgHD boars as well as ultrastructural, immunocytochemical and biochemical changes in testes and spermatozoa. In PhD thesis, I described in details the reproductive defects in TgHD...
|
|
|
Testicular Degeneration of Transgenic Porcine Model of Huntington's Disease
Skřivánková, Monika ; Motlík, Jan (advisor) ; Roth, Jan (referee) ; Petr, Jaroslav (referee)
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by an extended (≥36) CAG repeat in the huntingtin gene. Its hallmark is brain athrophy, but huntingtin is widely deposited in all tissues of the body, most notably in the brain and testes. Its pathogenic effect is conditioned by the formation of cytotoxic forms of aggregates and fragments, which occur in both brain and peripheral tissues. Testicular atrophy has been demonstrated in postmortem samples from human patients with Huntington's disease and in transgenic mouse models. We investigated reproductive decline in a large animal model of Huntington's disease. A transgenic (tgHD) minipig model was created by inserting a lentiviral vector into the genome of a pig. Vector contained a truncated form of the N terminal part of huntingtin gene. Boars of this transgenic line showed a reduced ability to produce offspring from 13 months of age. We confirmed apoptosis of seminiferous epithelial cells and Sertoli cells, and a production of morphologically damaged spermatozoa, which were unable to efficiently fertilize the oocyte under in vitro conditions. We found a reduction of mitochondrial metabolism parameters in the sperm of tgHD boars. These changes were not dependent on the age of the boars., It is directly related to the...
|
|
|
Psychosocial Aspects of Huntington's Disease
Uhrová, Tereza ; Roth, Jan (advisor) ; Zvolský, Petr (referee) ; Benetin, Ján (referee)
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...
|
guest ::
