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Neuropsychological aspects of preclinical stages of neurodegenerative diseases
Nikolai, Tomáš ; Roth, Jan (advisor) ; Holmerová, Iva (referee) ; Jirák, Roman (referee)
Neuropsychological aspects of preclinical stages of neurodegenerative diseases are an extensively studied topic in neuropsychological research. Neuropsychological assessment can be helpful for the estimation of conversion risk in individual cases. The focus of neuropsychological research shifted from the evaluation of dementia to mild cognitive impairment (MCI) or even to the detection of cognitive change before significant cognitive decline. In the theoretical part is presented a contemporary outline of preclinical stages of neurodegenerative diseases. The construct of MCI is the most studied topic in the prodromal stage of neurodegeneration and this part is dedicated to comprehensive analysis of MCI. The empirical research includes five studies on screening methods of cognitive abilities, memory and verbal fluency tests. We present normative and validity data in older adults and show their detection potential in MCI or preclinical stages of neurodegenerative diseases. Furthermore, we tried to show the detection potential of different memory measures in patients with MCI and estimate the relations between hippocampal atrophy and memory performance. Key words mild cognitive impairment, dementia syndrome, Alzheimer's Disease, neuropsychological assessment, diagnostic procedures
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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...
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Pathophysiology of non-motor symptoms in basal ganglia involvement
Majerová, Veronika ; Roth, Jan (advisor) ; Rusina, Robert (referee) ; Papežová, Hana (referee)
The basal ganglia (BG) are a group of brain nuclei situated deep in the cerebral hemispheres. While BG were primarily associated with motor functions, in recent years there has been an increasing evidence that BG are also significantly involved in a wide range of non-motor functions. This work focused on some of the non-motor symptoms associated with two typical basal ganglia disorders: Parkinson's disease (PD) and Huntington's disease (HD). The first study concerned spatial navigation impairment in patients with HD. Their spatial navigation skills were tested using the Blue Velvet Arena, technique evaluating spatial navigation in real space, capable to selectively differentiate between two components of spatial navigation - allocentric (environment-oriented) and egocentric (self-oriented). Allocentric navigation is linked to hippocampal function, whereas egocentric navigation is usually associated with striatum, a structure predominantly affected in HD. We found that spatial navigation is not significantly affected in the early stages of HD and that in more advanced stages, when spatial navigation is already impaired, there is no significant difference between allocentric and egocentric navigation impairment. We speculate that the striatal involvement does not contribute to the impairment of the...
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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...
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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...
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