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Automated diagnosis of sleep disorders using wearable devices
Sigmund, Jan ; Mekyska, Jiří (referee) ; Mikulec, Marek (advisor)
Sleep disorders induce many negative repercussions. Furthermore, research about their connection to cognitive health is increasing in numbers. This thesis concerns detection of poor sleep quality via raw actigraphy data. Existing method for assessing sleep was selected, it’s performance was validated against polysomnography on 27 patients. Used algorithm defines sleep as the absence of change in arm angle. Resulting 81 % sensitivity, 62 % specificity and 78 % accuracy is different from the outcome in the pilot study. Two approaches, to determine sleep quality were used. Both are based on comparing sleep features – first, with National Sleep Foundation recommendations and second, with control group without sleep disorders (7 persons). The goal was to pinpoint the remaining 19 patients with diagnosis. The recommendation for SOL, WASO, NA>5 and SE had higher sensitivity (75 %), lower specificity (71 %) and identical accuracy (74 %). These approaches were then also tested on 7-day actigraphy, consisting of 27 subjects, that are presumed to have prodromal dementia with Lewy bodies. Same principle was applied to try to predict LBD and thereby address the link between sleep quality and neurodegeneration. This resulted in 86 % sensitivity, 38 % specificity and 63 % accuracy. With regard to achieving solid sensitivity in all cases and good accuracy this could be used to indicate sleep quality.
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Mechanisms involved in neurodegenerative disorders origin and their consequences in neurobiological interactions.
Červinková, Monika ; Kulišťák, Petr (advisor) ; Šivicová, Gabriela (referee)
Neurodegenerative disorders represent due to their still increasing trend serious problem not only medical, but also socio-economic. The most common disorders in human population include Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Underlying ethiopathogenetical mechanisms are not closely clarified yet. Potential conjunction between neurodegenerative disorders and stress is mentioned. Supposed relationship between neurodegenerative disorders and stress is based on knowledge of functional interrelationships among nervous, endocrine and immune systems. Animal models are very helpful for research in objective field and they can contribute to the elucidation of involved biological mechanisms. Knowledge of these processes could enable development of new diagnostic and therapeutic approaches in future.
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Mechanisms of comorbidity of metabolic and neurodegenerative diseases
Tauchman, Martin ; Telenský, Petr (advisor) ; Brožka, Hana (referee)
In Czechia, number of people with neurodegenerative diseases is in the hundreds of thousands, and the lifetime health care costs and social impact of each patient's disease reach hundreds of thousands of euros, but these costs could be reduced by early and effective intervention. Its correct implementation could be helped by knowledge of causal links between neurodegenerative and metabolic diseases, whose prevalence is correlated in the population. One of the important factors is an increased pro-inflammatory immune response. In people with obesity and type 2 diabetes mellitus, systemic inflammation evolves into neuroinflammation, which subsequently leads to neurodegeneration. Another mechanism is hyperglycaemia, which is a consequence of insulin resistance. Hyperinsulinaemia and hyperglycaemia lead to impaired expression of glucose transporters and insulin-degrading enzyme, resulting in reduced clearance of amyloid beta. Genetic background is also recognized as a highly influential factor, affecting various mechanisms in both beneficial and harmful ways. Lifestyle is also an important factor. In general, smoking and alcohol consumption are harmful to health. Both increased consumption of alcoholic beverages and smoking tobacco products can lead to metabolic disorders as well as neurodegeneration. On the...
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ADP-ribosylation in ARH3-deficient cells and its impact on cellular functions
Kuttichová, Barbora ; Hanzlíková, Hana (advisor) ; Valihrach, Lukáš (referee)
ADP-ribosylation is a crucial post-translational modification that regulates various cellular processes, including DNA repair. It is catalysed by poly-ADP-ribose polymerases (PARPs) and involves the transfer of ADP-ribose moieties from the redox cofactor NAD+ to proteins, including histones. To maintain cellular homeostasis, ADP-ribose chains need to be rapidly degraded by ADP-ribosyl glycohydrolases. While poly-ADP-ribose glycohydrolase (PARG) is highly efficient, it cannot cleave the terminal ADP-ribose moiety. For the removal of the terminal mono-ADP-ribose, two glycohydrolases, TARG1 and ARH3, are involved. This removal process is necessary because it enables DNA repair factors to access the site of DNA damage. The primary goal of this thesis is to characterise cells derived from patients with homozygous ARH3 mutations and to develop appropriate tools to improve our understanding of the molecular mechanism by which ARH3 mutations affect ADP-ribosylation and how it contributes to the onset of the associated neurological disease. To achieve this, I measured the levels of ARH3 protein and detected increased mono-ADP-ribosylation in ARH3-mutated patient-derived fibroblasts. Furthermore, I assessed the sensitivity of these cells to different PARP inhibitors, which hold potential for the therapeutic...
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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
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Prevalence of neurodegenerative disorders in patients with esophageal achalasia
Jerie, Martin ; Vojtěch, Zdeněk (advisor) ; Šonka, Karel (referee) ; Bronský, Jiří (referee)
Introduction: Achalasia is a primary motility disorder of the esophagus due to degeneration neurons in myenteric plexus. Although the exact pathogenesis is unknown, autoimmune and neurodegenerative processes seem to be involved. We thus hypothesized that the prevalence of neurodegenerative and/or neuroinflammatory disorders (NDD) with autoimmune component could be higher among patients with achalasia and vice versa as the background pathogenetic mechanisms might be similar. Methods: This was a prospective, observational, comparative questionnaire-based study. Patients with achalasia from a gastroenterology center and patients with NDD from neurology centers in the Czech Republic were enrolled. Patients from achalasia group were then examined by neurologist and neurological patients by gastroenterologist, including further testing to confirm or rule out either NDD and achalasia, respectively. We assessed the prevalence of both achalasia and NDD and compared them with prevalences in general population. Results: A total of 150 patients with achalasia and 112 patients with NDD were enrolled. We observed an increased prevalence of NDD among patients with achalasia (6.0 % (9/150) as compared to the estimated 2.0 % prevalence of NDD in general population, p=0.003). In the NDD group, 32 out of 112 patients...
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The role of cholesterol in the pathogenesis of Alzheimer's disease
Tax, Martin ; Rudajev, Vladimír (advisor) ; Randáková, Alena (referee)
Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia affecting a significant part of the aging population. It seems that the main cause of this disease is the accumulation of amyloid β (Aβ). Cholesterol is an important component of plasma membranes where it is essential for proper synapse function. Changes in its concentration are considered to be a risk factor for the onset and development of Alzheimer's disease. Data show that this lipid has an effect on Aβ synthesis and also has a role in Aβ cytotoxicity where it may promote the negative properties of Aβ or on the contrary can be protective against them.
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Role of tau phosphorylation in formation of tau envelopes
Karhanová, Adéla ; Lánský, Zdeněk (advisor) ; Štěpánek, Luděk (referee)
Tau is an intrinsically-disordered microtubule-associated protein important for axonal development and a critical regulator of microtubule functions in axons. Tau activity is controlled by phosphorylation and its deregulation resulting in tau hyperphosphorylation and aggregation has been linked to multiple neurodegenerative disorders, collectively termed tauopathies. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive "envelopes" around microtubules. Tau envelopes regulate the action of other microtubule-associated proteins, such as the motility of molecular motors, and protect microtubules against degradation by microtubule-severing enzymes. How the formation, dynamics, and function of tau envelopes are regulated, however, is unknown. Here we show that tau phosphorylation impedes the formation and functioning of protective tau envelopes. Using a combination of reconstitution experiments and live cell imaging, we show that phosphorylated tau incorporates into tau envelopes and that it slows down the envelope growth. Importantly, we demonstrate that phosphorylated tau also destabilizes already existing envelopes leading to their disassembly. Together, our results demonstrate...
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Physiological principles of current therapeutic approaches in the treatment of Alzheimer's disease
Denisova, Elizaveta ; Rudajev, Vladimír (advisor) ; Veverová, Kateřina (referee)
Alzheimer's disease is a progressive neurodegenerative disease that affects millions of people worldwide. The pathology of Alzheimer's disease includes amyloid and tau hypothesis, mitochondrial dysfunction and neurodegeneration. Classical treatments for Alzheimer's disease include drugs targeting the cholinergic and glutamatergic systems, such as donepezil, galantamine, rivastigmine, and memantine. Diagnostic tools and techniques are constantly evolving to better identify and monitor the course of the disease. New approaches to the treatment of Alzheimer's disease include beta-amyloid-targeted therapies that seek to reduce the production or facilitate the clearance of these pathological peptides. Nutritional and lifestyle interventions, such as the potential effects of antioxidants on reducing oxidative stress, the neuroprotective effects of statins, and the potential benefits of a ketogenic diet for Alzheimer's patients, have become a key part of a multidisciplinary approach to treatment and are being explored as part of a comprehensive strategy to improve patients' quality of life. Key words: Alzheimer's disease, amyloid hypothesis, tau hypothesis, mitochondrial dysfunction, neurodegeneration, cholinergic system, glutamatergic system, new therapeutic approaches, nutrition, lifestyle.
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Role of the cannabinoid system in neurodegenerative processes
Akantisová, Lucia ; Novotný, Jiří (advisor) ; Búran, Peter (referee)
The endocannabinoid system (ECD) is involved in a significant number of physiological functions in the central and peripheral nervous system. The ECD consists of cannabinoid receptors (CB1 and CB2), endogenous ligands (ANA, 2-AG) and the enzymatic apparatus required for their synthesis (NAPE and DAGL) and degradation (FAAH, MAG). In the human brain, the cannabinoid receptor CB1 is the most widespread of the group of receptors that bind to G proteins. The signaling mechanisms of these proteins contribute to the overall homeostasis of the organism. With their activity, they affect the concentrations of second messengers, the activity of ion channels, the release of neurotransmitters, and regulate immune responses. In this context, studies in the last 20 years have focused on research in the field of neurodegenerative diseases. Today, i tis known that treatment with cannabinoid compounds improves neurological deficits associated with neuronal damage and alleviates inflammatory processes in animal models of Alzheimer's disease, Parkinson's disease and multiple sclerosis. At the clinical level, treatment with cannabinoids has helped with certain accompanying symptoms occuring in neurodegenerative diseases such as neuropathic pain, insomnia and spasticity. Key words: endocannabinoid system, cannabinoids,...
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