One-Carbon Metabolism in Alzheimer’s Disease and Parkinson’s Disease Brain Tissue

Disruptions in one-carbon metabolism and elevated homocysteine have been previously implicated in the development of dementia associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Moreover, a PD diagnosis itself carries substantial risk for the development of dementia. This is the first study that explores alterations in one-carbon metabolism in AD and PD directly in the human brain frontal cortex, the primary center of cognition. Applying targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS), we analyzed post-mortem samples obtained from 136 subjects (35 AD, 65 PD, 36 controls). We found changes in one-carbon metabolites that indicate inefficient activation of cystathionine β-synthase (CBS) in AD and PD subjects with dementia, the latter seemingly accompanied by a restricted re-methylation flow. Levodopa–carbidopa is known to reduce available vitamin B6, which would explain the hindered CBS activity. We present evidence of temporary non-protein-bound homocysteine accumulation upon levodopa intake in the brain of PD subjects with dementia but not in non-demented PD subjects. Importantly, this homocysteine elevation is not related to levodopa dosage, disease progression, or histopathological markers but exclusively to the dementia status. We hypothesize that this levodopa-induced effect is a direct cause of dementia in PD in susceptible subjects with reduced re-methylation capacity. Furthermore, we show that betaine best correlates with cognitive score even among PD subjects alone and discuss nutritional recommendations to improve one-carbon metabolism function

Data mining v medicínských datech

Cílem této práce je praktické zpracování (vyčistění, připravení a analyzování) medicínských dat tak, aby výsledky mohly být následně konzultovány s lékařskými odborníky a případně využity v lékařské praxi. Konkrétně jsou sestaveny dvě analytické úlohy. První se zaměřuje na predikci chorob a odhalení rizikových faktorů. V druhé jsou porovnávány rozdíly krevního tlaku mezi hypertonickými pacienty v závislosti na předepsaných lécích. Zpracovávaná data byla shromážděna v rámci projektu ADAMEK pod záštitou výzkumného centra EuroMISE -- Kardio. Součástí práce je přiblížení osmi známých technik pro dolování v datech. Při řešení úloh jsou využity dvě z těchto technik (logistická regrese a neurální sítě; pouze v první úloze) v kombinaci se statistickými metodami (testování hypotéz). Pro tyto účely byly prozkoumány a nasazeny analytické nástroje od společnosti Microsoft (Microsoft SQL Server Analysis Services a Microsoft Office Excel). Prezentované výsledky by mohly být uplatněny pro efektivnější cílení lékařské péče a vylepšení systémů včasné diagnózy, což by následně mohlo vést k poklesu nákladů na zdravotnickou péči či zajištění kvalitnější péče o pacienty.In this thesis, medical data have been cleaned, arranged, and analyzed to provide results, which could be further consulted with medical specialists and possibly reflected in medical practice. Specifically, two analytical tasks have been designed. The first one is focused on predicting diseases and revealing disease determinants. The second task is aimed at differences in blood pressure levels of hypertensive patients in dependence on their prescribed medications. The analyzed data have been collected under the aegis of the Research Center EuroMISE -- Cardio within the project of ADAMEK. An overview of eight popular data-mining techniques has been formed. The tasks have been solved using two of those techniques (logistic regression and neural networks; in the first task only) in combination with statistical methods (hypothesis testing). For these purposes, analytical tools by Microsoft (Microsoft SQL Server Analysis Services and Microsoft Office Excel) have been explored and employed. Possible applications of results include improvements in targeting health care and enhancements in systems for early diagnosis, which might result in reducing expenditures and providing patients with a better quality of life

One-Carbon Metabolism in Alzheimer’s Disease and Parkinson’s Disease Brain Tissue

Disruptions in one-carbon metabolism and elevated homocysteine have been previously implicated in the development of dementia associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Moreover, a PD diagnosis itself carries substantial risk for the development of dementia. This is the first study that explores alterations in one-carbon metabolism in AD and PD directly in the human brain frontal cortex, the primary center of cognition. Applying targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS), we analyzed post-mortem samples obtained from 136 subjects (35 AD, 65 PD, 36 controls). We found changes in one-carbon metabolites that indicate inefficient activation of cystathionine β-synthase (CBS) in AD and PD subjects with dementia, the latter seemingly accompanied by a restricted re-methylation flow. Levodopa–carbidopa is known to reduce available vitamin B6, which would explain the hindered CBS activity. We present evidence of temporary non-protein-bound homocysteine accumulation upon levodopa intake in the brain of PD subjects with dementia but not in non-demented PD subjects. Importantly, this homocysteine elevation is not related to levodopa dosage, disease progression, or histopathological markers but exclusively to the dementia status. We hypothesize that this levodopa-induced effect is a direct cause of dementia in PD in susceptible subjects with reduced re-methylation capacity. Furthermore, we show that betaine best correlates with cognitive score even among PD subjects alone and discuss nutritional recommendations to improve one-carbon metabolism function