Theses metadata

“Data exchange” service offers individual users metadata transfer in several different formats. Citation formats are offered for transfers in texts as for the transfer into internet pages. Citation formats include permanent links that guarantee access to cited sources. For use are commonly structured metadata schemes : Dublin Core xml and ETUB-MS xml, local adaptation of international ETD-MS scheme intended for use in academic documents.

Export
Rovčanin Dragović, Isidora
A new method for stratification of the risk of Alzheimer's disease in patients in Montenegro
2024

https://phaidra.ucg.ac.me/detail_object/o:1873?tab=0#mda

Autorstvo-Nekomercijalno 3.0 Srbija (CC BY-NC 3.0)
Academic metadata
Phd. theses

Medicinske nauke

doktor medicinskih nauka
Univerzitet Crne Gore
Medicinski fakultet
Studijski program Medicina

Other Theses Metadata 

Pathological and clinical features of Alzheimer’s disease (AD) are in temporal discrepancy and currently accepted clinical tests provide the diagnosis decades after the initial pathophysiological events. In order to reach the goal of early detection of this incurable disease, research efforts are directed to the identification of non-invasive, widely accessible biomarkers, which could open the screening possibilities and overcome the main disadvantages of the current AD biomarkers. The present study offers an innovative and broader research context in this regard based on the fact that two different diseases, AD and cancer, have been shown to have inverse incidences. Namely, this recent finding has brought a different and challenging context to the knowledge about shared biological mechanisms involved in these diseases, which are mainly opposite in their nature: AD is characterized by apoptotic cell death and cancer by uncontrolled proliferation. It has been postulated that these mechanisms might actually represent different sides of the same path: if dysregulation of the common AD-CAC signaling pathways leads to a higher risk of cancer, the risk of AD will be reduced in the same individual, or vice versa. However, the precise explanations underlying this negative epidemiological association between these two diseases remain unknown. Small, non-coding RNA molecules - microRNAs (miRNAs), which simultaneously regulate the expression of multiple target genes, are deeply implicated in both diseases and proposed as having the biological complexity to explain such a challenging relationship between AD and cancer. Being well documented as the leading regulators of cell proliferation and differentiation, migration and apoptosis, which are the main pathological features of cancer and AD, miRNAs may be the key points of the pathophysiological process of both diseases. Additionally, a series of studies have demonstrated their implication in a variety of human brain dysfunctions such as innate immunity, neuroinflammation, dysregulated amyloid metabolism and oxidative stress. In fact, these processes represent the backbone of the different AD theories. Studying the miRNA roles in this disease has thus been recognized as a promising research direction and number of the miRNA interactions with the key genes involved in the pathogenesis of AD has already been identified. The most dominant theories of AD and CAC are based on two closely interconnected processes - innate immunity and inflammation, and thus, they have been chosen as the pathophysiological focus of the present study. Neuroinflammatory signaling pathways and inflammation-related microRNAs (miRNAs) could possibly have a crucial role in AD making them promising potential biomarkers. All the miRNAs selected for this study, not only have a documented role in AD and CAC, but rather, each of them has at least one target involved in immune-related and/or inflammatory pathways: miR-29a, miR-101, miR-125b, miR-146a and miR-155. In addition, the possibility to use these molecules as non-invasive biomarkers contributes to the particular translational value of the whole research context presented. Objective: Expression of circulatory miRNAs which are deeply involved in the pathogenesis of AD and CAC: miR-29a/b, miR-101, miR-125b, miR-146a, and miR-155 were examined in healthy individuals, those whose cognitive performance on neuropsychological screening was in mild cognitive impairment (MCI) range, patients with AD and CAC. It was hypothesized that these miRNA expression levels could correlate with the level of participants’ cognitive decline leading to the identification of molecular signature of early AD. Additionally, it was expected that the expression pattern of selected miRNAs could explain the molecular basis of the inverse incidences between AD and CAC. Methods: The present study enrolled 54 subjects, out of a total of 75 examined individuals. During the recruitment, of 34 volunteers who felt physically and mentally healthy, 18 individuals were involved in the control group (CTRL-18). Participants who did not report subjective cognitive decline (SCD) but were in the MCI range on Montreal Cognitive Assessment test, formed the low-performance MoCA group (LP-MoCA-9). AD patients were retrospectively recruited at the Neurology Clinic of the Clinical Center of Montenegro (CCM) (AD-12). They were previously diagnosed according to the criteria of the National Institute of Aging and Alzheimer’s Association. AD group included patients in the early symptomatic disease stage (EAD) - MCI due to AD and mild dementia stage, (MoCA score > 17) and advanced AD (AAD) — moderate and severe dementia (MoCA score < 17). Cognitively unimpaired CAC patients with pathohistologicaly confirmed diagnosis were recruited at the Center for Digestive Surgery — CCM (CAC-15). Standardized questionnaires, physical and neurological examinations, open-ended type of SCD evaluation, neuropsychological screening tests, Geriatric Depression Scale (GDS), as well as biochemical laboratory assessment, were conducted to identify exclusion criteria. Selected miRNAs were extracted from plasma, quantified by qRT-PCR and expression levels normalized by miR-361-5p gene. Statistical data analysis was done with the GraphPad Prism 9 software. Results: As a control group, this study included volunteers without SCD, but interestingly, neuropsychological screening tests indicated that 33,3% of the apparently healthy subjects were in the MCI range. Neurological and laboratory findings could not explain their neuropsychological performance. However, in the LP-MoCA group, the two circulatory miRNAs, miR-146a and miR-155 were up-regulated compared to the CTRL group (p < 0.05). The expression level of miR-146a was also significantly higher in LP-MoCA compared to the AD group (p < 0.05). The EAD group also followed this interesting expression pattern for both, miR-146a and miR-155, the same as the heterogeneous AD group. The difference in the expression level of miR-146a and miR-155 between EAD and AAD was not statistically significant. Finally, ROC curve analyses suggested that these miRNAs could serve as non-invasive biomarkers of early cognitive impairment. Among five examined miRNAs in the present research, only the expression levels of miR- 101 in study groups were in agreement with the postulate about the inverse relationship between AD and CAC. The mean expression values of miR-101 for the CAC and AD groups were on the opposite sides of the range, while the expression level of the CTRL group was in the middle (AD-1.569, CTRL-1.171 and CAC-0.8340). Furthermore, miR-101 expression was significantly higher in AD compared to the CAC group (p < 0.05). The CTRL group was not significantly different neither from AD or CAC group. However, the results of ROC curve analysis indicated that on average, a CAC patient will have lower miR-101 expression than 64% of controls, and an AD patient will have upregulated miR-101 expression compared to 63% of people in the general population. This analysis provided the quality score which describes the performance of this AD-CAC inverse correlation model based on miR-101 expression, as a good one. This model was also tested with respect to the disease stage of the AD group. Interestingly, miR-101 expression level was significantly higher in EAD compared to CAC (p < 0.05), however, its expression values decreased with the progression of AD towards the later stage, approaching the level of expression in the CAC group. Therefore, no significant difference was observed between AAD and CAC groups, indicating that patients with AAD do not contribute to the significant difference observed between AD and CAC groups. Conclusions: This study accidentally identified that a certain number of patients with cognitive decline in the Montenegrin population remain undetected. Therefore, neuropsychological screening instruments should be routinely administered to the elderly in Montenegro, even if the patient does not complain of cognitive functioning. The up- regulation of miR-146a and miR-155 could serve as a non-invasive, circulatory biomarkers for the detection of people with CI who are at risk for AD. Together with neuropsychological screening, molecular markers identified by this study, could possibly become routine, easily- accessible tools for screening of the general population for AD. MiR-101 negatively regulates amyloid precursor protein (APP) gene and APP metabolism, therefore, its down-regulation found in AD is understood as a disease-contributing factor. However, the up-regulating trend of miR-101 in early AD and its decline with disease progression found in the present study, suggests that miR-101 might act within the negative feedback mechanism, related to APP metabolism. Given that miR-101 potentially reflects a progression of amyloid accumulation, it could serve to monitor the effects of amyloid lowering therapy, indicated in the early AD population. Considering miR-101's oncosuppressive role, increased miR-101 expression in long-lasting preclinical and early AD might protect AD patients from cancer. In fact, simultaneous negative regulation of oncogenes and APP gene, through the up-regulation of miR-101, as the overlapping point of different signaling pathways, might explain the opposite incidences of AD and CAC.