Saudi Cultural Missions Theses & Dissertations
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Item Restricted The Relationship Between Stigma and Level of Alzheimer's Disease Knowledge Within The Saudi Culture(Saudi Digital Library, 2023-11-30) Jambi, Amnah; Butcher, Howard KarlThere are two types of stigmas: self-stigma and public stigma. The focus of this dissertation was public stigma. The public stigma encountered by persons with Alzheimer’s Disease (AD) contributes to the isolation of families due to the effort made by AD caregivers to adjust to social challenges (Abojabel & Warner, 2019). According to the Saudi Alzheimer’s Disease Association (2022), there are 130 thousand documented cases of AD, which comprised 9% of the aged population. The severity of stigmas can vary across cultures because stigmas of disease are connected to cultural norms (Corrigan, 2014). Most studies conducted in Saudi Arabia have assessed public stigma regarding mental illnesses, but no study has been found regarding public stigma within the AD scope. Population-based approaches that attempt to clarify stigma level prevalence in representative samples are important to develop methods to address these disparities and ensure equitable access to health care within the population's cultural context. The aim of this study was to 1) identify the relationship between public stigma and the level of AD knowledge among the Saudi population and 2) identify the potential factors that were associated with public stigma and AD knowledge levels among Saudi community members, within the context of a caring science perspective using critical caring theory and specific-situation theory. A non-experimental, correlational descriptive, and cross-sectional design was used for this study. The method of collecting data was an online survey method (Qualtrics) using the Basic Knowledge of Alzheimer's Disease (BKAD) to measure knowledge (Wiese, et al., 2017, 2019), and an adapted version of the Attribution Questionnaire AQ-9 to measure public stigma (Kim et al., 2021; Werner et al., 2017). Data analysis was performed via SPSS version 29. A total of (N = 150) participants were recruited in a span of three months. Data analysis revealed: 1) a significant correlation (r = -.20, p = .016) between AD knowledge and public stigma level, 2) significant factors associated with public stigma level were gender (B = 1.89, t = 2.51, p = .013), an education level (B = -2.69, t = -3.42, p < .001); and experience as an AD caregiver professionally (B = 2.69, t = 2.30, p = .023), 3) Factors significantly associated with AD knowledge level were the a) age group 18- 24 years old (B = 2.78, t = 2.27, p = .025), b) occupation in the non-medical profession category (B = -1.77, t = -2.04, p = .043), and c) education level (B = 2.27, t = 2.75, p = .007). Stigma can vary based on various contextual factors, including cultural influences, in which further studies are needed to better understand the concept in versatile cultures. The findings provided valuable insights into the patterns and significance of relationships between public stigma, AD knowledge, and factors associated with stigma and AD knowledge.40 0Item Restricted Exploring potential glial senescence signatures in Alzheimer’s disease(Saudi Digital Library, 2023-11-01) Allehyany, Bshaier; Matthews, PaulBackground: Glial cells’ ability to maintain homeostasis in the brain and regulate neuroinflammation is altered in Alzheimer’s disease. Senescent glia – glia with irreversible cell cycle arrest, resistance to apoptosis, and pro-inflammatory cytokine secretion – are associated with exacerbated amyloid-β and tau pathology. GLB1 is widely associated with predicting glial senescence in ageing. Aims, objectives, and hypothesis: Using imaging mass cytometry data, we aimed to quantify microglia and astrocytes and identify their potential senescence signatures. We hypothesized that a glial senescence signature, predicted by GLB1 co-expression, exists in AD. Methods: Using in-house-generated imaging mass cytometry data from the mid-temporal gyrus of post-mortem brain tissue, cell counts of Iba-1-positive microglia and GFAP-positive astrocytes were determined in AD and control cases. The expression of senescence markers, and the co-expression of GLB1 in senescence-expressing glia were investigated. Independent sample t-tests with an FDR correction were used for between-group comparisons (or the Mann–Whitney U test if data failed the normality test). Results: There was no significant difference between groups in Iba-1-positive microglia and GFAP-positive astrocyte counts. Iba-1-positive microglia did not show a senescence signature, while GFAP-positive astrocytes showed increased senescence expression in p21, γ-H2AX, and GLB1. Cells positive for GLB1 and other senescence markers only showed a significant increase in GFAP-positive astrocytes. Conclusions and future directions: Reactive astrocytes were associated with a GLB1- associated senescence signature in Alzheimer’s disease, whereas microglia were not. This senescence-like phenotype may suggest the vulnerability of reactive glia to oxidative stress and DNA damage. This work highlights the possibility of targeting GLB1-expressing reactive astrocytes for senescent cell-eliminating drugs – senolytics.7 0Item Restricted YKL-40 PREDICTS TEMPOROPARIETAL GLUCOSE HYPOMETABOLISM AND Aβ DEPOSITION IN ALZHEIMER’S DISEASE TRAJECTORY(Saudi Digital Library, 2023-11-01) Allehyany, Bshaier; Edison, PaulAlzheimer’s disease (AD) biomarkers amyloid-β and tau aggregates have not been effective AD therapeutics, and it is important to investigate other biomarkers for AD to identify novel therapeutic targets that slow disease progression. Glial cell activation markers in the cerebrospinal fluid have recently been associated with AD, especially the astroglial activation marker chitinase-3-like protein 1 (YKL-40) and the microglial activation marker soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Another cerebrospinal fluid marker that has been recently associated with AD is the synaptic dysregulation marker growth associated protein 43 (GAP-43). Despite being associated with amyloid-β and tau pathology, the role of these biomarkers in AD-associated temporoparietal glucose hypometabolism and reductions in grey matter volume is still unclear. This study aimed to investigate the associations between cerebrospinal fluid YKL-40, sTREM2, and GAP-43 and brain glucose hypometabolism and reductions in grey matter volume. Participants (n = 385) were grouped into four conditions: AD, amyloid-positive mild cognitive impairment (MCI), amyloid-negative MCI, and controls. Regional analysis and voxel-level linear regression revealed that YKL-40 could predict temporoparietal glucose hypometabolism in amyloid-positive groups, and that GAP-43 is predictive of different patterns of hypometabolism in the AD group. Only sTREM2 and YKL-40 predicted reduced grey matter volume, but YKL-40 predicted earlier cognitive decline. YKL-40 may be more sensitive to earlier stages of cognitive decline in amyloid-positive participants than the other markers, possibly due to amyloid-induced neuroinflammation and neurodegeneration. However, correlational studies can only give indirect conclusions and future studies are needed to identify direct effects of neuroinflammation and synaptic loss on YKL-40 levels using cell cultures.8 0Item Restricted Role of Retinoic Acid Receptor β Signalling in Alzheimer’s Disease(Saudi Digital Library, 2023-08-27) Almuallim, Hassan Yousef Othman; Corcoran, JonathanAlzheimer's disease, the most common form of Dementia, is characterized by a debilitating progression of memory impairment and cognitive decline. The distinct neuropathological hallmarks characterizing Alzheimer's disease revolve around the existence of senile plaques containing amyloid-β, as well as neurofibrillary tangles composed of tau protein, precipitating oxidative stress and neuroinflammation. The therapeutic options for Alzheimer’s disease are either symptomatic treatments or disease-modifying drugs, with the latter currently showing significant investment in targeting amyloid-β. Interestingly, DNA double-strand breaks play a role in increasing the secretion of amyloid-β, consequently triggering the aggregation of amyloid-β plaques. However, there are currently no therapeutic options available for Alzheimer’s disease that specifically target the induction of DNA repair. KCL286, a synthetic retinoic acid receptor beta agonist with promising results from a phase I clinical trial, has demonstrated its capacity to initiate DNA repair mechanisms in a nerve injury model. In this context, we embarked upon an investigation into the effects of KCL286 administration in Tg2576 mice, a transgenic strain characterized by human amyloid precursor protein overexpression and consequently amyloid-β accumulation. A three-month treatment significantly reduced the DNA damage response protein γH2AX, in particular the gene expression of γH2AX within the hippocampus. The inducing of DNA double-strand break repair corresponded with the clearance of amyloid-β deposits and reduction in inflammation. The study underscores the potential of stimulating the RARβ signalling pathway via the RARβ agonist KCL286, as it appears to induce DNA repair mechanism and amyloid-β clearance. This reinforces the drug’s promise as a prospective therapeutic candidate for Alzheimer's disease.22 0Item Restricted The Effects of Iron and Inflammation on Alzheimer’s Disease in 5xFAD Mice(Saudi Digital Library, 2023-09-01) Aljuhani, Manal; So, Po-WahBoth neuroinflammation and iron dyshomeostasis feature in, and contribute to, Alzheimer’s disease (AD), and have been shown to interact synergistically. This thesis aims to investigate: 1) the short-term effect of peripheral iron administration on the progression of AD in 5xFAD and wildtype in both male and female mice and 2) the short/long term effects of peripheral iron administration, with and without inflammatory priming, on the progression of AD in 5xFAD and wildtype mice. A multimodality approach was used to assess the progression of AD: behavioural assessments to evaluate cognitive performance; in-vivo magnetic resonance imaging studies, relaxation rates R1 and R2, as putative indices of inflammation and iron accumulation, respectively; quantitative iron assessments and immunohistochemical assessments of both neuroinflammation and plaque deposition. Iron treatment led to increased numbers of plaques and microglia in the hippocampus accompanying cognitive impairment and higher levels of hippocampal iron in 5xFAD female mice. Conversely, 5xFAD male mice treated with iron demonstrated increased levels of plaque deposition, but cognitive impairment was not observed. Male and female mice had a differential response to iron treatment. In the short-term effect, hippocampal and cortical R1 were increased by lipopolysaccharide (LPS) treatment alone, and combined with iron, in wildtype mice. Moreover, microglial branch length and number of end points were higher in LPS and LPS + iron. Conversely, in 5xFAD mice, plaque deposition was increased post-iron and -LPS treatments in the hippocampus and cortex but reduced when the two treatments were combined (LPS+iron). In the long-term, hippocampal and cortical R2 were increased by LPS treatment in 5xFAD mice. Additionally, plaque deposition was higher by LPS, alone or combined with iron, along with an increase of iron concentration in the hippocampus. In the long term, R2 correlated with Aβ plaque deposition, and with iron content consistent with previous reports. I demonstrate sex- and region-dependent effects of peripheral inflammation and/or iron in 5xFAD mice and wildtype littermates. The data provides evidence for further study of iron dyshomeostasis and inflammation as potential therapeutic targets in AD.12 0