Saudi Cultural Missions Theses & Dissertations
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Item Restricted Ageing, Blood Pressure, and Neurodegeneration: A Lifelong Concern that Dietary Magnesium may Help Address(Australian National University, 2024-06) Alateeq, Khawlah; Cherbuin, NicolasThe growing global burden of neurodegenerative diseases, cognitive decline, and dementia highlights the urgent need to identify modifiable risk factors that promote healthy brain ageing and slow the progression of dementia. This thesis investigates the impact of high blood pressure (BP) – a prevalent risk factor – on brain ageing. It also investigates the role dietary magnesium (Mg) can play in addressing this risk factor and promoting brain health. Five studies were conducted to address the objectives of this thesis. The initial study involved a comprehensive literature review to generate insights into the relationship between BP, magnesium, neurodegeneration, and cognitive decline within the context of ageing. This process involved summarizing the mechanisms and effects to enhance understanding of how these factors potentially interact in the ageing brain. This review generated essential background knowledge that the subsequent studies sought to build upon. In the second study, a systematic review and meta-analysis were performed to quantify the existing literature on the relationship between continuous BP and total/regional brain volumes and white matter lesions (WMLs). The systematic review revealed a significant association between higher BP, lower brain volumes, and larger WMLs across the entire range, extending beyond individuals with hypertension or pre-hypertension. This finding suggests that high BP is associated with poorer brain health in non-hypertensive individuals within a broader population. The third study built upon the findings of the second study, examining the impact of age, gender, and other risk factors on the association between BP and brain health. This investigation quantified the relationships between continuous BP levels, brain volumes, and WMLs while also considering various risk factors such as age, sex, BMI, and use of antihypertensive medication. The findings reveal a consistent association between BP, lower brain volumes, and larger WMLs across the entire BP range, even within the upper normal BP range. This association affects individuals of all ages, particularly younger adults, and exhibits stronger effects in women. Notably, lower BMI and the use of antihypertensive medication appear to exert a protective effect against the detrimental impact of BP on brain health. These findings have substantial implications for population health, suggesting that even minor increases in BP over a lifespan can significantly contribute to the overall disease burden. This underscores the importance of implementing early preventative measures to maintain optimal BP levels. The fourth and fifth studies explored the associations between Mg intake, brain volumes, and WMLs. Additionally, these studies investigated whether BP and inflammation mediate the neuroprotective effect of Mg. The findings from both the fourth and fifth studies demonstrate that high dietary Mg intake is associated with larger brain volumes and lower WMLs. These results imply that a diet rich in Mg could contribute to enhanced brain health and potentially decrease the risk of dementia in the general population. Surprisingly, the neuroprotective impact of Mg is found not to be mediated by BP levels. Instead, the neuroprotective effect of dietary Mg is partially mediated through inflammation. This supports the potential of Mg intake as an effective, scalable, and affordable intervention in reducing inflammation and protecting against premature brain ageing in the general population. In conclusion, this thesis highlights the significant impact of high BP on brain health and finds that dietary Mg intake yields a neuroprotective effect, which can be attributed to its anti- inflammatory properties. Overall, the findings paint an optimistic picture for general population health, emphasizing the potential benefits of early interventions targeting modifiable risk factors. Thus, sufficient support at the health policy, clinical, and community levels can help reduce or prevent certain known risks to brain health.18 0Item Restricted The Role of Non-enhanced CT Characteristics for Differentiating Reversible and Irreversible Brain Tissue Injury and Estimating the Tissue Fate in Acute Ischaemic Stroke(University of Edinburgh, 2024) Alzahrani, Awad; Grant, Mair; Joanna, WardlawTreatment approach for patients with delayed presentation or an unknown time of onset following an ischaemic stroke has largely been based on advanced imaging techniques such as CT perfusion and MRI. However, the universal availability of these techniques is limited. Non-enhanced computed tomography (NECT) is the most widely accessible imaging technique and mainly used to exclude contraindications to treatment, such as haemorrhagic stroke or other conditions mimicking stroke. NECT also provides features on the area of the brain injured by ischaemic stroke. However, there remains uncertainty over what these features actually mean, and if we should use them to decide which patients might benefit, or possibly be harmed, by treatment. In addition, it might be possible to use the baseline NECT scan to determine how much of the brain injured by the ischaemic stroke can be reversible or not, especially when quick treatment decisions are needed, and advanced scans are not available. This thesis aims to better understand how particular features of the NECT scan can be used to distinguish between areas of salvageable tissue at risk (Penumbra), and irreversibly damaged tissue (infarct core) in patients with ischaemic stroke. It also seeks to predict the outcome of brain tissue fate - whether it will develop into infarct or show signs of recovery - within 24-48 hours after the stroke. I summarised the main aspects of stroke, covering techniques for stroke imaging and NECT ischaemic features, and the use of imaging for predicting tissue outcomes. I conducted a systematic review and meta-analysis to determine the diagnostic accuracy of NECT brain scans for 1) differentiating penumbra from infarct core, and 2) detecting any ischaemic brain injury. I used data from Saudi Arabia, King Abdulaziz University Hospital (KAUH) involving consecutive patients with acute ischaemic stroke. These patients underwent NECT and concurrent CT perfusion imaging upon admission. I used these data to visually correlate early ischaemic features observed on NECT with concurrent CTP changes indicating penumbra or core. Additionally, I sought to identify a specific NECT brain attenuation threshold that distinguishes reversible (penumbra) from irreversible (core) ischaemic brain tissue injury, as defined by CTP. Furthermore, I used a subgroup of IST-3 and EuroHype-1 trials patients, which used baseline NECT scans and subsequent 24-48 hours NECT follow-ups. I used these data to assess whether the CT attenuation of ischaemic lesions measured on baseline NECT can predict brain tissue fate at follow-up after stroke, and to develop and validate a novel nomogram model to predict tissue fate in acute ischaemic stroke. In my systematic review and meta-analysis, I included eighteen studies, with a total of 975 participants. Five studies contributed to the assessment of brain swelling and hypoattenuation on NECT to predict different subtypes of ischaemic brain injury, and thirteen studies to the assessment of NECT for detecting any ischaemic brain injury. I found that for predicting penumbra, swelling on NECT had a pooled sensitivity of 35% and specificity of 98%. For predicting infarct core, parenchymal hypoattenuation on NECT had a pooled sensitivity of 68% and specificity of 98%. For detecting any ischaemic brain injury, combined ischaemic features on NECT had a pooled sensitivity of 61% and specificity of 97%. In 142 patients from KAUH, I measured 206 ischaemic lesions (124 penumbra, 82 core). Optimal CT attenuation ratio for identifying penumbra was >0.87, with 86% sensitivity 91% specificity (area under the receiver operating characteristic curve, 0.95. In 122 patients from KAUH, I qualitatively assessed 976 cerebral regions (72 isolated swelling, 254 hypoattenuation). On NECT, isolated swelling usually corresponded to CTP penumbra (70/72, 97%), whereas visible NECT hypoattenuation was found with core (141/254, 56%) and penumbra (109/254, 43%). In 255 patients from IST-3, I demonstrated that CT attenuation measurements at baseline NECT enable the detection of brain tissue fate after acute ischaemic stroke, as defined using 24-48 NECT follow-up imaging. In addition to that, I developed and externally validated a practical nomogram model based on a few readily available variables for all patients to predict brain tissue fate outcomes after acute ischaemic stroke. The suggested nomogram demonstrated excellent discriminative ability, yielding a high C- index of 0.89 in the development cohort comprising 255 patients from IST-3. During external validation, this capability remained robust, resulting in an excellent C-index of 0.91 in the validation cohort consisting of 59 patients from EuroHype-1. Overall, these findings highlight the potential for assessing brain tissue viability after ischaemic stroke using NECT. My work holds promise for empowering frontline clinicians with a deeper comprehension of these methods, potentially enhancing patient selection for stroke treatment, especially where imaging resources are limited though this requires prospective validation. Moreover, further investigation is essential to fully grasp the impact of these methods on the long-term functional outcomes of individuals with ischaemic stroke. Furthermore, these results showed that early parenchymal hypoattenuation lesion in baseline NECT indicating ischaemic injury may not progress and can even be reversible on follow-up. Therefore, a critical reassessment of the conventional concept of core or infarct core on NECT, as applied in clinical practice, appears essential.101 0Item Restricted Regulation of Food Intake in Adults with and without Obesity: The Role of the Gastrointestinal Tract and Gut- Brain Axis(The University of Nottingham, 2023-11-03) Althubeati, Sarah; Salter, Andrew; Eldeghaidy, Sally; Lobo, Dileep.N; Avery, AmandaObesity is a complex global health issue affecting a significant portion of the population. In the UK, it is estimated that approximately 1 in 4 adults and 1 in 5 children aged 10 to 11 years are living with obesity. Impairment in food intake regulation, including hunger and satiety sensations, are key factors contributing to overeating and weight gain, particularly in individuals with obesity. While various mechanisms may explain these alterations, such as altered appetite and satiety regulators, accelerated gastric emptying (GE), and heightened brain responses to food cues and reward, it remains inconclusive whether these mechanisms are altered in people living with obesity compared to normal-weight (NW) adults. There are various approaches to studying food regulation, each offering unique insights into the complex mechanisms that control appetite, satiety, and food intake. Non-invasive imaging, particularly magnetic resonance imaging (MRI), provides a powerful tool for investigating the physiological mechanisms underlaying the regulation of food intake. The work in this PhD thesis aims to combine physiological measurements obtained by using MRI with behavioural assessments (i.e., subjective satiety rating), to provide a more comprehensive understanding of appetite control in NW adults and alterations associated with obesity. The work in this thesis included a functional neuroimaging meta-analysis, and three eating behaviour intervention studies, two of which used MRI techniques. A functional neuroimaging meta-analysis was performed to identify brain areas associated with changes in appetite and satiety regulators in NW and Obese adults. The caudate nucleus and hypothalamus were identified as key areas associated with satiety regulators in NW participants. However, conclusive findings for Obese participants were limited due to the small number of studies conducted in this area. An MRI study was conducted to investigate the effect of a standard meal on gastrointestinal (GI) responses. The study found that GI responses including gastric content volume (GCV), GE rate, small bowel water content (SBWC), and superior mesenteric artery (SMA) blood flow, and appetite and satiety regulators were not significantly altered by obesity following the meal. However, Obese participants showed lower satiety subjective rating, and higher insulin and triglyceride levels compared to NW participants. Different macronutrients play distinct roles in influencing feelings of fullness and satiety, and their impact on the satiety sensation can be a valuable strategy for weight loss. In a pilot MRI study combining gut and brain imaging, responses to a high-fat (HF) emulsion drink and a carbohydrate drink that is matched in caloric content, volume, and viscosity were assessed in NW and Obese participants. Data collection in this study was significantly impacted by the COVID pandemic; therefore, findings from this work are focused on GI responses. The results suggest that the HF drink might induce higher GCV, SBWC, SMA blood flow, and subjective satiety ratings when compared to an iso-caloric, and iso-viscous high carbohydrate drink (HC) in both NW and Obese. The final study investigated the satiating effect of acute high protein consumption compared to high carbohydrate in NW and Obese participants using ad libitum meal intake and subjective satiety ratings. This study found no significant differences in ad libitum energy intake, subjective satiety, or energy intake between the drinks in either NW or Obese participants. This research integrated different approaches to measuring the regulation of food intake and alterations in obesity. This holistic approach facilitates a comprehension understanding of the mechanisms governing food regulation, including the impact of macronutrient composition, hormonal influences, gastrointestinal responses, neural signalling, and eating behaviours. While the studies in the thesis did not reveal significant differences in certain aspects of appetite regulation between NW and Obese, including macronutrient compositions, they did highlight several areas requiring further investigations. The complicated nature of obesity and appetite regulation necessitates continued research to better understand these complex mechanisms and inform strategies for obesity management and prevention.12 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