AbstractBackground: β-amyloid plaque deposition is a pathological hallmark of Alzheimer’s disease and cerebral amyloid angiopathy. However, β-amyloid has also been shown to possess direct vasoactive properties and increased plasma β-amyloid has been associated with endothelial dysfunction in mice.
Aims: To investigate the metabolic and pharmacological determinants of plasma β-amyloid levels and to investigate the association of plasma β-amyloid with structural and functional markers of vascular integrity as well as cardiovascular outcomes.
Methods: Plasma β-amyloid 40 and β-amyloid 42 levels were measured in 407 subjects with type 2 diabetes (T2DM) and 245 subjects without T2DM from the Surrogate markers for Micro and Macro vascular hard endpoints for Innovative diabetes Tools (SUMMIT) consortium database. The SUMMIT database was used to analyse factors associated with altered plasma β-amyloid levels and to determine the relationship between plasma β-amyloid and biomarkers of cardiovascular health and disease. Biomarkers analysed included, reactive hyperaemia index (RHI) with EndoPAT, reactive hyperaemia in response to occlusion, arterial stiffness, skin microcirculation response to acetylcholine (ACh) and sodium nitroprusside (SNP) and carotid intima-media thickness (IMT).
Results: In the SUMMIT baseline cohort as well as in T2DM and non-T2DM sub-groups, renal function as estimated by estimated glomerular filtration rate (eGFR) was the most significant independent predictor of plasma β-amyloid 40 and 42 levels. In the T2DM subgroup, insulin use was also found to be independently associated with increased β-amyloid 40 and 42 levels. Use of diuretics was independently associated with increased β-amyloid 40 and 42 levels in the SUMMIT baseline cohort and increased β-amyloid 40 levels in the T2DM cohort. After adjusting for conventional cardiovascular risk factors of age, gender, diabetes status, systolic blood pressure (SBP), high-density lipoprotein (HDL) cholesterol and total cholesterol as well as independent predictors of plasma β-amyloid, β-amyloid 40 was independently associated with increased arterial stiffness as measured by pulse wave velocity, and reduced vascular responsiveness to ACh and SNP in the SUMMIT baseline and SUMMIT T2DM cohorts. β-amyloid was not found to be a significant predictor of cardiovascular outcomes over 4-6 years of follow up.
Conclusions: The research in this thesis shows that plasma β-amyloid levels are affected by a range of metabolic and pharmacological factors. Future studies should therefore take into account the importance of adjusting for factors such as eGFR, diuretic use or insulin use. The results also show that higher levels of β-amyloid 40, and to a lesser extent 42, are associated with increased arterial stiffness as well as impaired vascular responsiveness to endothelium-dependent and independent stimuli.
|Date of Award||2019|
|Supervisor||Faisel Khan (Supervisor) & Michael Ashford (Supervisor)|