Alzheimer’s disease (AD) is the most common cause of dementia and quickly becoming one of the most burdening diseases of the century. Effective treatments are still missing, partially because its... Show moreAlzheimer’s disease (AD) is the most common cause of dementia and quickly becoming one of the most burdening diseases of the century. Effective treatments are still missing, partially because its pathogenesis is still incompletely understood. This thesis explores the role of iron in AD, how it interacts with the immune system to influence disease pathogenesis and whether it could serve as potential biomarker. The first part of this thesis describes the importance of translational MRI, and how it can be used to increase our understanding of neurological diseases and help identify biomarkers. Subsequently, we used translational MRI to characterize the differences in iron accumulation in the brain between patients with AD and healthy elderly. The second part of this thesis investigated how the immune cells of the brain, microglia, interact with the accumulated iron. Using a combination of advanced multispectral immunofluorescence on brain tissue from AD patients and a human stem-cell derived microglia model, we studied the activation pattern of iron-accumulating microglia in human brains and emulated microglial iron accumulation in vitro. This enabled us to study the effect of iron on the gene expression patterns and function of the brain’s immune cells. Show less
This thesis addresses several pathophysiological and clinical aspects of both the Lambert-Eaton myasthenic syndrome (LEMS, introduced in chapter 1) and myasthenia gravis (MG).In chapter 2, the... Show moreThis thesis addresses several pathophysiological and clinical aspects of both the Lambert-Eaton myasthenic syndrome (LEMS, introduced in chapter 1) and myasthenia gravis (MG).In chapter 2, the search for new LEMS associated small cell lung cancer (SCLC) markers is described, leading to the discovery of ERC1 as a new antigen associated with LEMS.In chapter 3, a literature review of screening methods for SCLC in LEMS is presented, aswell as the role of associated SOX1 antibodies in SCLC-LEMS patients.In chapter 4 long-term follow-up, functional impairment and quality of life in LEMSpatients are described. We also report a normal survival in LEMS patients without associated tumour as well as an improved tumour survival in SCLC-LEMS patients.In chapter 5, we report that lowering the cut-off value for increment from 100% to 60% increases sensitivity for diagnosis of LEMS, without a negative effect on the specificity.Chapter 6 reports that a lower initial compound muscle action potential amplitude is a marker of more severe disease in AChR MG.In chapter 7, we show a small symptomatic effect of ephedrine as a symptomatic treatment in MG patients, in a placebo-controlled, double-blind, randomised, multiple crossover series of n-of-1 trials. Show less
