Noradrenergic Biomarkers and their relationship to Therapeutic Response in Clinical Alzheimer's Disease

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Attention - the act of focusing on relevant information - is often affected early in Alzheimer's disease. Patients and their families frequently notice early and disabling problems with attention and concentration, which worsen memory problems. The current treatments for Alzheimer's disease mainly focus on boosting levels of the brain chemical acetylcholine, which has limited effects on attention.The brain chemical noradrenaline is particularly important for attention. In Alzheimer's disease, the brain region that produces noradrenaline is damaged early on, and as a result attention is affected. Despite its small size, this brain region, the locus coeruleus (LC), can now be seen on magnetic resonance imaging (MRI) scans. Damage to the LC is visible on the scans of patients with Alzheimer's disease.I aim to develop accurate ways of measuring damage to the LC and reduced noradrenaline levels in patients with Alzheimer's. I will also assess how much the patients' attention and memory is affected by the disease and compare it to the damage we have measured. This will give us better understanding of the processes associated with the disease that result in problems with attention. It will hopefully also allow us to select patients who are most in need of treatments that will boost their noradrenaline.I will recruit patients who have finished taking part in an ongoing treatment trial of a drug that boosts noradrenaline (called guanfacine) and will test whether measuring damage to the noradrenaline system can predict who will respond well to the treatment. I will use detailed MRI brain scans to assess damage within each patient's noradrenaline centre - the LC. I will also develop a new way of measuring noradrenaline based on changes in pupil size. Using surprising sounds, we can cause changes in pupil size, and this is dependent on the level of noradrenaline in a person's brain. I will design an experiment that uses sound to produce these changes and measure them using a high-quality camera. I will also look to measure the level of noradrenaline in the patients' blood which should give us an idea of how much is being produced by their LC. These 3 measures; MRI, pupil fluctuations and blood, will be related to performance on tests of attention. These tests are well established and frequently used to assess attention in patients with dementia. They will be done with the patients before, during and after the clinical drug trial to see whether guanfacine has any effect on their scores.All of this testing will be performed at Imperial College Healthcare Trust and Imperial College London. Analysis of the blood samples will be done at University College London (UCL).My principal supervisor is Professor David Sharp - he is a consultant neurologist, director of the Dementia Research Institute Centre at Imperial, and is one of the world-leaders in brain-imaging research. Dr Paresh Malhotra, a consultant neurologist who specialises in dementia disorders of attention, is leading the clinical drug trial. He will be a key supervisor in the design and implementation of this project. Professor Henrik Zetterberg works at UCL and is an expert in the analysis of blood samples in brain diseases. Dr Pete Lally is a physicist who specialises in using MRI to look in detail at the brain stem and will be heavily involved in this project. Regarding the pupillometry, I will have input from Dr Kinan Muhammed who works at Oxford University and has experience in this area.The results from this project will help us understand why patients with Alzheimer's disease have such varying degrees of attentional problems and may provide methods to allow doctors to personalise the way that they treat patients' cognitive problems. We would hope our findings could be translated to clinical practice and result in real improvements in the quality of life of a large number of patients.