A new noradrenergic strategy to treat Impulsivity in Progressive Supranuclear Palsy

点击翻译按钮获取中文摘要

Progressive Supranuclear Palsy (PSP) is as complex as it is devastating for patients and families, combining a kind of movement disorder that does not respond to standard therapies, choking, loss of speech, personality changes, and dementia. Research by our team has shown that in the UK around 7,000 people are living with PSP.Although physically very disabling, it is cognitive and personality changes in PSP that have the greatest impact on quality of life. Despite being slow and unresponsive for many activities, the same patients are often reckless and impulsive for actions that they do make. For example, a person living with PSP may "rush into things" and or "jump to conclusions" without thought for the consequences, or behave in a way that has high risks of falls or choking. These problems are also called "impulsivity". Impulsivity is highly dangerous for patients with PSP, in several different ways. It can make patients walking or moving around alone even though they have a very poor balance and fall. Eating too fast while choking is another form of impulsive behaviour which can lead to life-threatening chest infections. Impulsivity can also be highly distressing for carers and families. There is currently no cure for PSP, although some of the symptoms, including impulsivity, are potentially treatable. However, there is yet a big gap between our knowledge of what is happening in brain cells of patients with PSP and how we should use the available treatments to help people with PSP to achieve the best possible quality of life. We must therefore build better "bridges" between basic studies and clinical trials. To do this, our team will run a series of studies using the most advanced technologies in basic and clinical neuroscience, using advances in imaging, pharmacology, and psychology. We will take advantage of the link between a brain chemical, noradrenaline, and the control of behavior. Noradrenaline is made by a tiny region of the brain called the locus coeruleus. It acts on other parts of the brain, especially the frontal lobe, to help control behavior, including flexible thinking and action control. First, we will quantify the changes in the locus coeruleus, in PSP patients who we have followed through their illness in clinic and who then donated their brain to the Cambridge Brain Bank. Second, we will measure the locus coeruleus in living patients with PSP. The locus coeruleus is small, and hard to see with normal brain scans. Working with Prof Emrah Duzel from Magdeburg, we will use the new technology of ultra-high field magnetic resonance imaging (known as "7 Tesla") to measure the size and degeneration of the locus coeruleus. His groups have developed new robust tools to measure this brain region. We will then use functional magnetic resonance imaging to measure how well the locus coeruleus connects to the frontal lobe and other brain regions. Finally, we will measure the effects of a specific drug that enhances noradrenaline (called "atomoxetine") on impulsvity and cognition in PSP. This drug has been shown by our group and collaborators to improve impulsivity in a significant proportion of patients with Parkinson's disease, and in animal models of impulsivity. It is well tolerated, and approved for such research use in PSP. We believe that the results of our study will lead on to clinical trials for impulsivity in PSP and will eventually contribute to enhance the quality of life of people suffering from PSP.