A new noradrenergic strategy to treat Impulsivity in Progressive Supranuclear Palsy

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.

Impulsivity is a distressing and injurious aspect of PSP that is commonly under-recognised and poorly managed, even when coupled with balance and swallowing difficulty, with high risk of falls, injury, and choking. It typically coexists with apathy and bradykinesia, and is not relieved by current dopaminergic therapies. Impulsivity is a complex construct, with dissociable pharmacological and anatomical mechanisms that impair response inhibition, reward sensitivity, and decision making. Our group and collaborators have provided robust evidence that response inhibition in patients with Parkinsonian disorders linked to PSP (e.g., Parkinson's disease and frontotemporal dementia) is modulated by noradrenaline (NA), a key neurotransmitter mainly synthesized by the locus coeruleus (LC). Our overarching hypothesis is that enhancing NA function via NA reuptake inhibitors can improve response inhibition and impulsivity in PSP patients, mediated by the prefrontal cortex and its connections to the caudate and subthalamic nucleus.

This study will: (1) provide new quantitative evidence for the degree of loss of neurons in the LC, using post-mortem samples from PSP patients whom we have followed over the last 10 years; (2) apply advances in ultra-high-field MRI to quantify the LC in living PSP patients, together with a battery of behavioural tests of impulsivity and neuropsychology; (3) use formal models of behavior to track decision variables behind impulsive actions, and relate these to neural and disease markers, including brain network connectivity, and (4) test a repurposed drug, atomoxetine, to restore core neurocognitive systems governing the inhibition of motor responses in PSP.

Our work will promote bidirectional translational research, between non-clinical and clinical neuroscience, mapping disease states to preclinical models of cognition and behavior; and guide subsequent clinical trials with better outcome measures and patient selection and stratification.

The beneficiaries of our research will extend beyond the academic environment and will include:

1. Patients with PSP: Impulsivity in PSP represents a significant burden to the affected individuals. PSP patients with problems as impulsivity and cognitive inflexibility have an increased risk of falls, injuries, chocking episodes, aspiration pneumonia, and early death. It is hoped that increasing our understanding into the brain mechanisms of impulsivity in PSP will reduce these risks. The absence of biomarkers for detecting impulsivity in PSP and the high inter-patients variability in drug response have also made the treatment of behavioural problems in PSP and other neurodegenerative disorders a major challenge. The cause of this variability in treatment response remains largely unclear, although heterogeneity in core neurochemical systems that determines a reduced sensitivity to specific therapy may play a significant role. Brain-based mechanistic accounts of impulsivity in PSP could therefore help clinical decision making and improve the management of these disabling behavioural symptoms in PSP and related disorders.

1. Non-academic clinicians: Our findings may provide useful information for clinical neurologists and other professionals who work with PSP patients (e.g., speech and language therapists, physiotherapists, and specialist nurses) and will raise awareness on a common and too often under-recognized problem in PSP. In particular, our project will reveal: (1) why some patients with PSP display impulsive behaviours and behavioral problems; (2) what happens to the brain of PSP patients with impulsive behaviours, and (3) that there are potential targets for treating impulsivity in PSP (i.e., via enhancing the noradrenergic system).

2. Carers of patients with PSP: Parents, relatives, friends, social workers, and other carers of people with PSP may also benefit from our research. In the short term our project may have a positive effect by, for example, helping carers understand PSP and its associated problems better. In the longer term, it is hoped that our results will translate into clinical trials that will provide better treatments for managing challenging behavioural syndromes in PSP.

3. Other neurodegenerative disorders: PSP is a complex disorder that share some molecular, pathophysiological, and clinical features with other neurological disorders such as Parkinson's disease, Huntington's disease, and frontotemporal dementia. Taken together, these neurodegenerative disorders represent a very significant burden to society. We therefore hope that research enabling the development of more effective interventions to manage behavioral syndromes in PSP could be also applicable to other common neurodegenerative disorders.