Does the central noradrenergic system play a role in agitation in Alzheimer's disease?

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WHAT IS THE CONTEXT OF THIS RESEARCH?Alzheimer's disease (AD) is the most common cause of dementia, and many individuals with this condition develop distressing and difficult-to-treat behaviours as the disease progresses. One of the most distressing and challenging behaviours is agitation, which is when an individual with dementia shows emotional distress along with overactivity, verbal or physical aggression. Agitation substantially reduces quality of life for patients and caregivers, frequently precipitates admission to a hospital or nursing home and is associated with rapid disease progression and earlier death. The only licensed medication for agitation in dementia is an antipsychotic drug, which works primarily by sedating patients and can lead to dangerous side effects, so we urgently need better, safer and more targeted treatments for agitation. The earliest brain changes in AD have been shown to occur in a small structure near the base of the brain called the locus coeruleus (LC). This structure contains cells that produce a chemical substance (neurotransmitter) called noradrenaline (NA), which plays an important role in controlling how the brain responds to noticeable or important aspects of the environment. To fulfil this role, the LC is connected to and influences other regions of the brain involved in controlling emotions and suppressing actions (response inhibition). There is evidence that these brain regions are dysfunctional in young adults who show aggression or anxiety, as well as in agitated patients with AD. We know that NA allows these brain regions to perform their function properly in healthy people, but no study has yet investigated whether AD-related changes in the LC (and its effects on NA activity) make an individual with AD more likely to have agitation. In support of this concept, there is consistent evidence from post-mortem studies that agitated patients with AD may have a more overactive NA system in their brains to compensate for greater LC cell loss. WHAT WILL THE RESEARCH AIM TO ACHIEVE AND HOW WILL IT BE CONDUCTED?To investigate whether the NA-system in the brain plays a role in agitation in AD, fifty participants with AD and agitation will be asked to:1. Undergo an magnetic resonance imaging (MRI) scan to test whether greater agitation is related to worse LC function and structure. 2. Complete behavioural tests to measure their brain's ability to regulate emotion and inhibit responses, and whether this is related to agitation scores. 3. Receive a single dose of propranolol (a commonly prescribed medication for high blood pressure, which also blocks the action of NA in the brain) to test whether this improves emotion regulation and response inhibition.Healthy older adults are presumed to have a more intact LC-NA system compared to patients with AD, so fifty healthy volunteers without cognitive impairment (controls) will also complete the behaviour and pharmacology studies (2 and 3 above) to test whether propranolol influences emotion regulation and response inhibition in healthy older adults, and whether this is influenced by trait anxiety and anger scores. WHAT ARE THE POTENTIAL IMPLICATIONS AND BENEFITS?This study provides a unique opportunity to further our understanding of the brain processes underlying agitation in AD, and whether there is a role for the NA system. If successful, the findings have potential to lead to new approaches for detecting and treating this condition, for example by using medications that target the NA system (e.g. propranolol).