Assessing the role of the noradrenergic locus coeruleus in healthy ageing and early Alzheimer's disease

In pathological ageing, like dementia of Alzheimer's type, some cognitive functions are affected earlier and more severely than others. The earliest observable cognitive symptoms in Alzheimer's disease are often memory problems and difficulties in adapting to changes. Similarly, in healthy ageing, some cognitive capacities are known to improve with more life experience (such as general knowledge and vocabulary) while many cognitive functions that are necessary for dealing with daily cognitive challenges (such as memory and adapting to changes in the environment) get worse with ageing.
The anatomical and neurochemical setup of the brain changes substantially during healthy and pathological ageing. A key challenge of dementia and ageing research is to understand how changes in the brain relate to cognitive decline and how this cognitive decline can be ultimately slowed down to improve day-to-day life quality. As mentioned above, memory and adapting to changes are among those abilities that are affected by dementia and also get more and more difficult in healthy ageing. Interestingly, animal research suggests that both of these functions are supported by a small brain structure called locus coeruleus (LC). In healthy ageing, neurons in the LC start dying by the age of 20, accumulating to a volume loss of about 30% by the age of 60. The LC is therefore among the brain structures most prone to volume loss in healthy ageing. In dementia of the Alzheimer's type, the role of the LC appears to be pivotal as well. The LC is among the first brain structures to exhibit lesions and forms connections with many of the other brain areas that are affected by lesions later-on.
What is the role of the LC in the brain and cognitive changes typical for Alzheimer's disease and healthy ageing? It has been suggested that the shrinkage of the LC might be in part responsible for the difficulties in remembering things and adapting to changes. Unfortunately, this idea could not be tested so far because non-invasive measures that examine the LC in the living brain have only recently been developed.
We have recently shown that it is possible to measure the anatomical structure as well as functional activation of LC non-invasively in younger and older adults. In our proposed research project we will use these new brain imaging procedures to examine to what extent the LC has shrunk in healthy older adults as well as older adults with mild Alzheimer's disease. Also, we will be able to test how changes in LC volume and function relate to a decline in memory and adapting to changes. To do this, we use a memory task as well as a newly developed computerized gamble task that simulates a changing environment. Using these tasks we can examine whether reduced LC activations can explain the impaired memory as well as difficulties to react to changes in Alzheimers disease and old age. Finally, we also measure how strongly LC and other brain areas that are important for memory and adapting to changes are connected and whether changes in brain areas connected to LC show the same pattern of shrinkage as the LC.
If successful, our research will provide novel insights into the mechanisms of cognitive and brain decline in healthy ageing and dementia. We also anticipate that we will establish new methods for psychiatric and dementia research. Our insights will ultimately help to develop interventions that aim at maintaining a high level of well-being in healthy ageing and provide tools to examine causes of pathological ageing. Given the increasing proportion of older adults in Europe, our research has considerable economic relevance in the longer term.

Pathological studies show that the major source of cortical noradrenergic projections, the locus coeruleus (LC), shows evidence of neurodegeneration during healthy ageing but that this is accelerated in conditions such as Alzheimer's disease (AD). Indeed, volume loss in LC precedes volume loss in earliest affected cortical areas such as entorhinal cortex in AD. However, because the LC has been a technically difficult structure to image in vivo, the role it might play in both the neurobehavioural as well as cognitive changes that accompany healthy and pathological ageing has remained largely unexplored. Our earlier work demonstrated successful and reliable protocols for functional and structural imaging of the LC in younger and older adults.
The research outlined in this proposal will use these novel structural and functional imaging protocols, as well as pupillometric recordings, to investigate the contribution of changes in the LC to cognitive and behavioural changes in ageing. We will recruit younger adults, older adults with mild AD and healthy older controls. We will examine how decline in the structure and function of the LC contributes to the declines in episodic memory and decision making seen during healthy ageing and in the early stages of AD. Unlike previously reported paradigms, our task allows us to disentangle the respective roles of noradrenergic and dopaminergic brain structures, both of which are known to decline in dementia and ageing. Finally, we will examine whether a reduction in LC integrity is linked to reduced resting state connectivity and brain atrophy in relevant cortical target areas of LC (entorhinal and anterior cingulate cortex).
The project will provide novel translational insights that can drive understanding and development of potential interventions to alleviate the cognitive and behavioural declines seen in healthy and pathological ageing.

Our proposal fits within the MRC spotlight area 'Neurodegenerative Diseases: dementia', as well as the MRC's initiative 'Lifelong Health & Wellbeing'. Specifically, we will provide novel mechanistic insights into how a change in noradrenergic brain structures in healthy ageing and early Alzheimer's disease contributes to a decline in physiological and cognitive functions. Our proposal has the potential to provide a mechanistic framework in which to study how to ameliorate decline in brain function during healthy ageing and in dementia, with substantial potential economic impact.

Academic impact

Noradrenergic brain structures are among the first brain structures to be affected by neurodegeneration in dementia (Alzheimer as well as Parkinson type). However, the topic of a decline in noradrenergic brain structures in healthy ageing and dementia has so far not received its due attention: This is because of the limited availability of measures that allow quantifying the relevance of structural integrity and function of these brain structures for age differences in cognitive tasks. With the research project outlined here, we propose how to overcome this limitation. We will validate recently developed cutting-edge tools for an assessment of locus coeruleus structure and function in ageing. The proposed research will be of great relevance for researchers in ageing, psychiatric research as well as dementia research.
Furthermore, the proposed study follows a multi-method approach, which includes standard screening tools and cognitive tests used in dementia diagnosis, as well as pupillometry, and midbrain imaging. Taking advantage of this range of methods, we will examine to what extent diagnostic tools suitable for clinical settings (pupillometry and standard screening tools) reflect insights obtained with cutting edge imaging of midbrain nuclei. If successful, our research can therefore add readily usable tools and test paradigms for a diagnostic assessment in early stages of Alzheimer's disease.
Finally, our study will advance research on the role of noradrenergic modulation in episodic memory and decision making. Our computational model of the role of noradrenergic modulation in decision making will provide a powerful tool for communicating our research agenda. Moreover, this computational model opens exciting research possibilities in the future with respect to testing hypotheses on how to improve cognitive functions in healthy as well as pathological ageing with pharmacological interventions.

Public engagement and data sharing

During the completion of the project, the expertise on cognitive and brain ageing present in the project team will allow educating the interested public about factors and behaviours that maintain cognitive functions and reduce the risk for dementia during ageing. Also, as we have done in previous studies with older participants, all published papers will be sent to the participants that participated in the experiments along with a summary for the lay reader, subject to informed consent and expression of interest. In our experience, participants are very curious and enthusiastic about receiving the final outcome of the research in which they participate.

Economic and societal impact

By 2030, almost a quarter (23%) of European citizens are estimated to be older than 65 years (as compared to 17% in 2013). More than America or Asia, Europe is faced with an increasingly larger workforce that has to be recruited from older adults. Moreover, with increasing life expectancy, prevalence rates of dementia are estimated to increase to a level where 1 in 4 older adults above 90 is affected. Understanding successful cognitive ageing and creating knowledge to develop interventions and preventive methods for healthy as well as pathological ageing is hence of prime economic importance for Europe.