The noradrenergic system´s contribution to neural resource in ageing

A08

The integrity of the locus coeruleus- noradrenergic (LC-NA) system is important in determining late-life cognitive abilities. However it has yet to be investigated whether pharmacological modulation of the LC-NA system or cognitive training interventions tailored to boost noradrenaline (NA) function may prevent cognitive decline in old age. The proposed project examines whether the LC-NA system offers hidden potential in boosting neural resource in ageing. This will be done by increasing NA function pharmacologically as well as by training particular cognitive functions known to recruit the LC-NA system.

Principal Investigators

CRC 1436 member Matthew Betts

Dr. Matthew Betts

CRC 1436 member Dorothea Hämmerer

Prof. Dr. Dorothea Hämmerer

Dr. Matthew Betts

Matthew is a Principal Investigator at the Institute of Cognitive Neurology and Dementia Research (IKND) located at the Otto-von-Guericke University Magdeburg (OVGU). He leads a research program that aims to understand how structural changes to subcortical neuromodulatory systems relate to cognitive decline in aging and to the clinical and pathological manifestations of neurodegenerative diseases. This incorporates a combination of novel structural MR imaging techniques using ultra high-field MRI, PET imaging, CSF biomarkers and behavioural tasks. He is the cofounder of the Locus Coeruleus imaging meeting that brings together clinicians, neuropathologists, physicists and cognitive neuroscientists to try to better understand the role of the noradrenergic locus coeruleus in neurodegenerative diseases.

Institut:Otto von Guericke University Magdeburg, Medical Faculty

Project Titel:A08 The noradrenergic system´s contribution to neural resource in ageing

Prof. Dr. Dorothea Hämmerer

Dorothea Hämmerer studied psychology at the University of Trier, the University of Paris X Nanterre and the University of Freiburg. Starting with her doctoral thesis at the Max Planck Institute for Human Development in 2006, she used cognitive neuroscientific methods to understand why we have different cognitive abilities at different ages. Dorothea Hämmerer’s post-doc studies took her to the Technical University of Dresden, the University College London (Institute for Cognitive Neuroscience and the Welcome Trust Center for Neuroimaging) and the German Center for Neurodegenerative Diseases in Magdeburg. They have enabled her to expand her skills in magnetic resonance imaging and in the physiological and cognitive assessment of aging and dementia. She still maintains close collaborative relationships with the Institute for Cognitive Neuroscience in London and the Institute for Cognitive Neuroscience. In her research, Dorothea Hämmerer tries to understand how age differences in the brain, especially in neuromodulatory systems, affect age differences in cognitive functions, especially attention control, decision-making and memory across the lifespan. Together with her collaboration partners, she is developing cognitive paradigms and non-invasive imaging methods that can capture correlates of individual neuromodulatory systems (especially dopamine and noradrenaline) in a more targeted manner. For reasons that are still unknown, neuromodulatory systems are particularly vulnerable in old age and are among the earliest and most severely affected brain regions in neurodegenerative diseases such as Parkinson’s and Alzheimer’s dementia. In her current research, Prof. Hämmerer focuses in particular on exploring the noradrenergic locus coeruleus and uses structural and functional imaging methods to map the earliest cognitive and neurophysiological changes in neurodegenerative diseases. She is co-founder of the Locus Coeruleus Imaging Meeting Magdeburg, which brings together clinicians, animal researchers, physicists and cognitive neuroscientists to try to better understand the role of the noradrenergic locus coeruleus in neurodegenerative diseases. Her research was recognized with the Brenda Milner Award and a Senior Research Fellowship from Alzheimer Research UK.

Institut:Otto von Guericke University Magdeburg, Medical Faculty

:Universität Innsbruck

Project Title:A08 The noradrenergic system´s contribution to neural resource in ageing

Co-Workers

CRC 1436 member Guruprasath Gurusamy

Guruprasath Gurusamy

CRC 1436 member Marina Leiman

Marina Leimann

CRC 1436 member Hartmut Schütze

Dr. Hartmut Schütze

Guruprasath Gurusamy

Guru obtained his Bachelor of Technology in Bioengineering from Sastra University and his Master of Technology in Biomedical Engineering from SRM University, Tamil Nadu, India. He is currently working with Dr Matthew Betts in CRC1436, IKND, to understand the contribution of the noradrenergic system to neural resources in aging by modulating the locus coeruleus-norepinephrine system (LC-NA) through physical exercise and cognitive intervention. He is interested in exploring the neural, cognitive and behavioural markers of ageing and dementia using physiological, psychophysical and MRI (magnetic resonance imaging) measures.

Marina Leimann

I studied Psychology and Clinical Neuropsychology (University of Buenos Aires, Argentina), and also obtained a Master’s Degree in Behavioural Science (University of Almería, Spain).

I have always found human behaviour and cognition as a fascinating field, especially healthy ageing and neurodegenerative diseases. Therefore, I would like to develop a research career in Translational Neuroscience to help improve public health policies and the healthcare system.

As a PhD student at IKND, my project focuses on noradrenergic pathways to improve cognition in older adults.

Dr. Hartmut Schütze

coming soon

What is the locus coeruleus?

The locus coeruleus (LC), a small nucleus located deep in the brainstem, is the major source of noradrenaline (NA) modulation in the brain and has been shown to be involved in regulating a wide range of higher cognitive functions including working memory, learning and attention, memory consolidation and retrieval vigilance and arousal/wakefulness (for reviews see Sara, 2009; Mather & Harley, 2016; Betts et al. 2019).

What do we know about the role of the locus coeruleus in cognition and brain health?

A core function of the LC is to support the encoding or processing of (emotionally) salient events (Arnsten, 1998; Luo et al., 2015). Within this saliency network, increases in extracellular NA through LC activation may increase neural resources via activation of α and ß-adrenoreceptors in the prefrontal cortex and hippocampus to enhance working memory (Ramos & Arnsten, 2007) and episodic memory (Luo et al., 2015), respectively. It has been shown that boosting the LC-NA system may also increase cognitive performance by reorganizing functional connectivity of brain regions that are implicated in particular cognitive processes. For instance, pharmacological increases in NA have been shown to increase connectivity between frontal and parietal regions during a visual attention task via enhancing the influence of LC inputs − the principle source of NA in these regions (Coull et al., 1999). Moreover, recent evidence indicates that age-related differences in the LC-NA are associated with reduced cognitive abilities relating to episodic memory (Hämmerer et al., 2018; Dahl et al., 2019) and cognitive reserve (Robertson, 2013; Wilson et al., 2013; Clewett et al., 2016).

NA modulation is also important for preserving long-term brain health due to its anti-inflammatory properties and role in supporting local vascular function (Satoh & Iijima, 2017). This is particularly relevant for brain health in ageing as animal studies show that the combination of lower NA levels and higher age-related pathologies such as amyloid-beta (Aß) or neurofibrillary tangles (NTF) accelerate the decline in brain health by increasing the spread of protein pathologies and increases microglial and neurovascular dysfunction (Chalermpalanupap et al., 2017; Satoh & Iijima, 2017; Weinshenker, 2018)

The goals of our project

The integrity of the LC-NA system is important in determining late-life cognitive abilities. However it has yet to be investigated whether pharmacological modulation of the LC-NA system or cognitive training interventions tailored to boost NA function may prevent cognitive decline in old age. The proposed project aims to examine whether the NA system offers hidden potential in boosting neural resource in ageing. This will be achieved by increasing NA function pharmacologically as well as by training particular cognitive functions known to recruit the LC-NA system. We aim to tailor the assessment of cognitive and physiological changes according to known neurophysiological effects of increases in NA function (e.g. with respect to increased functional activity/connectivity) and to examine the functional effects of boosting NA levels pharmacologically or via cognitive training in the context of a multi-faceted assessment of interindividual differences in the integrity of the LC-NA system. We will also examine whether so called ‘super agers’, octogenarians which show far above average cognitive performance, have a particularly intact noradrenergic system.

Towards the future

The long-term perspective of this project is to assess whether in vivo assessment of the LC-NA system can identify individuals with hidden neural resource in older age and whether interventions aimed at increasing NA levels may benefit clinical or at-risk populations in ageing. In the future, we aim to broaden our understanding of LC-mediated plasticity in target areas of LC projections including understanding the role of LC-mediated dopamine release and the mechanisms regulating LC activation. We also aim to explore how boosting noradrenergic modulation affects cortical layer activation using ultra high-field MRI. Animal studies suggest that noradrenergic projections exert their cognitive effects by altering the signal to noise level of neurons particularly in layer 4 of the cortex (Berridge & Waterhouse), however this remains to be explored in humans.

Publications of the project A08