"A small blue spot plays an important role in the development of Alzheimer's dementia."

Martin Dahl discusses his research

A small blue spot in our brain is considered one of the first sites to show signs of potential later onset of Alzheimer's dementia. The blue spot plays an important role in the production of neurotransmitters for the consolidation of memory. For a long time, its research was considered difficult due to its small size and location. Martin Dahl and his team combine special imaging techniques and neuropsychological measurements to explore this little-studied brain region. In the interview, he talks about his research, the mapping of the blue spot, and the hope for early interventions.

You lead the project "Neuromodulation of cognition across the lifespan". What is its focus? 
Martin Dahl: We use imaging techniques such as magnetic resonance imaging (MRI) to investigate how neuronal changes in adulthood and in neurodegenerative diseases are linked to cognitive impairment. We are particularly interested in the role played by certain neurotransmitters such as dopamine and noradrenaline, which help to transmit signals between nerve cells and are crucial for strengthening the connections between them. As a result, these neurotransmitters are involved in several cognitive processes such as stabilizing the contents of memory. 

What is the significance of these neurotransmitters in connection with age-related memory impairment? 
Dahl: The typical symptoms of age-related diseases, such as memory loss in Alzheimer's dementia, occur in old age. However, studies on the brains of people who have died at different ages show that the first signs of Alzheimer's can appear in the brain much earlier. These are the so-called tau deposits, the precursors of which can already be detected around the age of 30, especially in the blue spot. As these deposits spread throughout the brain, the nerve cells in the locus coeruleus die off, and the neurotransmitter system becomes dysregulated. In other words, there is an important time lag between the early changes in the brain and the cognitive impairments that occur later. If we could develop or refine methods to see these early changes in the brain in living people, we might be able to detect diseases earlier and intervene in disease development. 

You are focusing on researching the locus coeruleus, the so-called blue spot. Why? 

Dahl: The blue spot lies deep in the brainstem, and its small size – barely the size of a fingernail – has prevented it from being studied in living humans for a long time. We have recently been able to do so with the help of special MRI sequences. The blue spot produces important neurotransmitters, such as noradrenaline and dopamine, and significantly regulates the activity of neurons throughout the brain via an extensive network of nerve fibers.  

When we encode memories, on a neuronal level the connections between nerve cells are strengthened. However, these changes are transient and disappear again after a while if they are not consolidated. The neurotransmitters produced by the blue spot allow these neuronal changes to become permanent and therefore play a crucial role in memory processes. 

What research methods do you apply? 
Dahl: In order to precisely localize small brainstem nuclei like the blue spot, we use high-resolution MRI that allows us to create three-dimensional images of the brain anatomy of the study participants. To measure the activity of the blue spot and its influence on other parts of the brain, however, we use techniques such as eye tracking – a method to measure pupil size – and electroencephalography (EEG) – a recording of brain waves from the scalp. In some of our studies, participants are invited to the lab for many years so that we can link the changes in neural measures over time to longer-term changes in behavior. 

Are there already preliminary results that you can share? 
Dahl: In a recently published study, we showed that we can measure how the blue spot changes with age using repeated MRI measurements. These changes were more pronounced with increased age, indicating a death of the cells that produce the neurotransmitters. Those participants showing a decrease in the blue spot signal in the MRI measurements, performed worse in later memory assessments. In follow-up studies, we are trying to determine whether the participants with these changes in the blue spot are more likely to develop Alzheimer's dementia. We were also able to show that the neurotransmitters noradrenaline and dopamine are differently involved in age-related memory impairment. 

You are working on a "Locus Coeruleus Probability Map." Can you tell us more about this? 
Dahl: The blue spot is a tiny structure deep in the brainstem that is only a few millimeters in size. In our research, it is crucial to locate it precisely to be able to draw correct conclusions about this neurotransmitter system. However, when we started researching it, we realized that different scientific publications did not agree on the blue spot’s exact location in the brain and its size. This can lead to different studies producing results that are difficult to replicate. That is why we first published our map of the blue spot so that other research groups could also use it (Dahl et al., 2019). In a follow-up project, we have also integrated many published maps of the blue spot to establish a consensus for the size and location of this small brainstem structure – we also share these results with other scientists (Dahl et al., 2022; Meta Mask). I am pleased that this is widely used by the scientific community and serves as a basis for many studies by other research groups. 

Which institutions or researchers are you collaborating with in your project? 
Dahl: For many years, we have been working closely with Professor Mara Mather, who investigates neuronal, emotional, and cognitive changes in late adulthood at the University of Southern California and is an expert on the blue spot. During my postdoc, I also visited her Emotion & Cognition Lab. Currently, it is conducting a study in which I am involved, examining whether the blue spot and Alzheimer's-associated markers can be influenced by a six-month behavioral intervention. 

What plans do you have for future studies?   
Dahl: The blue spot lies deep in the brain that makes it difficult to measure and experimentally manipulate its activity. In ongoing experimental studies, therefore, we are trying to activate the blue spot by electrically stimulating a peripheral nerve. The long fibers of this nerve extend from the ear into the brainstem, the region in which the blue spot is located. This is performed via an electrode that is worn in the ear like headphones. This experiment iscarried out in the MRI scanner, and we hope to learn more about the role of the blue spot in memory processes. For example, results from animal models suggest that different activity patterns of the blue spot could contribute differently to the spread of tau deposits. 

How do your research findings contribute to a better understanding of neurodegenerative diseases? How do they fit in with previous findings in dementia research? 
Dahl: We recently collaborated with the University of Southern California and conducted a study with people who have a specific genetic mutation. This mutation leads to a very rare hereditary form of Alzheimer's dementia. People who have this disease show symptoms early in life, between the ages of 30 and 50. The genetic alteration plays a causative role in the development of this disease. This allows us to study the processes that are related to the disease itself and not just to age. 

We examined the blue spot in people with this Alzheimer's-causing mutation and their family members without the mutation using MRI. In the patients with the mutation, we found signs of degeneration in the blue spot. This degeneration was also associated with a greater amount of tau deposition in the rest of the brain, which is an essential disease mechanism in Alzheimer's dementia. To better understand our MRI results, we also examined tissue samples from people who died with the same mutation, as well as people without the mutation. We again found degeneration of the blue spot in the individuals with the mutation, confirming our previous MRI results. In summary, we can say that the blue spot plays a role in the development of Alzheimer's disease. 

Can measures/interventions already be derived from your findings as to how age-related memory loss can be counteracted? 
Dahl: In our research, we are initially interested in a precise identification of the changes in the blue spot and deciphering its role in memory development. We recently received a grant from the BrightFocus Foundation, which allows us to include blood-based Alzheimer's biomarkers in this research programme. This is a prerequisite for potential later interventions for the treatment of Alzheimer's dementia. Other research groups are already working on clinical studies in which the blue spot is stimulated experimentally to find out whether such stimulation has a positive effect on cognition (cf. ClinicalTrials.gov NCT04908358). In addition, pharmacological studies are currently testing the influence of manipulating the neurotransmitters of the locus coeruleus on the development of Alzheimer's disease (e.g. https://doi.org/10.1093/brain/awab452). 

Martin Dahl
Martin is head of the Lifespan Neuromodulation of Cognition (LINE) project at the Center for Lifespan Psychology. He is interested in the effects of age- and disease-related degeneration of neuromodulatory systems on cognition.