Home Health U of O Researcher investigates the utility of NM-MRI to interrogate the role of the norepinephrine system in Alzheimer’s disease

U of O Researcher investigates the utility of NM-MRI to interrogate the role of the norepinephrine system in Alzheimer’s disease

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Specialized brain imaging used to investigate the role of neurotransmitters in Alzheimer’s disease

Dr. Clifford Cassidy is an Assistant Professor at the University of Ottawa School of Medicine and Royals Institute of Mental HealthHe is interested in neuroimaging to understand the brain mechanisms of psychopathology, which broadly refers to the study of psychiatric disorders.

Fulcrum sat down with Dr. Cassidy to discuss 2022 study, Details were recently published in Neuropsychopharmacology.

What are Neurotransmitters?

“There are different neurotransmitters in the brain,” explains Dr. Cassidy. “Particularly relevant neurotransmitters, called neuromodulators, have a profound effect on people’s moods, emotions and levels of arousal. I’ve done research and others may have heard of serotonin.In this case it is sometimes called norepinephrine, or noradrenaline.

Norepinephrine is one of the most important neuromodulators in the brain and has a profound effect on a person’s level of alertness. Consider two different situations. One when sleeping and the other when attacked. In both of these two scenarios, there is a range of arousal that neuromodulators influence. It also plays an important role in learning and memory. This is because it is also related to attention and agitation.

What is the locus coeruleus (LC)?

When asked more about the locus coeruleus and its connection to Alzheimer’s disease, Dr. Cassidy said: (LC). We are interested in that particular brain region. Because the neuromodulators are based there and they transmit projections like a big tree with a very wide arbor branching across the brain. ”

Dr. Cassidy explains why LC is important in Alzheimer’s disease is a more complicated story. That is because there is some debate and debate as to whether LC is an important part of the cascade of events that lead to Alzheimer’s disease.

“At this point, we have some idea of ​​what Alzheimer’s disease is, but we don’t know why some people get Alzheimer’s disease and others don’t. We know that Alzheimer’s disease isn’t necessarily a problem with the system. However, it is part of the context and may be part of the initial changes that lead to a series of other changes. tausaid Dr. Cassidy.

“Most people believe that the LC is the first place in the brain to accumulate tangles of hyperphosphorylated tau. We don’t know exactly what role LC plays, and we don’t know either, but it’s possible that tau was present in that part of the brain decades before Alzheimer’s disease. I know something,” he added.

Magnetic resonance imaging (MRI)

Dr. Cassidy, while studying neuroimaging, realized that MRI machines can take many different types of images. Differences between different types of images can be seen in the contrast of different tissues. In some images, gray matter and the white matter, or where gray matter is dark and white matter is light. On others it is reversed depending on the type of contrast you are looking at. That said, there are different types of contrast that can be performed on MRI.

“The idea of ​​using MRI and applying it to observe neuromelanin The research has been going on for 15 years, but people are still trying to best understand how to optimize this method and how specific it is to neuromelanin,” he said. “However, the part of the brain of interest in this study is the LC, so it can show what most MRI sequence types cannot show. On most MRI scans, you can’t see these things at all, they just fade into the background, but with a neuromelanin MRI they become apparent.”

Research method

Cassidy says he’s been working on the method for eight years, but he wasn’t sure where it would lead since it began during his postdoctoral days at Columbia University. Since he had always worked in psychiatry, he thought that these structures could be useful for people with non-degenerative mental illnesses, even if they were not mere markers of neurodegeneration.

“When we started using this method for our particular use, it worked well and gave us a lot of expertise. We built our own tools to study it. In many ways it seemed very obvious to try to use it in different areas. [where] This type of method is most needed. I wasn’t the first to use it in Alzheimer’s disease, but our study is the largest study I know of that has the most supportive data using this method.

Supporting data are not only neuromelanin MRI (NM-MRI) above, but also PET measurements. PET imaging of tau and amyloid in the brain. There are also clinical measures of cognitive status and neuropsychiatric symptoms.

The important points to note are: It is not something that can be built overnight. My strategy for that has been to work with people who are already doing this work. I persuaded him. ”

Since the researchers obtained all measurements related to Alzheimer’s disease, not only from Alzheimer’s patients, but also from healthy, elderly individuals, they were able to examine the extent to which LC is involved in the disease. . Individual variability gave us a better sense of when changes occurred and which other characteristics were associated with the disease.


Not many studies have been done using this method in Alzheimer’s disease, so it was important for the researchers to start with the basics.The degeneration of LC was well understood through postmortem work.

“First, we wanted to confirm that in Alzheimer’s disease, structural degeneration leads to a loss of signal, and that it is a progressive disease that appears to get worse in people with more advanced disease.” We can quantify it very precisely with imaging because we can see the progression of tau spread, which is basically a stage of Alzheimer’s disease using the Braak staging system,” said Dr. Cassidy. Told.

Researchers found a gradual loss of neurons in the LC as Alzheimer’s disease progressed. This correlation was pretty strong on its own, but they wanted to go a little further in trying to understand the relevance of this brain system or the norepinephrine system in Alzheimer’s disease.

Although one important effect of LC neuron loss may lie in the cognitive symptoms of Alzheimer’s disease, much attention has focused on the role of the LC-norepinephrine system on the neuropsychiatric symptoms of Alzheimer’s disease. The disease is more than just memory impairment, and can be accompanied by a variety of symptoms. Even in the early stages, you may experience symptoms like depression, anxiety, impulse control problems, socially inappropriate behavior, and even psychosis. There is previous evidence that it is related.

He continued, “We found a relationship between neumelanin MRI signals and these types of symptoms, particularly impulse control problems. It can help indicate whether it is dysregulated and perhaps suggest that doctors use drugs that target this system to treat the neuropsychiatric symptoms of Alzheimer’s disease.”

Early detection of Alzheimer’s disease

“There is indeed evidence that the structure (LC) accumulates tau before any other part of the brain, so it seems like an obvious place to look for early warning signs of Alzheimer’s disease. There’s not much degeneration in the early stages, which is what our study and others have suggested, but with sufficiently sensitive measurements, the more obvious clinical symptoms of Alzheimer’s disease, such as memory impairment, emerge. Some degree of degeneration may be seen before

In general, identifying something early helps you deal with it. As for visualizing tau in LC, Dr. Cassidy is currently unsure if neuroimaging is sensitive enough to detect changes. Because this is a very small structure. But it’s entirely possible that researchers could use different methods to look more closely at the structures and get early markers of Alzheimer’s disease risk.

future application

Regarding the application, “[NM-MRI] can Measure the content of neromelanin. When cells die, they lose neumelanin, possibly reducing their signal.This is the basis for using the method as a measurement or neurodegeneration

“In psychiatric disorders in which these systems are dysregulated, such as the dopamine system in schizophrenia or the norepinephrine system in PTSD, there is no marked degeneration of these systems, but their cells are hyperactive. A life-long increase in neuromelanin accumulation in cells, which can be detected using MRI, thus measuring the history of the activity of these neurotransmitter systems. , provides a practical method to detect imbalance even in the absence of neurodegeneration.”

Dr. Cassidy has evidence to suggest that it is a marker of neurotransmitter imbalance in schizophrenia and PTSD. That is, if there is an imbalance, or if the system is overactive for a long period of time, the signal can rise, or if the activity is low, the signal can fall.

To learn more about Dr. Cassidy and his research on using neuroimaging to understand the relationship between brain activity and behavior, visit his website. here.

  • Emma Williams was Fulcrum’s Science and Technology Editor for the 2021-22 issue. Emma is her junior in environmental science at the University of Ottawa. As a returning editor, she wants to continue sharing her love of science with her U of O community. When she’s not studying, she enjoys her outdoor hikes in Gatineau Park, reading and biking with friends.

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