“It is a debilitating disease”: Finding biomarkers for the early detection of Alzheimer’s disease

(Photo provided by Mark Russell)

“The focus of this study was to try and identify potential biomarkers of Alzheimer’s disease. There were two potential biomarkers found in this study - one was specific to males and one was specific to females.” ~Mark Russell 

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*In the following article, TS refers to The Synapse and MR refers to Mark Russell;

TS: Could you briefly introduce yourself, your supervisor, the topic of your thesis, and the field it contributes to? 

MR: Hi, my name is Mark Russell. I have recently completed my Bachelor’s of Science in Chemistry (Biological) with Honours at Memorial University of Newfoundland (MUN), and the research I’ll be talking about was completed as part of my honours thesis. My supervisor is Dr. Lindsay Cahill of the MUN Chemistry department. 

My thesis is on identifying biomarkers (i.e. substances in the body that indicate disease) for neurodegenerative diseases using high frequency ultrasound (i.e. using sound waves to create images of the body) in a mouse model. Neurodegenerative diseases are a set of diseases that involve the breakdown of brain tissue. The most prevalent of these diseases is Alzheimer’s Disease (AD), which involves extreme deficits in memory and thinking. There is currently no cure for AD; all treatments rely on slowing its progression.  As such, it is essential to identify biomarkers for early detection of AD so that treatment can start as soon as possible. 

In this study, I sought to identify AD biomarkers in mouse carotid arteries. The carotid arteries send oxygen-rich blood to the brain, which the brain needs to function. I measured the blood flow in mouse carotid arteries to indirectly measure how much oxygen is reaching the brain. The goal was to see if AD shows altered carotid blood flow. This would allude to changes in how much oxygen gets to the brain, and thus to altered brain function that might mean AD is beginning. 

TS: What is the inspiration for your study, and the research question? How does your study relate to neuroscience or psychology? 

MR: This study was inspired by the growing number of AD patients in Canada and the world. It is a debilitating disease that affects many lives and can take a toll on everyone involved in the treatment process. 

The idea for my thesis is rooted in the fact that the brain is the most active organ in the body. Using about 20% of the body’s energy, the brain requires a lot of oxygen to function. Most of this oxygen is delivered by the heart pumping oxygen-rich blood to the brain through the carotid arteries. The ultimate goal of my study was to determine if there were any alterations in carotid artery blood flow or anatomy prior to AD symptoms in the mouse model, and whether these alterations related to further deterioration in AD. Ultrasound, which uses sound waves to generate images of our bodies, is a non-invasive and relatively inexpensive technique that can be used to gauge carotid artery blood flow and anatomy. In clinical settings, ultrasound could then be used to screen people at risk for AD.  

While my research was completed in a biophysical chemistry research group, the work is interdisciplinary. Some of the fields that the research overlaps with include biology, as we look at anatomy and physiology; neuroscience, through our focus on the brain; and also medicine, as our goal is to help inform treatments for AD. 

TS: Could you provide a brief summary of the experimental procedure used in this study? 

MR: To complete this research, the first thing needed was an appropriate animal model for neurodegeneration. The mouse model that was used is called the decrepit (dcr) mice model. This mouse model is a result of a spontaneous genetic mutation that occurs within  mitochondrial ribosomal protein L3 (Mrpl3), a gene of unknown function, which causes AD-like symptoms. Dcr mice can be selectively bred in labs, and they have very reliable disease onset and progression. Specifically, onset occurs at 70 days of age and premature death occurs at 150 days of age. 

With this in mind, the ultrasound was planned at 3 timepoints: 50 days of age (prior to disease onset), 75 days (shortly after onset), and 125 days (prior to premature death). The study was completed using 8 dcr mice and 8 wild type controls, with an equal number of males and females in each group. 

The data was collected using high frequency ultrasound on the carotid arteries. To accomplish this, the mice were anesthetized. While sedated, their heart rate, respiration rate and temperature were monitored, and a series of measurements were taken. The measurements taken were “M-mode” images of the arteries, which allow us to determine the artery diameter and wall thickness. In addition, the speed of the blood in the arteries was obtained using pulsed Doppler measurements, which use sound waves to detect movement. This, along with the diameter measurements, allowed us to obtain the “pulse wave velocity”, a measure of how fast blood leaves the heart. We then used this information to gauge the stiffness of the artery walls. 

TS: What are the main results you observed? 

MR: The focus of this study was to try and identify potential biomarkers of AD. There were two potential biomarkers found in this study - one was specific to males and one was specific to females. 

We found that male dcr mice at the 50 day timepoint (i.e. prior to any signs of neurodegeneration) had significantly dilated arteries compared to controls and females. In females, dcr mice were shown to have significantly greater average blood flow through the carotid arteries. Both these changes would allow more oxygen to reach the brain. As such, these results can be interpreted as the body trying to compensate for a problem in the brain by increasing oxygen levels. It is notable that this change occurs prior to any brain abnormalities being detectable on MRI.

Another interesting result was the significant difference in arterial stiffness in female dcr mice compared to male dcr mice. In males, arterial stiffness decreased as the disease progressed, while females showed a steady increase. This may mean that females retain compliant arteries as the disease progresses, while the males, who were maximally dilated early on in the study, don’t have this compliance anymore. As compliant arteries indicate that oxygen levels sent to the brain can be regulated, the ability of female mice to increase arterial stiffness prior to AD onset might explain why, in humans, it has been observed that women live longer than men following a diagnosis of AD.

Another notable finding was that the major differences we found between dcr and controls also depended on biological sex. For example, the dcr mice appeared to have stunted growth and decreased heart rates, and this differed in males and females.

TS: What would you consider the most intriguing part of the research process? 

MR: The part of my research that I found the most interesting would definitely be the experience I gained working with the mice and the ultrasound. I plan to pursue veterinary medicine and love working with animals, so any environment where I can work with less common animals - like dcr mice - is always great. 

I loved working with the ultrasound machine specifically because I would like to specialize in veterinary radiology; the various technologies available have always intrigued me, so getting accustomed to using the ultrasound was a great experience. 

TS: Is there anything else you wish to share about the research experience? 

MR: One thing I would like to add regarding my honours research is that, if anyone is on the fence about pursuing an honours thesis or any research for that matter, I would 100% recommend that they do it. Throughout my honours research, I got to meet an amazing team of researchers who all shared common interests, and the feeling of accomplishment when I started to see results was very fulfilling. It was genuinely the most enjoyable part of my degree at MUN. Ψ

Created for The Synapse by Incé Husain.