Sudha Seshadri, MD, founding Director of the Glen Beggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Hill San Antonio and Matthew Pase, PhD, Senior Research Fellow at The Florey Institute for Neuroscience and Mental Health, Australia talk about a new marker for detecting dementia earlier in life.
This CD14 that we’re talking about is an inflammatory marker, and we’re hearing more about inflammation leading to disease. Can you explain that a little bit?
SESHADRI: We are increasingly recognizing that infection and inflammation play a role in neurodegeneration and vascular diseases where we had not recognized their importance. In the past two years, some of the genes that change the risk of Alzheimer’s are genes that control how microglia and macrophages remove toxic substances, whether this is amyloid in the brain or whether this is abnormal lipids in the wall of the artery. Soluble CD14 is something that comes into the blood from the membrane of the macrophage or microglia where its role is to bind with bad things like bacterial toxins or other body generated toxins, like amyloid, and help remove them. This is a marker of the degree of inflammation that’s happening in the brain and the blood. The macrophages can cross the blood brain barrier and when they are inside the brain, they’re microglia. What we are measuring in the periphery is we believe a marker of the inflammation in response, not just peripherally but possibly also within the brain. In the study that we had looked at with Framingham participants and cardiovascular health participants, we had seen that the higher markers of soluble CD14 predicted a higher risk of developing dementias of all types, and even among people who did not develop dementia over a seven-year period. If you looked at the change in the size of their brain or a change in their ability to do complex executed function tasks, that seemed to go down more in people with higher levels. It was like they were aging faster. There was another study called the regard study, which is a 48-county study. They found also that this soluble CD14 increased risk of dementia, and the effects seem to be greater in African Americans than whites. In Framingham and CHS, the participants are largely white, although there are some African-Americans. Neither of these two studies look specifically at Hispanic populations. We are now measuring these levels in some of our San Antonio participants and population.
How do you measure the levels of CD14?
SESHADRI: It’s not that difficult. We can measure it using what’s called Eliza S.C. You need to have antibodies to this circulating protein and then you can measure the levels with good levels of precision. Or, what we call inter-acidity of around 3 to 4 percent.
So, it’s your body in overdrive fighting this inflammation? That’s what that marker is?
SESHADRI: When we have inflammation in the body, let’s say you have a bacterial toxin lipopolysaccharide, it binds to the soluble CD14 on the surface of the cell and the soluble CD14 and lipopolysaccharide seem to get broken off and removed by other cells. Both the synthesis of the soluble CD14 as well as it’s breaking off from the membrane into the fluid around it, seem to increase in situations of inflammation.
If a person goes to a doctor, how is this going to help them?
SESHADRI: At this point, we have been studying it in research settings. I would not say you can go to your doctor and get a soluble CD14 level. Whether that is useful or not is something we study. The people with dementia, for instance, their risk of developing dementia or stroke is multifactorial. A part of it is inflammation, and a part of it is perhaps other things like endothelial injury, or amyloid Tao. We expect that a multi-marker panel may tell an individual which part needs to be more aggressively treated. For instance, today in Kansas, we look at biomarkers and say you have an estrogen receptor so you can go on and assume that would help your type of breast cancer. Some of the studies are being done right here at our cancer center. This sort of recognizing the heterogeneity of dementia identifying subgroups of patients who might be most at risk from one pathway and may benefit most from drugs that treat that pathway is we think the way we are going to be effective in treating people.
Because we’ve talked about walking indicating dementia, how does that collective marker for dementia come together?
SESHADRI: At present, age, sex, etc. are really the only markers we use to say what is somebody’s risk. And, we know that leaves a lot of unexplained risk. We believe that a range of these simple clinical markers like walking and looking at the vessels in your eye along with blood markers, which are also relatively easy at the point of contact, could help us better predict an individual’s risk of dementia. We may find that these markers need to be fine-tuned. The predictors in a 65-year-old white woman may be different from the predictors in an 85-year-old Hispanic-Latino man. That kind of information is something we need to put together. I expect over the next five, six years, we’ll be able to provide more tools to people in primary care settings to give targeted advice.
Matthew Pase, PhD, Senior Research Fellow, The Florey Institute for Neuroscience and Mental Health, Australia.
Why is it such a preferred option to diagnose dementia sooner?
PASE: There are two aspects here. One aspect is diagnosis and another aspect is identifying who’s at high risk. Earlier diagnosis has many advantages including earlier access to medications that may help manage symptoms and more time to plan for the future. Identifying persons at risk is very important because by the time someone shows symptoms of dementia, a lot of people feel like it’s too late to intervene to stop dementia permanently. We need to identify people who are much earlier in the disease course at a time when we think drugs might still be effective in preventing dementia onset.
I’ve noticed, even with COVID-19, they seem to be worried about a cytokine storm and inflammation?
PASE: Cytokine release is part of the normal immune response, and we know that in dementia there is a large inflammatory response which we can measure.
When you say inflammatory response, what exactly do you mean? What happens to the individual physically?
PASE: Inflammation is a normal response within the body to help it heal or to fight infection or injury. Whereas it may be useful in the short term, sustained inflammation, particularly in the brain, may be detrimental. In dementia, for example Alzheimer’s disease, there’s the accumulation of different pathologies. You can have an immediate reaction which can help to fight whatever’s going on, but sustained chronic inflammation, this sort of heightened response of the brain, might actually do damage to the brain in the long term.
If people were aware that inflammation is the culprit, how do they tamp down or keep the inflammation at bay?
PASE: We’re still in the very early stages of understanding about the role of inflammation in dementia and other neurological diseases. It’s still very early to know what we can do about it. There are now some therapies looking at whether we can start to reduce inflammation in the brain and see what effect this might have in the long term. From a general health perspective, it seems that looking after your health and maintaining exercise routines and healthy lifestyles might help to keep inflammation down in a more general sense. But, in terms of brain inflammation, it can happen alongside other injuries that cause dementia, such as damage to blood vessels or the build-up of abnormal proteins. We still don’t know what might be effective in combating it.
Is it a protein that you were seeking in this?
PASE: CD-14 is a protein involved in the inflammatory response to different things. When pathologies accumulate in the brain, whether it’s the result of head injury, stroke, or proteins which cause Alzheimer’s disease, CD-14 may kick into action and help create an inflammatory response to help the brain fight injury or are harmful changes.
What’s the trigger that sets that off?
PASE: The triggers can be multiple. The trigger could be something just like hitting your head. It could be having a more serious thing like a stroke. Or, it could be this very sort of insidious or silent accumulation of the pathology that causes Alzheimer’s disease which happens over many decades. So, the triggers are not specific, and can be many things.
What is the main goal of conducting this study and what do you hope comes out of it?
PASE: We don’t have any inexpensive and easy to measure biomarkers which are good at determining who is at a greater risk of going on to develop dementia in the future. This is a major barrier to the development of therapeutic interventions to help prevent people from getting dementia. By identifying people who might be at an increased risk, we might be able to invite these people into these studies in universities and other clinics and try and start to accelerate our pipelines for drug discovery so that we might have an intervention that might be effective against dementia. More generally, we also wanted to understand whether inflammation was linked to the risk of future dementia.
So, your study is sort of a set up for the actual hit from the medication, right?
PASE: Yes. And, to more completely understand the role of inflammation in dementia. For example, when measuring something in the blood in the periphery. What we measure in the blood in the periphery is not necessarily a good reflection of what’s happening in the brain. But measuring things directly in the brain is very difficult and invasive, and very costly if you’re talking about expensive brain scans. So, we will try to look at what is in the blood that might be informative in telling us about what’s happening in someone’s brain.
Is there any way to measure something in the brain without drilling a hole in it?
PASE: Yes. We’ve developed very good imaging techniques now to look at the pathology that causes Alzheimer’s disease. But these involve imaging scans which require a dose of radiation, and they’re also very expensive. They’re only available in very specialist centers. The other alternative is to have a lumber puncture which involves a needle which goes into the space around the spine to extract cerebrospinal fluid. Again, participants don’t like having this procedure unless it’s necessary because it is somewhat invasive.
Could you give us the chronological timeline of when this study started, where you are right now within the next 60 days, and what you hope to see at the end?
PASE: We looked at data from two ongoing prospective studies, one being the Framingham Heart Study and being the Cardiovascular Health Study, both based in the United States. The investigators measured blood from participants a few decades ago and stored this blood under appropriate conditions. We then used these blood samples to measure CD-14, this marker of inflammation. Once we had our samples analyzed, we were able to examine if those people with high CD-14 were more likely to develop dementia within the next 10 or so years. We looked at the relationship between CD-14 in blood and the risk of getting dementia in the future. We also related the blood samples to other markers of brain health including brain volume and thinking and memory performance on what we call neuropsychological testing. Then, we published these results in 2020. Moving forward in the near future, we hope to look at other markers of inflammation and other processes trying to more completely understand what factors might be contributing to dementia and to more accurately identify persons at an increased risk.
Can you expand on when the Framingham Heart Study was started, I guess they had no idea that you were going to “repurpose” those well-stored blood samples and look for these particular markers?
PASE: The Framingham Heart Study was founded in 1948 and designed to understand why some people went on to develop heart disease and why some people didn’t. In fact, I don’t think the term risk factors existed before the heart study. It was really Framingham that led the way in understanding what were the causes leading people to develop heart disease. Since then, the Framingham Heart Study has expanded to be much more than a study of heart health. It’s a study of all conditions of aging. The people who founded the Framingham Heart Study and who’ve worked on it since have really had a lot of forethought. For example, they stored extra blood from participants so that future investigators like me could look at new biomarkers and tests that were not around at the time. For example, even now when we assess Framingham Heart Study, participants, we put aside samples of blood so that in the future when other promising biomarkers or other promising things are discovered, we can go back and measure these from the data.
How exciting is that to you from a visceral and emotional standpoint?
PASE: It’s an amazing study to work on for several reasons. One, because scientifically it’s so excellent and so many people have given so much to the study to make it what it is today. Also, because of the dedication of the participants. There are three generations of participants in the heart study. There are the original cohorts who were enrolled in 1948, then their children and also their grandchildren. So, it really is a community study that involves a huge amount of dedication from thousands and thousands of people.
And, where are you and Dr. Seshadri in your study now?
PASE: Dr. Seshadri continues to lead the Neurology core of the Framingham Heart Study. . And, I remain a Framingham Heart Study investigator with a number of ongoing projects. I did my post-doctoral training at the Framingham Heart Study under Dr. Seshadri, and now I run my own lab here in Australia but continue to work very closely with her on several projects. We are planning more studies on Framingham Heart Study participants, and also continuing to look at data that we’ve already collected to answer important questions about Alzheimer’s disease, stroke and other neurological conditions as well.
So, what really happened with the study? What does this mean to someone sitting on their sofa?
PASE: We found that a marker of inflammation measured from blood was related to the risk of developing dementia in the future. Our results were derived from two large populations. Having high levels of inflammation certainly is not a guarantee that any one individual will get dementia. But it’s another piece of the puzzle. It suggests that there are multiple pathways which might contribute to dementia. And this is important as we move forward to developing better drugs and better therapies that might help people avoid dementia into old age.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Will Sansom
Claire Smoorenburg, Public Relations
Florey Institute of Neuroscience and Mental Health, Australia
claire.smoorenburg@florey.edu.au
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