Important Alzheimer’s Risk Factors via Imaging

Robert Lufkin, M.D.

Oh, it’s great to be here, Heather. I’m really excited about participating in your summit, and I can’t wait to hear the other speakers too. I’m really looking forward to it.

Heather Sandison, N.D.

Thank you, and thank you also, Dr. Lufkin and I are collaborating on some research that we’re both in Southern California. And so we feel very, very fortunate to be able to send some of our study participants up to get imaging from him. So he really is on the cutting edge of the research and science around getting the best imaging for Alzheimer’s patients and dementia patients. So I wanna dive right in. Imaging is one part of our workup in an Alzheimer’s patient, because we can see not only the brain, but other anatomy through the pictures that we take, as they say a picture says a thousand words. And so I wanna understand more about what imaging can and can’t do. Can we rule Alzheimer’s in or out based on a picture of the brain?

Robert Lufkin, M.D.

Okay, yeah, that’s a very good question ’cause anytime we do any imaging study and my background is, as you mentioned, I’m a neuroradiologist. So I specialize in imaging and that’s what I do all day. But anytime we do an imaging study for a patient, it’s important to consider the question and why we’re doing it. So for example, a patient who comes in with new cognitive impairment, and we’re trying to diagnose what might be the cause of that, there are a number of conditions that are rapidly treatable.

Some are even emergencies that can cause cognitive impairment. So the very first thing with a patient with cognitive impairment is to do an imaging study that will exclude immediately treatable causes of dementia and cognitive impairment. So that can either be a CT scan or an MRI scan. Either one of those allows us to look at the brain and find treatable things like if the patient was involved in an accident, they may have a bleed in the brain, something called the hematoma where blood accumulates and pushes on the brain gradually. And that with the increased pressure will cause cognitive impairment that will occur over a short period of time. But that’s something that can be treated with a drill hole in the brain by a neurosurgeon and the patient’s completely resolved. Other causes of cognitive impairment in the brain also can be recognized, things like brain tumors, like glioblastoma or meningioma. 

These grow more slowly, and the cognitive impairment can come on over a much more gradual period. But again, these are things that can be addressed with surgery or other types of treatment. And treating the tumor will in most cases treat the cognitive impairment as well. So first thing we wanna do is exclude all those immediately treatable conditions. Then once we’ve done that, then the next thing is to look at the brain and look at the other causes of dementia that may not be immediately treatable, but it’s important to recognize them because they may be slightly different than all Alzheimer’s disease. So the types of long-term treatment or lifestyle modifications that we make for them may be slightly different.

Heather Sandison, N.D.

So when we are talking about Alzheimer’s, one of the things that we’ve talked a lot of the other summit interviewees about is that it’s not always one thing. And oxygen, especially at night, airway is a really, really big piece of one of the big contributors to cognitive decline. And so you have shared with me that you can actually see when you do these MRI studies, you can actually see part of the airway and get a lot of great information about that as well. Can you speak to how you’re doing that?

Robert Lufkin, M.D.

Sure, absolutely. And that’s one of the very exciting things about Alzheimer’s disease because for many years it was the amyloid hypothesis for Alzheimer’s disease and still many investigators are looking for a single drug that will somehow work on that. There’s now growing and very compelling evidence that Alzheimer’s disease may be based on, I have a multifactorial origin things like it can involve airway problems, it can involve insulin resistance, inflammation, metabolic syndrome, trauma history, and as well as toxins, which I’m sure your other speakers have been addressing. 

But to the point about imaging studies with an MRI scan of the brain, we’re able not only to look at images of the brain itself and identify specific biomarkers for Alzheimer’s disease that we can talk about. But as you asked about, we can also see other areas on that image of the brain, which covers essentially from the neck up through the top of the head includes the brain. But we also get a view to your point of the airway. So we can look for signs anatomically that would predispose for obstructive sleep apnea, which sleep disorders are a huge risk factor for Alzheimer’s disease. And that can be done as part of the MRI imaging of the brain Alzheimer’s study.

Heather Sandison, N.D.

So I wanna go into that. You mentioned other biomarkers of Alzheimer’s that would be readily visible on these pictures that you’re getting, what are they?

Robert Lufkin, M.D.

Okay, well, the classic biomarker for Alzheimer’s disease is atrophy in a part of the brain that is the basis for memory and that is the hippocampus. And the hippocampus is a bilateral structure. And studies have shown that in patients with Alzheimer’s disease, not all of them, but a significant portion of them will show hippocampal atrophy or loss, atrophy meaning loss of volume of that structure. And the interesting thing about it that that really surprised a lot of people when this was just discovered a few years ago, was the hippocampal atrophy can happen before any sign of cognitive impairment, which is the usual thing that brings a patient to the doctor thinking they have Alzheimer’s disease. 

This hippocampal atrophy can occur 10 or 20 years before the onset of cognitive impairment. This creates a great window for therapy, especially these lifestyle interventions and other things that can be done because researchers have shown that the earlier these things are started, these therapeutic interventions, the more successful they are. So if you can wait before you have any cognitive impairment at all and begin these things, these treatments, then you can have much better results than if you wait until the brain is actually damaged and the memory occurs. 

So the hippocampal atrophy is the key finding, and many people are now recommending in patients who have risk factors for Alzheimer’s disease, such as the APOE-ɛ4 carrier state in the gene, or else, if they have a family history of Alzheimer’s disease that it’s worthwhile going back 20 years from the date of the onset of your Alzheimer’s disease in your relative, for example, God forbid, if your parent had Alzheimer’s disease and it began at age 70, then it’s probably worthwhile at age 50 to begin thinking about evaluating risk factors in yourself for possible Alzheimer’s disease, because we’re already seeing the changes starting to occur. And that’s when ideally you would start the lifestyle management and the treatments make it better. So hippocampal atrophy is really the key finding for Alzheimer’s disease, but there are a bunch of other biomarkers that we can see on the scan. If you’d like, I can talk about those if you want, sure.

Heather Sandison, N.D.

Please do.

Robert Lufkin, M.D.

Yeah, so in addition to the hippocampal atrophy, we can also see evidence of vascular disease in the brain, which Alzheimer’s disease and vascular causes of dementia are the two main causes of dementia. So there are classic findings of vascular changes in the brain that can be recognized on an MRI scan. And quite honestly, vascular dementia overlaps with Alzheimer’s disease. So it’s not a clear finding there, but you can find the vascular disease signature as well. Going outside of the brain, in addition to the hippocampus and the vascular structures, we can look at the airways. We already mentioned looking for signs of obstructive sleep apnea, and that can then indicate the patient might benefit from a sleep study or looking at their blood oxygenation while they sleep and doing that. 

Other things, we can look at are the sinuses. It’s interesting chronic sinus disease is an independent risk factor for Alzheimer’s dementia and treating patients’ sinus disease have improved the cognitive impairments in these patients. It’s interesting to think that the sinuses are separate from the brain yet they can have the effects. But if we think about inflammation, we think about some of these other factors that we know now cause Alzheimer’s disease, it all sort of makes sense. So the sinuses can be beautifully evaluated on the MRI imaging study. And it’s important to note that patients can have sinus disease visible on EMR without symptoms. So it can be asymptomatic and it’s just there, and possibly contributing to their Alzheimer’s disease, but they’re not even aware of it because they don’t have symptoms of sinusitis. 

When we’re looking at the sinuses on the MRI Scan, another thing that we can look at specifically, is there a specific hallmarks of fungal sinus disease, which is a particularly troublesome biomarker for Alzheimer’s fungal infections at various locations in the body can contribute to risk for Alzheimer’s disease. So there are specific imaging findings, the sinuses that indicate a fungal sinus infection and the MRI scan can pick that up and like conventional, chronic sinusitis, this fungal sinusitis may be clinically silent also, in other words, the patient may not be aware that they even have it. 

So in addition to the sinuses and the brain structures, if we go down one step lower, the scan will also include the teeth, the mandible, the maxilla, and all the dentition. And as we’re learning now, inflammation in the teeth, interestingly can predispose a patient to a risk for a heart attack, but also for Alzheimer’s disease. So you don’t wanna get Alzheimer’s disease, brush your teeth every day. The things on the scans that we can look at the markers for teeth is we can see periodontal disease. We can see endodontal disease that in some cases may be clinically silent, that the patient may not be aware of, but we can also detect abnormalities of the teeth. And then suggest that they might benefit from a thorough dental exam as well. 

On the scans that the MRI Scan is also very sensitive to metal, it just detects, it distorts the magnetic field when the images are obtained. So metal anywhere in the head and neck area will show up on the scan. So patient may have had surgery in the past, and they may not even remember that metal was put in, or they may not know it, or they may have dental work with metal embedded and while a good dentist should be able to see it with the MRI. We can immediately detect metal and at least raise the possibility that that metal is there. And some researchers are even advocating removal of certain types of metals that may contribute more to Alzheimer’s disease. In addition to the sinuses, the brain, the airway, and the teeth, the other area we can look is just the overall facial structure of the bones and the skull, trauma is a risk factor, an independent risk factor for Alzheimer’s disease. And it may not be immediate trauma that the patient even remembers that may have been something that occurred 10, 20 years ago. 

We’re even seeing a career in high school football with relatively minor head injuries, even no concussions or loss of consciousness may contribute and is a known risk factor for dementia later on in life. So the imaging studies in some cases will provide evidence of trauma, such as a nasal bone fracture or facial fractures that the patient forgotten, or doesn’t remember anymore that they occurred. And so it can basically begin the conversation with the patient about the history of trauma and also depending on what their lifestyle is or their current employment, they may wanna be counseled about not being in a position where they have continued head trauma, if they’re at a risk for Alzheimer’s disease or have other biomarkers.

Heather Sandison, N.D.

So as our listeners and yours may imagine, when I heard that we could get all of this from one image, I was ecstatic. I mean, this changes the game because so many patients I’ll ask a little bit about their dental history, or did you ever hit your head? As you mentioned so many times, these things are not showing up clinically, patients will not complain of a toothpick or even remember that they hit their head. 

And so they’re not always making the connections that can often be there and being able to rule these in, rule these out, or at least consider them is really, really, really important. So of course I was thrilled when you told me that you do this, and my next question was, well, can everyone get this? Do they need contrast? How long does it take? What if they’re claustrophobic and they can’t get in the MRI machine, how long do they need to be in there for? What are some of these barriers to entry?

Robert Lufkin, M.D.

Sure.

Heather Sandison, N.D.

And it doesn’t cover it. I can certainly speak from a clinician standpoint that I’ve done NeuroQuants volume metrics. And the information I get is very simply just how big are the different regions of the brain, including the hippocampul But it really doesn’t go beyond that. It’s not looking at airway, which we know is so important. It’s not looking at bones, it’s not looking at the sinuses as you’ve mentioned. So you are unique as a radiologist that you are considering all of these things. So I wanted listeners to know how they can access your interpretation of these pictures.

Robert Lufkin, M.D.

Yeah, just to be clear. Yeah, all of the information is on the scan, but many radiologists based on their training, if they’re not focusing on Alzheimer’s disease or don’t have an interest in it, necessarily the average radiologist doesn’t pay attention to the airway and may not make an effort to comment on some of the other areas that I mentioned. So I’m very excited about Alzheimer’s disease, and the possibility of how this can help people. Maybe later on I’ll give you some information about a website that we’re setting up, that they could send us the scans for that. 

We can put that in the show notes, if you want. Specifically, the questions you asked is very good about what are the barriers for these types of studies and everything, because the great thing about MRI magnetic resonance, other than things like CT scans, computer tomography, or pet scanning, which have been, and are used for Alzheimer’s disease, the problem with these is those two types in particular, when they’re expensive and they also use radiation, as your listeners probably may know, any exposure to radiation, x-ray radiation from a CT scan or pet scan raises the possibility of developing cancers later on in your life. 

So it limits the ability to do repeat scans for follow-up. And the great thing about magnetic resonance is there’s no x-rays, there’s no ionizing radiation, so there’s no known harm to the patient. The other thing that we’re working on is coming up with a tailored MRI scan that is relatively inexpensive, that omits a lot of the unnecessary things and unnecessary charges, so that it would be something that would be affordable, that the patient could actually have done more than once. And even as a followup to monitor their treatment, because amazingly, even things like brain atrophy and the hippocampus has been shown to be reversible by lifestyle and other treatments in as short a time as six months. 

So this would be a tremendous driving factor for the patient to be able to see I’m actually fixing my brain, I’m fixing the part of the brain that controls memory. And I can see it on this followup scan that I do in maybe a year or something like that. And of course the airway and the sinuses would also, you could see the improvement there. So the great thing about magnetic resonance is that there’s no radiation with it. We’re keeping the costs down very low with this limited, very limited scan. And then also there is no injection. You asked about contrast material, which usually involves putting a catheter or a needle into a vein, and then injecting things. We don’t do any of that with the MRI Scan. So it’s completely noninvasive. I even having my 12-year-old daughter doing it. So to look at her brain for a science project. But so it’s an ideal imaging study for this type of evaluation.

Heather Sandison, N.D.

Yeah, when you mentioned that somebody should be looking at this 20 years before the onset of symptoms, that’s exactly what I started wondering, well, if we’re measuring hippocampus volume, that area of the brain, that’s so associated with memory, and if we measure it, when someone’s already got symptoms, how do we know if maybe they’re not just they maybe were born with a little bit smaller hippocampus on the curve, the standard deviation. And so what if that’s part of what’s going on? If we don’t have a baseline from before when they had symptoms, then we don’t really know what’s caused it. So, yeah, I’m just curious, like if in an ideal world, how often would somebody who has risk factors be getting one of these images?

Robert Lufkin, M.D.

Okay, that’s a very, very good question. And this technology is literally just developed in the last 10 years or so. It’s involving large amounts of computing power. And actually it involves deep learning and artificial intelligence with the convolutional neural networks that everyone’s talking about. But to your point about how do we know if the hippocampus volume is not some pre-existing thing, or how do we know it’s even abnormal? Well, the first thing that is done when these volumes, these brain volumes are calculated, so a patient gets an MRI scan of their head. And the first thing you do is we measure the size of the head on the scan, and I may have a big head, and my hippocampus will be big, or I may have a very small head and my hippocampus will be small so we need to account for that. 

So the first thing we do is we take the size of their, we either shrink it, or we enlarge it to a normal Atlas, sort of a normal volume, but that’s really not enough because the hippocampus changes in size with aging. It gets bigger as you’re younger, and then it gets smaller as you get older. And those changes actually are different in men and women. So both of those things have to be taken into account. So in addition to the shrinking or expanding the head to the normal Atlas, then the next thing we do is we map it onto an age matched and gender matched normal Atlas for that person. 

So we look at a 50-year-old man, and we compare it with that so that does the comparison. But your point about follow-up scans is very important because if I do one scan and my hippocampus volume is let’s say it’s low normal, it’s still normal, but it’s low normal. I could still be at risk for Alzheimer’s disease because six months ago or a year ago, it may have been high normal. But from that single study, it’s still within the normal range. So the real advantage and many investigators are advocating this is, it’s not a single scan, but it’s a change over time. So do a repeat scan in one year. and I could be low normal the first scan, and then the second scan, I could be very low normal, but still normal. But the fact that it has a downward trajectory is very concerning and that in effect is the positive biomarker for Alzheimer’s. So having at least two scans is valuable to assess essentially the velocity of the change rather than a static point in time.

Heather Sandison, N.D.

Great, that change over time is what’s more important than even maybe that number itself. And that that number is criminalized so that we know what is normal and what’s not in your age, your sex, and hopefully compared to previous, because it does sound like a baseline would be very, very helpful, particularly if you have high genetic risk or other factors.

Robert Lufkin, M.D.

And it’s been shown that people who are APOE-ε4 are homozygous, which means they have both alleles or APOE-ε4, they genetically have smaller hippocampus volumes than do normal people. And we’re still gathering data and understanding if they increase their hippocampus volume, what that does the risk. And as you might expect, the homozygous, APOE-ε4s have a smaller volume, the heterozygous with one APOE-ε4 and one APOE-ε3 or two have a slightly larger hippocampus volume, but work is being done on this. And with more and more experience, we’ll hopefully be able to understand this better and make better recommendations for people trying to manage their risk.

Heather Sandison, N.D.

That’s fascinating. Yes, I’m excited to collaborate and hopefully to answer these questions. I’m curious if you could design any study, we’re working on some research together, and if you could design any study and answer any questions, there’s no constraints financial or otherwise, you have all the participants you want, and all of the money you need to finish it, what question would you ask? What is the burning question in your mind we don’t know about the subject yet?

Robert Lufkin, M.D.

Well, I think the real exciting question for me is the ones that many investigators are beginning to address, like Dale Bredesen and the work that you’re doing, and in your clinic. And that is how these long-term risk factors can contribute to Alzheimer’s disease and how we can manage the risk factors through lifestyle changes and other management, and thus prevent developing Alzheimer’s disease later on. And the tools that I would offer for that would be imaging to take a look at the brain and the other areas, and just do it as inexpensively as possible to make it affordable and of course, with no radiation. 

I think one of the question you asked about insurance payment for these. And this varies according to insurance companies and varies according to different things. But my general experience is if the patient has a diagnosis of cognitive impairment or dementia, significant clinical finding there that most insurance companies and Medicare will pay for an imaging study, at least one imaging study, like we talked about earlier to rule out other immediately treatable causes of dementia. It’s been my experience. They won’t pay necessarily for follow-up ones, unless the patient changes, unless something happens that they really change their pattern that way. 

And then as far as prevention, patients who don’t have any cognitive impairment yet, but let’s say they have a family member who developed it, or they’re APOE-ε4 positive, it’s been my experience that the insurance companies won’t cover imaging studies for this, which is really sad because just from a financial perspective, Alzheimer’s disease is incredibly expensive in the healthcare system. Just aside from the cost to the families and everything, but the financial costs are very high. You’d be much better off beginning lifestyle management and changes early on and preventing Alzheimer’s disease than waiting till people actually have cognitive impairment, which as we’ve said is really a late finding in Alzheimer’s disease. Although for most people, the first finding that they detect to acknowledge they even have it.

Heather Sandison, N.D.

It really is so heartbreaking that I think you and I now, we feel strongly that this is preventable, that there are interventions you can take. We can get the information early enough that we can prevent Alzheimer’s and even reverse it. We’re seeing lots of that in my clinic. And I think we wanna share that information and what you are doing creates so much hope. And so seeing that picture, I think it’s really, really, really valuable. 

We can talk about lifestyle changes and we can talk about the genetics. And I think they tend to be a little nebulous popular. It’s not as tangible as seeing a picture of their brain and going, “Wow, that is shrinking and I got to do something about it.” So I think in a very real way, you give people not only the motivation they need, but also the hope that these things can change that you’ve watched the images change, that you’ve watched the symptoms change, that you’ve seen people do this successfully, and that there is a way to avoid this heartbreak like you described, Alzheimer’s so destructive financially, but also it robs us of this generation that has so much wisdom and it’s so much to offer us. It’s almost in my mind, it’s a squandered resource, right? The height of their wisdom and experience our elders are being removed from society because of dementia, that is .

Robert Lufkin, M.D.

Yes, yes.

Heather Sandison, N.D.

And thank you for doing the work that you’re doing.

Robert Lufkin, M.D.

Oh, well, thanks. It’s such an exciting area. And the changes that are happening now with the possibility of treatment, which wasn’t there a few years ago, the possibility of prevention that wasn’t there a few years ago, the work you’re doing in your clinic, the work that researchers like Dale Bredesen and others are doing, it’s really revolutionary. And it’s so exciting to be involved with this and to try and get the message out, to help as many people as we can.

Heather Sandison, N.D.

Yeah, very, very hopeful and exciting time. Thank you again, Dr. Lufkin, it’s just an absolute pleasure. Not only to get to have these conversations with you to get to share them, but also to be collaborating in other ways to advance this field and give more and more families hope and answers so that they don’t have to suffer.

Robert Lufkin, M.D.

Great, well, thanks a lot, Heather, and really looking forward to your summit and hearing the other speakers. It’s gonna be very exciting.

Heather Sandison, N.D.

Can you give our listeners, you have ProHEALTH, is your business, is there a website or other places where they can find out more information about what you do?

Robert Lufkin, M.D.

Yeah, if I could pass it… to you afterwards in the show notes,

Heather Sandison, N.D.

Yeah. 

Robert Lufkin, M.D.

If that’s possible, we have a website

Heather Sandison, N.D.

Absolutely.

Robert Lufkin, M.D.

… that they can go to and get more information. We’re just putting it together now.

Heather Sandison, N.D.

Perfect, wonderful. We’ll have that in the show notes.