Go with the (4D) Flow: Neuroimaging Technology Used to Study Overlap of Cerebrovascular Disease and Alzheimer’s

leonardo rivera
Leonardo Rivera-Rivera, PhD

A recent study from Alzheimer’s disease researchers at the University of Wisconsin–Madison used neuroimaging technology called 4D Flow MRI to study the relationship between blood vessel disease and Alzheimer’s disease. Published in December 2021, the study found that people with Alzheimer’s disease symptoms had stiffer blood vessels in their brains, which could lead to inflammation and a buildup of Alzheimer’s biomarkers like amyloid and tau proteins. Lead researcher Leonardo Rivera-Rivera joins the podcast to discuss his findings, the developments made with new 4D Flow MRI scans, and how these developments could impact future Alzheimer’s disease research and clinical practices.

Guest: Leonardo Rivera-Rivera, PhD, neuroimaging scientist, Wisconsin Alzheimer’s Disease Research Center

Episode Topics

8:55 How does the 4D Flow MRI technology used in your study compare to MRIs used in clinics?

13:18 What did you look at in your study? What were your findings?

17:54 Did you see more pronounced findings in particular individuals with APOE4 or other chronic conditions like diabetes?

20:37 Why is this an important finding for Alzheimer’s disease research? Do you think 4D flow MRIs could be incorporated into clinical settings?

Show Notes

Read Leonardo Rivera-Rivera’s publication “Cerebrovascular stiffness and flow dynamics in the presence of amyloid and tau biomarkers,” published in the journal Alzheimer’s and Dementia: Diagnosis, Assessment & Disease Monitoring. 

Learn more about Leonardo Rivera-Rivera’s research at the Wisconsin Alzheimer’s Disease Research Center website.


Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Today I'm joined by Dr. Leonardo Rivera Rivera, a neuroimaging scientist at the Wisconsin Alzheimer's Disease Research Center. Dr. Rivera Rivera is the lead researcher on a recent study focused on the links between vascular health and Alzheimer's disease. Using new imaging technology developed here at UW-Madison, the study found that individuals with symptoms of Alzheimer's disease had stiffer blood vessels in the brain which could lead to buildup of the Alzheimer's biomarker, amyloid. Dr. Rivera-Rivera, welcome to Dementia Matters.

Dr. Leonardo Rivera-Rivera: Hi Nate. Thank you so much for having me.

Chin: Well we're excited to have you. And before we get to your actual publication, I'd like to know what got you interested in Alzheimer's disease research and blood vessel imaging of the brain?

Rivera-Rivera: Yeah that's a story that started around ten years ago. I was finishing my bachelor's degree in physics and electronics in the University of Puerto Rico and I wanted to combine that physics knowledge with some medical application. I heard that the department of medical physics at UW-Madison was one of the best in the nation so I applied to it. I got lucky to have an invitation. During one of the presentations of the PIs, the professors that were hiring graduate students, Dr. Oliver Wieben showed these beautiful images of the brain but also of the blood vessels that were in those brains and he created these movies where you could see the blood flow incoming through the brain. So I said, oh no, that looks really cool, I would love to work doing that and improving the technology. And then I joined Dr. Oliver Wieben’s lab. I was looking for a project to get things started and around that time Sterling Johnson and Howard Rowley had added this vascular imaging method or technique called 4D flow MRI, specifically the technique developed at UW-Madison, PC Viper. They have added this imaging to the ADRC and the WRAP imaging protocols and they have acquired this data for seven years. They were finally at the point where they wanted somebody to work on this data – some grad students to work and analyze on this data. So I was looking for a project and the opportunity kind of came out of nowhere and I started working on the applications of 4D Flow MRI to understand vascular contributions to dementia and interactions with Alzheimer's disease and I got hooked. It has been such a great journey since, largely because of the great people that surround me here at UW-Madison.

Chin: And we're going to ask you about 4D Flow in a few minutes but before I get to that  question. You know, cerebrovascular disease, or blood vessel narrowing in the brain, can cause dementia itself which we term vascular dementia. However, in your paper you mentioned this overlap can exist between blood vessel disease and Alzheimer's disease which we biologically define as this accumulation of proteins called amyloid and tau, so now we're talking about blood vessels and these other proteins of amyloid and tau. Can you provide for our listeners, what is this potential interaction between blood vessels and amyloid Tau?

Rivera-Rivera: Right. So cerebrovascular disease, as you mentioned, by itself can lead to vascular dementia but it also happens to be one of the risk factors for Alzheimer's disease. Most of the time neuropathology findings show up - mixed pathology between Alzheimer's markers and vascular markers. Right now this has led to a number of hypotheses that are trying to perhaps link a relationship between vascular disease and Alzheimer's disease, and one of these leading mechanisms or models is the one related to the clearance of this amyloid protein from the brain. As you mentioned this is a biomarker of Alzheimer's disease – amyloid is. Something is going wrong in the brain that is not being able to clear amyloid properly or there is just too much. And it happens that one of the major pathways for clearance of metabolites and waste proteins, such as amyloid in the brain, happens to be driven by vascular related pulsations. And here is where the models come in saying that if you have vascular stiffness, you're decreasing the postitility of your blood vessels in the brain. You are removing a driving force that pushes this amyloid protein outside of the brain and thereby you're creating some kind of exacerbation of the accumulation of the protein in the brain. That's the link –  that’s one of the links that we are trying to mechanistically study with our imaging techniques.

Chin: So it sounds like pulsing – the pulse – is really important because when you have vascular disease, there's stiff blood vessel which means flow can actually be pretty high pressure but you're not going to have the pulsing, and it's the pulsing that might push amyloid to whatever system then that clears it out of the brain.

Rivera-Rivera: Right. And now there are two major systems that we believe where things are being pushed through. One is the glymphatic flow system. This is cardiac pulsations induced by the heartbeat that are believed to push in interstitial fluid with his amyloid protein through the CSF outside of the brain. And then there is another model that suggests that it's not the heartbeat pulsations but much slower – still cardiac pulsations – but these ones are driven by muscle cell contractions and all the regulatory processes. This fluid transport no longer happens through perivascular spaces but through paravascular spaces. So we have two leading models, one that uses high frequency cardiac pulsations from heartbeats and another one that uses low frequency oscillations from smooth muscle cells in the vessel wall.

Chin: And you're saying models and concepts, so these are still being worked on as far as trying to prove that one of them is actually happening in leading to amyloid clearance?

Rivera-Rivera: That's exactly right. And one of the reasons why they're just models is because we have been lacking the technology to test some of these in human populations. Now in these past recent years, these models have been tested in mouse models where you can be invasive and you can look directly at the cerebral vasculature. In fact, there has been in the scientific literature there have been papers reporting mouse models where hypertensive mice showed a reduction in cardiac pulsation and also a reduction on clearance of amyloid through the CSF flow. Also others have shown that a reduction on smooth muscle cells – and its muscle cell driven low frequency oscillations – has been associated with increased cerebral amyloid angiopathy.

Chin: Well so that leads perfectly. We need the right instruments if we're going to answer these types of really important questions, which gets me to your study now. In your study you utilize brain MRIs, which is something that I can get in the clinic actually. For our listeners MRI stands for magnetic resonance imaging and it is different from the PET scans which we often talk about on this podcast. The PET scans can identify those actual proteins of amyloid and tau. So in your paper, you talk about those limitations of MRI scans when it comes to identifying vascular disease, particularly in the context of Alzheimer's disease work. Can you share with us what these limitations are and then move to what this quantitative 4D Flow MRI is that you used in your study?

Rivera-Rivera: Yeah, more than happy to do so. For the last ten years, imaging protocols have not heavily focused on the vascular component when they are studying Alzheimer's disease and I think, in a way, this has created sort of a stagnation on the development of new imaging markers, Most of the current longitudinal studies of Alzheimer's that want to study vascular disease, they they use MRI to measure structural changes called white matter hyperintensities. For example, these are lesions that you can see in the brain and they are non-specific. They can have many sources of origin – small vessel disease, leukocyte infarcts, microhemorrhages – so they don't tell you much about deceasing interaction. They just tell you that something went wrong and here's a mark. The same thing happens with microhemorrhages, also a very common vascular biomarker. These microhemorrhages, micro-bleeds, again this is a marker that there was a leakage of blood; something went wrong. Then finally, cerebral blood flow perfusion using MRI. It basically tells you how much blood is being delivered to the tissue. Also very popular marketing in AD studies. But the situation is that what happens if you have a change in neural density, if you have a loss of neurons, then you will have less metabolic demand so it might drive reduction in this CSF flow – this CBF perfusion, which means it's not necessarily telling you a lot about vascular health but more about metabolic demand. And that has limited hypothesis testing of cerebrovascular disease and AD interactions. Here is where we are needing more specific and sensitive markers of vascular function and where the utilization of quantitative 4D Flow MRI can really deliver new image markers that can directly probe the vessel health. I might be over optimistic about these things, (laughs) but I think we have preliminary data to support such claims. UW-Madison has a long history with this quantitative 4D Flow MRI. It was originally conceived by Chuck Mistretta in the medical physics department and subsequently developed by Oliver Wieben,  Kevin Johnson,  and other people that have come along. Right now it’s a very unique sequence that we have here at UW-Madison that we are trying to bring it to other centers because we are showing promise to helping us understand cerebrovascular disease interactions with Alzheimer's Disease. What this imaging does is it captures the blood flow along the cerebrovasculature and you can actually see the blood flow moving and you can then characterize the vessel health such as vessel stiffness, pulsatility, this contraction and this expansion related to the smooth vessel cells and whatnot.

Chin: So it is an MRI scan, just like most MRI scans, but now you're able to actually measure the flow of blood through the blood vessels in the brain?

Rivera-Rivera: Exactly. And it takes as long as your typical MRI – 5 minutes. It doesn't have too much scan time, but very smart people have developed very smart ways of acquiring the data and now we can generate these really cool brain images that let us reach previously unattainable vascular biomarkers.

Chin: So the fourth dimension is flow, is that right?

Rivera-Rivera: So we create a movie – so you have your 3D spatial dimensions and we see it as it evolves through time.

Chin: That's pretty darn cool. All right, so then with all that in mind – and I spent a lot of time kind of building that background because your paper is technical – so what did you look at in this study? And it was published in Alzheimer's and Dementia. So what were you looking at and what did you end up finding?

Rivera-Rivera: So during my PhD studies and my postdoc and now scientist position, we have been working using this imaging modality in Alzheimer's. Those original studies look at the cerebrovascular health in clinically diagnosed Alzheimer's disease patients. These are people that were showing cognitive impairment, and we identify stiffer vessels and some decrease in the cerebral blood flow. This was always on clinically diagnosed participants and, as you know, they might have a mixture of neuropathologies. It could be vascular dementia. It could be Alzheimer's disease. So in order to truly understand the Alzheimer's disease relationship with cerebrovascular disease, we need AD biomarkers. Finally after all those years, the great efforts here at the UW ADRC and the Wisconsin Registry for Alzheimer's Prevention, Sterling Johnson and all the other great researchers, Sanjay Asthana, and everybody else, we have a large cohort of really well-characterized individuals with AD but also at risk of developing AD that have AD biomarkers that have these – either from CSF or from PET imaging – they have this amyloid burden and tau burden markers that we can utilize to truly understand the relationship between CVD and AD. So in these papers, we did look exactly at that. We look at how does  cerebrovascular health look in cognitively healthy adults that have AD biomarkers. Those were the most interesting group because we already have looked at those that had already cognitive decline. We wanted to see what is going on in the cerebrovasculature of people that are perfectly normal but they are accumulating amyloid protein on the brains or tau proteins on the brains.

Chin: And so what – because this is a perfect example of the importance of people volunteering for research because you have this huge cohort, you have a lot of data, you have a lot of imaging scans. And instead of looking at people that I might see in my clinic that have cognitive impairment, you're looking at healthy research volunteers – who don't have symptoms presumably and we know though based on the amyloid and tau pet scans that they have proteins that look like Alzheimer's disease – and now you're looking at their their blood vessel health in these individuals. So knowing that, what did you find?

Rivera-Rivera: So yeah, we know that once you start accumulating amyloid, it seems to follow a very predictable time course of accumulation. We also know that it can take up to more than 20 years to start developing symptoms after initial amyloid accumulation. So a study in this preclinical phase is so important because that's where targeted treatments might have the highest impact and and again if we want to study these CVD interactions, we need sensitive markers that can look at things before it's too late. Before looking at downstream effects we want to look at early vascular modifications. And in fact what we found was that in preclinical subjects that were accumulating amyloid and tau, they did show an increase in vessel stiffness and also a decrease of these vasomotion-induced, low-frequency oscillations suggesting that there are vascular alterations happening during the preclinical phase of Alzheimer's disease. And this, perhaps, is distinct from vascular dementia contributions to cognitive impairment.

Chin: Now you're not able to determine which came first though, right? The vascular stiffness or the amyloid or tau proteins. Is that true?

Rivera-Rivera: That is true and determining causality is such a hard question. At this point what I believe is that perhaps there is a synergistic influence happening where you have AD pathology and then, in addition to that, there's some vascular changes that are happening and they create an exacerbation of the AD biomarker accumulation which could help explain the heterogeneity that you often see in the clinic from presumably Alzheimer's disease patients.

Chin: And did you see a more pronounced finding in certain individuals? I'm thinking about those with that genetic risk factor – apoE4 – or people who have other serious chronic conditions like diabetes. Was there a difference in that group of people?

Rivera-Rivera: So in the previous paper that came out in 2020, we specifically found that middle age adults that were cognitively healthy but that had apoE4 at least in one of the alleles and also had parental history of dementia due to Alzheimer's, they actually did show a higher amount of vessel stiffness compared to age-matched people that did not have apoE4 and not have any familiar history of dementia which suggests, again, there is something happening in the vasculature that is linked some way or another to Alzheimer's disease. It's not surprising necessarily because vascular disease and Alzheimer's disease share risk factors. ApoE4 is one of them but there are other risk factors that are shared between diseases.

Chin: And speaking of which, your paper also looked at traditional vascular markers like high blood pressure and high cholesterol or the use of medications to normalize those levels but they were not different among the groups of people that you were looking at in this preclinical pre-disease population. However, you did find more small bleeds in people with amyloid and tau. What does that mean?

Rivera-Rivera: So I think it generally means two things. One is that we do have sensitive vascular imaging markers that are more specific that systemic markers as the one that you mentioned. And regarding the presence of microbleeds in these subjects that had both amyloid and tau burden is likely related to the downstream effects of the toxicity that these proteins create on the neural environment. At this point these participants likely have been accumulating amyloid for 20 years and you can imagine this can lead to cerebral amyloid angiopathy, for example, due to the deposition of amyloid on the membranes of the vessel leading to microbleeds.. I think microbleeds on these on this group that had more AD biomarkers – it just indicates that they're way further along on this progression ultimately leading to cognitive decline.

Chin: And so, overall, why is this an important finding in the field of Alzheimer's disease and do you see potential for 4D Flow MRIs being incorporated into a clinical setting?

Rivera-Rivera: I think it's important because we are finally getting to the point where those models that could only be tested in animal experiments, now we have non-invasive technology that can let us study specific AD-CVD interaction mechanisms in human populations. I think here with the research that people like Kevin Johnson, Laura Eisenmenger, and other researchers in radiology and medical physics are doing, we are creating an imaging platform that we want and we will be able to share with the larger ADRC sites and other multi-site longitudinal studies that will definitely bring a key missing information of the vascular function, in related to Alzheimer's disease and interactions. So overall I think we're moving in a very interesting direction. We're finally seeing how these imaging markers can help us understand the relationship between these two types of diseases and we're getting to the point of sharing it with other sites, which is very exciting.

Chin: One of the things I love about your answer, Leonardo, is that you mentioned the different groups of people who are involved in this work and that's medical physics. That's radiology. That's neuroscientists, neuropsychologists, geriatricians, neurologists. I mean this requires a lot of different perspectives in order to put all of this together which is wonderful. So I know your study can't answer this upcoming question, but do you think it's possible that exercise and maintaining a healthy weight through eating healthy foods and getting good sleep could change some of the results that you're seeing with this 4D Flow MRI and in essence lead to a healthier brain?

Rivera-Rivera: Regarding your first comment, it's just amazing how clinicians and scientists can come together here at UW–Madison to help each other to get to the point where you can answer these questions. I don't think it can be done any other way. If people are working in silos, we cannot make the kind of advancement that we're doing. So that's why UW–Madison is such a great place to work at. Regarding your second question, overall we know that vascular dementia, stroke, cerebral small vessel disease, it leads to deterioration of brain health. We know that hypertension – it's one of the risk factors. And we know that we can – if we take good care of ourselves by eating well and exercising we can create fitness of the cardiovascular, cardiorespiratory system that most certainly will lead to a reduced chance of developing some of these problems that would lead to cognitive impairment. And regarding sleep, I just think it’s common sense. Either nature is wrong and we know more than nature. But when you think about it, we spent such a big chunk of time of our day devoted to sleep. We are not looking for food at that time. We are not mating at that time. We’re vulnerable to predators – (laughs) thinking about our ancestors. But nature decided that this is so important. You have to sleep. That I think it is common sense that we have to take good care of our sleep too. And some pretty cool research is coming out suggesting that brain clearance gets enhanced during sleep and you get these CSF flow waves that have some very interesting functionalities and changes in amplitude that happen through the phases of sleep. So most certainly eat well, exercise and sleep well, and you will help you keep your brain healthy.

Chin: You have a pretty strong answer there and so, you know, I thought I was going to peg you for this next question as someone who's going to tell me exercise and maybe that'll still be your answer. but I always like to know what our cutting edge scientists do for their own personal health in keeping their brain as sharp as possible? I would have assumed you're going to say exercise but you seem pretty set on sleep too. What is the one thing that you focus the most on to keep your brain sharp?

Rivera-Rivera: (laughs) I wish it was sleep, although I sleep not too bad but one could always sleep more. I think in today's digital age, nobody sleeps eight hours. Perhaps very few people are sleeping seven these days. Me, for the most part, right now I enjoy exercising but particularly swimming a lot. I like the idea of just jumping into the pool and letting my thoughts run wild. It's very refreshing and then I feel like I did you know some cardiorespiratory fitness. Also I'm trying to get better at chess, but it seems like my 17-year old nephew gets the better part of me all the time. So I don't know how much better I can get but I am naively optimistic that you should always try to get better. So lately those things keep my brain sharp when I'm outside of work.

Chin: Well, I appreciate those honest answers. And with that I'd like to thank you for being on Dementia Matters, and as more of your work evolves we look forward to having you back on.

Rivera-Rivera: Thank you so much, Nate, for the invitation, for the time. And please keep doing what you do. This is a great podcast and interesting to a large audience. Thanks again for having me.

Outro: Thanks for listening to Dementia Matters. Be sure to follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you get your podcasts to be notified about upcoming episodes. You can also listen to our show by asking your smart speaker to play the Dementia Matters podcast. And please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing.

Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers.

This episode of Dementia Matters was produced by Rebecca Wasieleski and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions.

To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu. You can also follow our Facebook page at Wisconsin Alzheimer’s Disease Research Center and our Twitter @wisconsinadrc. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.