Exploring Perivascular Spaces and Their Impact on Cognitive Impairment

Vascular cognitive impairment is a common and often underrecognized contributor to cognitive impairment in older individuals, with heterogeneous etiologies requiring individualized treatment strategies. 

In this episode, Katie Grouse, MD, FAAN speaks with Lisa C. Silbert, MD, MCR, FAAN, an author of the article “Vascular Cognitive Impairment,” in the Continuum December 2024 Dementia issue.

Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California.

Dr. Silbert is is co-director at Oregon Alzheimer's Disease Research Center, a Gibbs Family Endowed professor of neurology, a professor of neurology at Oregon Health & Science University, a staff neurologist, director of Cognitive Care Clinic, and director of the Geriatric Neurology Fellowship Program at Portland Veterans Affairs Health Care System in Portland, Oregon.

Additional Resources

Read the article: Vascular Cognitive Impairment

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Lisa Silbert about her article on vascular cognitive impairment, which is part of the December 2024 Continuum issue on dementia. Welcome to the podcast and please introduce yourself to our audience. 

Dr Silbert: Hi Katie. Thanks for having me here today. Like you mentioned, my name is Lisa Silbert. I am a behavioral neurologist at Oregon Health and Science University and my research focus is in the area of vascular contributions to cognitive impairment and dementia.

Dr Grouse: It's such a pleasure to have you and I really enjoyed reading your article. Just incredibly relevant, I think, to most practicing general neurologists, and really to any subspecialty. I'd like to start by asking, what do you think is the main takeaway point of your article for our listeners? 

Dr Silbert: Yeah. I think, you know, the field of vascular cognitive impairment has changed and evolved over the last several decades. And I would say the main take-home message is that vascular cognitive impairment or vascular dementia is no longer a diagnosis that is only considered in someone who's had acute decline following a clinical stroke. That we have to expand our awareness of vascular contributions to cognitive impairment and consider other forms of the disease that can cause a more subacute or slowly progressive form of cognitive impairment. And there are many, many forms of vascular cognitive impairment that present in a more slowly progressive manner. The other thing I would say as a major take-home message is that we know that cerebrovascular disease is a very common copathology with other forms of dementia and that it lowers one 's threshold for manifesting cognitive impairment in the context of multiple pathologies. And so, in this way, vascular cognitive impairment should be considered as a contributing and potentially modifiable factor in any dementia. 

Dr Grouse: I found that last point just really, really fascinating. And also, you know, the reminder that a combination of pathologies are more common than any one. To your initial point, I'm actually curious, could you kind of outline for us how you approach diagnosing vascular cognitive impairment? 

Dr Silbert: Yeah. So with everything in neurology, a lot of it comes down to the initial history taking. And so part of the work up always includes a very detailed history of the presentation of cognitive impairment. Any time there is an acute change in cognition, vascular contribution should be considered, particularly if it's in the context of a clinical stroke or some kind of event that might have lowered cerebral blood flow to the brain. And then having said that, I already mentioned there are many forms of vascular cognitive impairment that can mimic neurodegenerative disease in terms of its course. So being more slowly progressive. And so because of that neuroimaging, and in particular MRI, has become an extremely valuable tool in the workup of anyone who presents with cognitive impairment in order to evaluate contributions from cerebral vascular disease. And so, MRI is a really helpful tool when it comes to teasing out what may be contributing to a patient's clinical syndrome, as well as their other comorbid medical issues, including stroke risk factors and other kind of medical conditions that might contribute to reduce cerebral blood flow.

Dr Grouse: I'd love to talk a little bit more about that. You know, as is often the case with neurologic disease associated with vascular pathology, the importance of prevention, you know, focusing on prevention of vascular diseases is so important. What are some things that we can make sure to focus on with our patients and, you know, particularly anything new to be aware of in counseling them?

Dr Silbert: Yeah, I'm really glad you asked me that question because like I mentioned, you know, cerebral vascular disease is so common, it lowers one's threshold for cognitive impairment in the face of other age-related brain pathologies. And so, it's really important for all of us to focus on preserving our cognitive health, even starting in midlife. And so, there are a number of areas that I counsel my patients on when it comes to preserving cerebral health and maximizing cerebrovascular health. And so, these stem from the American Heart Association's Life's Essential 8 because we know that preserving cardiovascular health is likely going to also preserve cerebral vascular health. And so, some of the things that I'm very commonly discussing with my patients are controlling stroke risk factors such as blood pressure, blood sugars and cholesterol, maintaining a healthy weight, and then also working towards a lifestyle that includes a healthy diet, no smoking, regular exercise. And then new within the last couple years is also the recommendation that people get adequate sleep, which is something that hasn't been focused on previously.

Dr Grouse: I was really interested in reading your article to learn about enlarged perivascular spaces and the role as a mediating factor in the interaction between through a vascular dysfunction and development and progression of neurodegenerative pathology. Can you elaborate on this further?

Dr Silbert: So, this is an area that's still largely unknown in the field, and it's an area where there's a lot of emerging work being done. The short answer is, we really don't know with great certainty how it directly connects with accumulating Alzheimer's pathology. But there is some evidence to suggest that the perivascular space is involved in the clearance of toxic solutes from the brain, including Alzheimer's disease pathology. And so there's a lot of work looking at how potentially cerebrovascular risk factors might affect the clearance of those toxic solutes through the perivascular space, including pulse pressure changes that might occur with accumulating cerebrovascular disease and other potential contributors. But one thing I can say with more certainty is that the, you know, location of perivascular spaces is thought to help distinguish those who might have cognitive symptoms due to cerebrovascular disease versus due to cerebral amyloid angiopathy. Or I guess I should say location is helpful in terms of recognizing vascular contributions to cognitive impairment that's due to arteriolosclerosis versus that due to cerebral amyloid angiopathy. In so much that… when we see a lot of perivascular spaces in the basal ganglia in the subcortical structures, that is thought to be more associated with arteriolosclerosis and hypertension type related vascular cognitive impairment. Whereas when we see multiple perivascular spaces within the centrum semiovale, that tends to be more associated with cerebral amyloid angiopathy.

Dr Grouse: That's so interesting. And on the topic ofcerebral amyloid angiopathy, you did go into this a good deal. And you know, I think I encourage everybody to revisit the article to remind themselves about, you know, the findings that can increase the suspicion of tribal amyloid angiopathy. However, you also talked about transient focal neurologic episodes, which I think is just a great reminder that, you know, these can occur in this setting and definitely not to miss. Tell us more about what to look for with these types of episodes. 

Dr Silbert: Transit focal neurologic episodes can be very difficult to tease apart from a transient ischemic attack. And these transient focal neurologic episodes due to CAA can present in a number of different ways. And I think the important take home message for that is that in people who have neuroimaging evidence of CAA to inform them that they are at increased risk for having these focal neurologic episodes and that if they do present to a hospital or an emergency department with any kind of neurologic event, that those treating them are aware that they have evidence of CAA on their neuroimaging because the treatment of course is quite different. So, it's someone presenting with ATIA who has transient neurologic symptoms might be considered urgently to get a thrombolytic or, you know, TPA, whereas someone who has known cerebral amyloid angiopathy or suspected CAA, they likely already have microbleeds on their neuroimaging and in those cases thrombolytics and TPA would be contraindicated and not helpful in terms of the etiology of their neurologic symptoms.

Dr Grouse: That's a really good point to make. And I think also in your article you mentioned the use of aspirin if you're suspecting ATIA versus a, you know, a transient amyloid related focal neurologic episode. You know, one you would treat with aspirin and the other one you wouldn't. 

Dr Silbert: That's right. 

Dr Grouse: Another sort of interesting topic you delved into was cerebral microinfarct and how this can also contribute to vascular impairment. Could you elaborate a little more on that?

Dr Silbert: Yeah. So cerebral microinfarcts are kind of the hidden cause of or a hidden cause of vascular cognitive impairment. And it's extremely challenging because by definition they are not visible on routine clinical neuroimaging. It's something that we are more aware of based on pathological studies and neuroimaging studies that have been done at ultra-high field strength like 7T MRI. And so, we are just learning more about how prevalent they are in certain conditions and how we can only look at these after death when we're looking at brain tissue and then go back and realize that these play a significant role in cognitive decline when someone is alive. It's important to understand that we're probably only appreciating kind of the tip of the iceberg when we're evaluating a patient and looking at their neuroimaging. That what we're actually seeing on MRI are only the things that are actually quite relatively big and obvious. And that a lot of these neuroimaging features of vascular cognitive impairment are actually associated with pathologic features that we're missing such as microinfarcts. But the hope is that by treating all individuals, particularly those who already have signs of vascular cognitive impairment, by modulating their stroke risk factors and focusing on maintaining brain health, that those will, interventions will also reduce the incidence of microinfarcts.

Dr Grouse: What do you think is the greatest inequity or disparity you see in treating patients with vascular cognitive impairment?

Dr Silbert: I think the greatest disparity is- really starts way before I treat a patient. That relates to really focusing on healthy lifestyle factors early in life and being able to, you know, afford fruits and vegetables, and having the advantages of being able to exercise regularly, and just being aware that all of these things are extremely important before older age. So, these are things that, you know, I think more education and awareness and greater access to healthcare will definitely improve access to. Even preventative healthcare is a disparity and not available across all of the population and geographic locations. So, I think of the- all the dementias, vascular cognitive impairment probably has the greatest association with health and social disparities in terms of primary prevention and access to care. 

Dr Grouse: All really important things to consider. I have to say when, you know, reading your article, dare I say I came away with a little bit of hope thinking, you know, even with, you know, how little we still, you know, or how much we still need to do to really learn how to fight Alzheimer's and, you know, prevent it and, and, you know, help with its progression. The idea that in so many cases, even just doing what we can to prevent the vascular or cognitive impairment can really help any type of dementia. That was really a strong message for me. Do you mind elaborating on that a little more? 

Dr Silbert: No, not at all. I agree. I really am hopeful about the prevention and treatment of dementias and through the treatment and prevention of cerebrovascular disease. I think that is a true reality, just like, you know, as we were discussing before, the treatment and prevention of cerebrovascular disease really should be a part of the treatment of any type of cognitive impairment and recommendations for prevention of cognitive impairment. This is the, you know, one thing we know is largely modifiable and preventable in most cases. I think the, really the key thing is just education and making sure that people understand that these are things that really need to be, they need to be engaged in in midlife and that it's much harder to reverse these- the damages once you have them in later life. Having said that, I do think that there's greater awareness of maintaining healthy lifestyle and maintaining awareness of stroke risk factors. And I think we're already starting to see a reduction in dementia worldwide in several large population-based studies, and probably that is due to more attention to the modifying stroke risk factors. So, I agree with you, it's very encouraging. 

Dr Grouse: Is there anything exciting on the horizon that you can tell us about that we should all be keeping our eyes out for?

Dr Silbert: Yeah. So, you know, I'm really interested in this connection between vascular cognitive impairment and Alzheimer's disease. And it's a real area of exciting new research. And so I think we're going to have more answers as to how, whether and how, cerebrovascular disease is directly linked to accumulating neurodegenerative disease or neurodegenerative pathologies. The other area that's, I think, really exciting, that's moving forward, is the in the area of blood-based biomarkers for vascular cognitive impairment. As these emerge, we'll be able to really identify those at greatest risk for vascular cognitive impairment, but also identify novel mechanisms that lead to VCI that can be targeted for therapeutic intervention.

Dr Grouse: Well, I'm really excited to see what's coming down the pipeline and what more we'll learn in this area. So, thank you so much for everything you've done to contribute to this field.

Dr Silbert: Yeah. 

Dr Grouse: I wanted to ask a little bit more about you. What drew you to this work? 

Dr Silbert: Well, actually, so my very first published manuscript in medical school was a case report and review on MELAS, which is mitochondrial encephalopathy with lactic acidosis and strokelike syndrome. And so, I was really fortunate to have Dr Jose Biller, who is a renowned expert in stroke and cerebrovascular disorders, as my mentor for that paper. And so, that got me really interested in neuroimaging findings of cerebral vascular disease. And so when I was a fellow at Oregon Health and Science University, I was then really fortunate to  be able to work with Jeffrey Kaye's oldest old population. And in working with that population, I really became interested in their neuroimaging findings of these white matter lesions and just realizing how prevalent they were in that population, you know, it just led me to start investigating their clinical significance and etiology, which kind of led me along this path.

Dr Grouse: You know, Lisa, thank you so much. I really learned a lot from your article, and I think our listeners will definitely find that it was very helpful for their practice. Thank you so much for joining us.

Dr Silbert: Thank you so much, Katie. It's been really fun. 

Dr Grouse: Again, today I've been interviewing Dr Lisa Silbert, whose article on vascular cognitive impairment appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.