today about carotid stenosis. This is a concept, I think, that has been misinterpreted for too many years. So what we're really talking about is carotid atherosclerosis and its role in stroke, especially ischemic stroke. To do that, I want to frame this in the past, the present, and the future of our concepts of carotid stenosis and introduce two very important concepts. If we, as neurosurgeons, are to be active in this disease, we must use as an endpoint cognition and cognitive decline, which are probably very important aspects of stroke, as well as the concept of unstable plaques rather than stenotic plaques. Although the two are related, the pathophysiology clearly points to instability of the plaque. To illustrate that, we must look at past, present, and future. I have no disclosures regarding this talk. I represent the University of Wisconsin and the AANS. The past of carotid stenosis is an interesting concept, which emphasized the narrowing of the vessel at the internal carotid origin, at the bifurcation of common into internal and external. This emphasized flow, perhaps wrongly, whereas this illustration shows embolization through the brain may be far more important than stenosis as well. The concept of stenosis goes back to the early 1980s. And I must admit that I was part of that problem because in that time, we were trying to find a consistent way to measure the amount of atherosclerotic disease was present at the carotid bifurcation for clinical studies. And those studies used angiogram, CTA, MRI, duplex Doppler, et cetera. Each could measure different things, but all could measure the lumen of the vessel and the lumen at the narrows. Therefore, the concept of looking at the narrowest spot and comparing that to what is the usual physiologic narrowest spot in the more distal internal carotid was the way the calculation of carotid stenosis came to be known. I would argue that this was heavily influenced by a concept that flow decreased at approximately 60% stenosis. And that was because the velocity increased there. Much as a river, as it narrows with a canoe ride, it accelerates when it becomes narrowed, you'd see that acceleration, therefore 60%. But different studies use 50, 60, 70 or continuous measures. It didn't really make sense. If indeed the disease is primarily embolic and most of the disease from carotid atherosclerosis is downstream emboli, concept from 1951 C. Miller Fisher, then perhaps we must have some idea, not just of the size of the plaque or the narrowing of the vessel, but rather the stability or instability of the plaque. Its ability to break apart or create emboli. And that concept becomes very essential. As we debate things like endarterectomy and stenting, as if the goal was to reduce stenosis, we have to understand the full impact because stroke is a massive problem for health worldwide. That impact is really the basis of a lot of the research, which I've been interested in for three decades. The idea of stopping stroke requires us to use the tools of our time, if that's what our research will be, and build upon those tools to try to identify the pathophysiology and how we might change that. My mentors started me thinking about this over 30 years ago when we were doing carotid endarterectomies. I believe that our thinking there was rather primitive, but as we begin to understand pathophysiology, it becomes expanded. Years ago, I challenged the joint section of cerebrovascular neurosurgery to rethink their priorities when I demonstrated that 95% of the talks at their meeting were on hemorrhagic stroke, only 5% on ischemic stroke. And yet the impact on society is exactly opposite. We have a disproportionate number of ischemic strokes to hemorrhagic strokes. And indeed, the measurement of strokes has been missing while the Stroke Association estimates between 700,000 and 1 million strokes per year in the United States with far more impact worldwide, they're absolutely missing the minor or lesser strokes because they're emphasizing only hemiplegia, vision loss, speech loss. These are relatively crude compared to the impacts of the smaller strokes. We know that for every recognized clinical stroke, at least five silent strokes take place. Only 13% of people that have a stroke have given us a warning by something we can clinically identify by our present techniques or our past techniques. We have to be thinking about what is the impact of emboli, especially the warning or silent stroke emboli. And modern imaging tells us a lot about that. We with looking at modern imaging see approximately 11 million silent strokes per year calculated in the United States, suggesting this is an even far more major health disease that we're missing. How could we be missing that? Well, if you look at your post-operative exam, can you move both sides and talk? That's pretty primitive. We must be thinking about the cerebral functions of cognition, which define us as uniquely human, whether Nobel laureates, artists, painters, music, et cetera or just normal adults. If the earliest manifestation of cerebral vascular disease is cognitive decline, we are treating the disease of greatest importance to our elders and to society. Because cognitive decline, by that I don't mean just memory loss, but rather the loss of spontaneity, creativity, decision-making may be one of the more important markers. You look at stroke and cognitive impairment, you'll see that this is extremely common in elderly, especially those that have had a stroke. If you look at people over age 75, 65, who've had a stroke, a quarter of them have cognitive decline. And then a third of the people over 65 will go on to stroke or dementia. So these are major, major health factors and major disability factors, which have great impact both personally and to society as a whole. The links between what we call Alzheimer's and cerebral vascular disease are many and are important. The earliest presentation of Alzheimer's is defined by memory loss. However, cerebral vascular, which leads to eventual memory loss, executive cognitive decline, that decision-making, creativity loss, which can be measured. And these have identical prevalence curves and identical risk factors. They run together, although the cerebral vascular cognitive decline approximately 10 years before the memory decline, which we call Alzheimer's. Indeed, some of the studies that I was involved in when I was at University of Kentucky, the classic nun study under Snowden and collaborator Smith showed that in nuns that donated their brain at death for autopsy, there was significant amount of pathologic, histiologic changes of Alzheimer's in the brains. However, only half of those nuns had the clinical presentation of Alzheimer's dementia unless they'd had a stroke. If they had had a stroke, even silent, 93% had dementia. So this would suggest that the correlation between these two is tight and that the possibility that one may trigger the other is important. When you begin to look at cognitive testing, you do not simply look at memory. You look at executive function, and that's been a clear predictor of stroke. The risk factors for stroke and silent stroke are the same. And indeed, it would suggest strongly that silent strokes cause cognitive decline and cognitive decline is the result of small vessel ischemia or emboli. The statement is this is a research challenge. Neurosurgery has seen these patients. We can impact a tremendous patient population even though we're a small number of doctors. So to look at the past of carotid disease, you must bring it to the future and what's possible. And from that we predict, from the present we predict the future. If you look at plaque, this is probably the most important slide. The unstable plaque on the left has this thin fibrous cap which allows it to embolize or have clots, platelet clots form, which may be embolizing even though the vessel lumen remains relatively compatient. This narrower vessel on the right is a stable plaque. The plaque is reinforced, thickened, and does not embolize. So I would argue that the question of what causes embolization are even more important. Now, how are the molecular processes of these changes triggered? Gene regulation. So if we borrow from our colleagues, the science of our time, usually borrowing from our colleagues from oncology who looked at gene upregulation in cancers, I asked the simple question, are the stable plaques which I took out at surgery and the unstable plaques, symptomatic and asymptomatic, different genetically? And the answer is yes. When we looked at these genes, we saw that there are multiple angiogenesis promoters, growth factors, oncogene transcripts, and growth factor receptors in the unstable plaques. This was regardless of how narrow they were. And this would show an example here of an asymptomatic plaque with few vessels and a symptomatic plaque with many fissuring it. When you look at these genes, you begin to understand that degenerative processes of the brain are found in the markers of these genes of unstable plaque, suggesting that some of these conditions, such as ALS, Alzheimer's, myeloepilepsy, may be part of a systemic disease of vessels. And that would be intriguing and would make sense from a symptomatology. Could we predict then which patients with a plaque will become unstable and embolized? Well, local gene regulation suggested this, suggested that increase in microvassals within a plaque could cause a spectrum of disorders which could fissure the plaque, causing it to break apart or bleed into the plaque, causing it to become symptomatic. Does that relate to cognitive decline? Well, physics gave us a tool to look at this. This is ultrasound. We're very used to looking on the left at an ultrasound. We can see the actual structure of the vessels in the plaque or on the right, the Doppler that flow through it. But when we began to look with the ultrasound for shear or shattering of the plaque with pulsation, we began to see an interesting thing. This plaque here, which is not highly stenotic, leaving a fairly capacious lumen, has areas of stress with pulsation seen here by the pulsating lines which occur. These are not very severe, but they're quantifiable. This is an asymptomatic plaque. Compare this degree of strain and you would see that the higher the strain, the more the cognitive decline, suggesting that the more unstable plaques, more advanced atherosclerotic disease indeed correlated directly with cognitive decline. Look at a much more stenotic plaque here with an ulceration in it. You can see that through the narrow lumen is a jet which is creating shear on the wall of the plaque. This suggests to me more instability and more emboli. So the conclusions at this point, we found that both the classically symptomatic and asymptomatic plaques had cognitive decline, which was not related to whether they'd had hemiplegia or blindness, major things which would call them symptomatic, but rather to whether or not their plaque showed shear or instability. Indeed, more cognitive defects were often found in the asymptomatic people because they were not intervened. If you have a major motor stroke, your doctor sees it, you intervene. And we found that if we did end arterectomies and remove the unstable plaque, the cognitive decline stabilized. That's unheard of, but that was very important. This suggests that treating atherosclerosis by any method to stabilize it may have important clinical implications for the future of carotid sclerosis. What about emboli? Can we measure it? Well, yes, we can. That is an emboli plaque, and that is an emboli from a plaque being measured in the middle cerebrum. You can actually hear it as it arrives as a disturbance in the doctor's flow. If we quantify those, how many emboli do you have in an hour of time? We see a direct relationship to the degeneration of the brain from microvascular disease by white matter hyperintensities on MRI. So this suggests that the strain of the plaque correlates to the number of emboli and the emboli to cognitive demyelinating processes of brain, suggesting a direct relationship with these. So if this is a major symptom of cerebrovascular disease, we must emphasize emboli and instability of plaque and outcome measures such as cognition. The links are the new microvessel formation in the unstable plaques, the genetic markers, which suggested rapid turnover in the plaque, and a way to measure by the physics the instability of plaque and the presence of emboli. As we began to pay more attention to emboli, we began to think not just stop it from starting, but actually remove it. And in 2015, four studies showed that a remarkable 40% improvement in outcome with timely mechanical removal of emboli from the middle cerebral, this revolutionized cerebrovascular neurosurgery. And it was because we were paying attention to emboli in a very, very structured fashion. It could not have been possible. Attempts to remove emboli earlier were unsuccessful until the development of these stent retrievers. This allowed us the science of its time to understand the disease and actually introduce it. So where's the future? The 21st century, a person will identify a stroke, a neuroprotective yet to be identified will be given. They'll be scanned. If they're in a hemorrhagic stroke, they'll go in one direction. If they're an ischemic stroke, a clot dissolving and a mechanical reopening will be done rapidly, followed by protective drugs and recovery drugs, both under development. The recovery will be far aided by artificial intelligence to identify a plan of rehabilitation to their exact needs and their recovery course. And we will look at total treatment of stroke because we must take the lead in both prevention, treatment and recovery of stroke. This would be triggered by understanding atherosclerotic disease, which I believe is the major cause of stroke and understanding its clinical pathophysiology based on instability of plaque and cognitive outcome. I predict a future where patients at risk will be unidentified by unstable plaques. Outcomes will include cognition and neurosurgery will have a major role because they understood the pathophysiology of what was initially called carotid stenosis, but understand it's an active process of atherosclerotic instability, embolization and repeated embolization leading to cognitive decline and eventual major stroke. With those concepts, neurosurgery is positioned to take the lead in this and we must. Thank you.

carotid stenosis

stroke

ischemic stroke

cognition

cognitive decline