Chapters Transcript Video Cerebral Microvascular Pathology: A Common Endophenotype Between TBI, CVD and Dementia? Randel Swanson, D.O., Ph.D., presents at the Johns Hopkins Department of PM&R’s Grand Rounds on September 21, 2021. So thank you so much for the kind introduction. First of all I have no financial conflicts of interest. I do have some active grant funding from the Department of Defense and also pennsylvania's Department of Health and I'm on the consumer advisory board for the V. A. And D. O. D. S. Long term impact of military relevant brain injury consortium. Um I also have to note that the contents of this presentation do not represent the views of the department of veteran affairs of the United States government. Um So my objectives for today is the first. I'll give a brief introduction to the current state of TB. I. Diagnosis intervention and prognosis as a background for this talk. And then we're going to move into a review an overarching review of some of the existing literature looking at dementia risk and T. B. I. Survivors followed by a review of the evidence suggesting cerebral microvascular pathology is a common endo phenotype between traumatic brain injury and dementia. And then explore some avenues for future research for which myself and my lab are pursuing so to begin with um traumatic brain injuries multiple different definitions. But the D. O. D. And V. A. Se. T. B. I. Is defined as a traumatically induced structural injury and or physiological disruption. The brain function as a result of an external force. This is extremely heterogeneous both in the mechanism of TB exposure. Um The underlying molecular pathology and the long term outcomes. So you know you can have a traumatic brain injury from a severe motor vehicle accident from the fall downstairs from a blast like our military veterans are experiencing from repetitive trauma like boxing or soccer. So there's multiple different mechanisms and I'm sure most people here are familiar with the fact that we clinically diagnosed traumatic brain injury as either mild, moderate or severe based on some specific criteria, including structural imaging, the presence or absence of a loss of consciousness. And if so, how long any alteration of consciousness and how long post traumatic amnesia, which you know, the board's question is this is the duration of post traumatic amnesia is the most accurate predictor of long term outcome. And then there's the Glasgow coma scale um which is falling out of favor, you know, since I think 2015 or 2016 the dod and the Dia uh specifically recommended against the use of the Glasgow coma scale in any type of prognostication or diagnostics for traumatic brain injury. So, as a clinician, we group this as mild, moderate or severe based on this criteria. Now, both in the civilian world and in the military world, the overwhelming majority of all traumatic brain injury exposure can be classified as mild. These are the latest numbers from the Department of Defense. From over the last 20 years there has been over 430,000 service members officially diagnosed With traumatic brain injury, of which 82% are mild traumatic brain injury And according to the CDC, about 150 Americans die every single day from traumatic brain injury related events and those who survived a traumatic brain injury can face effects that last from a few days to the rest of their lives. So everyone that's in the field of physical medicine and rehabilitation knows that there is a plethora of symptoms that one can experience after a traumatic brain injury exposure, which varies widely. There are physical symptoms and cognitive symptoms and behavioral or emotional symptoms. You know, if we look at this, some of the most common are, there's cognitive complaints, there's ocular motor problems, there's problems with balance, the autonomic nervous system and some others. And this really spans the gamut from mild TBI I. Too severe TBI and it's really on a spectrum. Um and any given patient might have variable amounts of ocular motor versus balance versus cognitive deficits. And it's really hard to predict how a given patient that's presenting in the acute phase is going to be presenting in the sub acute or chronic phase. There was just a recent paper published in neuro trauma. It's um just out electronically right now by mary, jew, mary, jo Pugh and her colleagues at the Salt Lake city via in the university of Utah were there trying to look at distinct T. B. I. Outcome phenotype and how there's basically a wide variety. So it's really hard to predict. So, you know acutely we have the T. B. I. Which we can classify from mild to severe, then if we look at the day's to up to a month post injury, there's a variation in the phenotype. And then if you go out to the sub acute phase, let alone the chronic phase, patients continue to diverge. And so it's really hard to predict which patients are going to fall in which long term category. Now it's a brain injury doc when I'm seeing patients, especially in the military setting where patients have had their brain injury exposure usually several years ago. Um The biggest long term outcome that they're looking at um is dementia. But before we get there, what I've presented so far from TB diagnosis and then these phenotype, the real thing is there is a big elephant in the room here in the field of brain injury medicine namely that traumatic brain injury is a non specific diagnosis and this leads to non specific treatment recommendations which lead to non specific outcomes. So let's say instead of a brain injury doc, I was a oncologist and a woman found a lump in her breast and she came to see me and we did a fine needle aspiration. And so now the woman is sitting in our office and we say I'm sorry Miss Smith but you have cancer and when after the shock when she says what type we say moderate and based on this moderate cancer, we're going to give chemotherapy regimen X. And you know, we're going to basically hope for the best and look at the long term outcomes. There's a lot of problems with that, right? And that's not what we do in oncology at all. Instead they're going to, you know, look at the specific receptors that are expressed whether the tumor cells express like Herceptin or estrogen and then there's gonna be targeted chemotherapy for that based on the specific endo phenotype or that sub diagnosis, not just a global breast cancer. And so in the brain injury field, really we are not giving specific diagnoses and therefore there is a huge problem with non specific treatments and non specific outcomes. So again, I had jumped ahead before, but the majority of patients in the sub acute to chronic phase are really asking, am I going to get dementia because of my T. B. I. Exposure And is there anything that I can do that's evidence based to reduce the risk for dementia as I age and especially in the military population. I mean, I'm confronted with this on a daily basis in clinic. You know, there's tons of stuff in the news. This is from three years ago, a 60 minutes interview where you know, they're talking about combat veterans coming home with chronic traumatic encephalopathy or CTE and you know, this is a disease and a problem that we're going to be dealing with for decades. It's a huge public health problem, a huge problem for veterans administration and a huge moral responsibility for all of us. Okay, so with this background let's review some of the existing literature looking at the risk of dementia in TBI survivors. So there's been several well done studies with the first one we're going to look at is a study that was actually done out of the Hopkins Bloomberg School of Public Health with Andrea Schneider. So she was an MD PhD student at Hopkins and she since moved up the pen as an attending. So she's a neuro critical care physician that has a PhD from the Bloomberg School of Public Health. So she just published this paper a few months ago in the prestigious journal of Alzheimer's and Dementia. Where they looked at the 25 year risk of dementia in about Little over 14,000 participants in the atherosclerosis risk in communities study. So here they looked at. First of all they did not parse out whether a brain injury was mild, moderate or severe. They just had the I. C. D. Nine and 10 codes and it was traumatic brain injury. Yes or no. And then there was dementia codes. And what they were able to show is clearly there was an increase in the hazards ratio of dementia diagnosis from those patients without a history of TB versus a history of one traumatic brain injury or substantially greater if you had two or more head injuries. But again this wasn't parsed out as mild moderate or severe. If we look at this as a function of age really as a function of time from when the person was initially enrolled into the study Over the 25 years you can see with time there is an increased incidence in dementia diagnosis And if you don't have any traumatic brain injury still it goes up. If you have a single traumatic brain injury there's a statistically significant increase. And if you have two or more then you're really at a statistically significant increase. And they concluded that their findings confirm the association between head injury and dementia risk and expand the literature by providing evidence for a dose dependent relationship which notably exists that the association is stronger amongst women versus men and amongst whites versus blacks. I didn't show the data here. But this is a very interesting study for people on the call. If they're interested in looking at this. Then there was another study by Kristine Yaffe out it um U. C. San Francisco and her colleagues That was published in Jama in 2018. And this was a huge study in veterans. It was a retrospective propensity matched cohort study of more than 350,000 veterans with and without traumatic brain injury. And they looked at T. B. I. Diagnoses from two sources. So when a veteran um comes into the V. A. After getting off active duty they go through um a whole bunch of screening with their primary care doctor And one of them is if they screening to see if they've ever been exposed to traumatic brain injury. Well um in the military if they scream positive they have to see a brain injury doc like myself. And they undergo a comprehensive TB evaluation. So they were able to search the national database to look at all the diagnoses of um traumatic brain injury. Using that T. B. I. Second level evaluation as well as all the patients that came into the V. A. That didn't go through that pipeline. Um So they had 178,779 patients that were diagnosed with traumatic brain injury. And then what they did is they got an equal number of propensity matched comparison group. So then they looked at Haitians that were in the vagina from across the United States From 2001 October 2001 until September of 2014. And all those patients that did not have a history of TB exposure. And then they matched them, propensity matched them based on the same other co morbid diagnoses and um different demographics? Okay. And the mean age was about 49.5 years at baseline when they were in the study. So what did they show? First of all if we just look at the unadjusted risk of dementia by TB i severity. So first of all they looked at all patients that had a history of one traumatic brain injury or more. Okay the hazards ratio of dementia diagnosis was 3.41, then they had three sub models. So the first model is they adjusted for demographic characteristics such as sex race, education and income. Then the second model was they adjusted for everything in model one, but also co morbid diseases like diabetes, high cholesterol, heart attack stroke and peripheral vascular disease. And finally, the third model was taking into account adjustments for um models one and two, but also adjusting for psychiatric comorbidities such as anxiety. PTSD substance use, tobacco use and sleep disorder. So where you can see, no matter which adjustment they did clearly, um there was about the same hazards ratio for dementia diagnosis with TB exposure, if they then parse this data out based on the severity. So we have mild TBI without a loss of consciousness, mild TBI i with a loss of consciousness, mild TBI. Where the loss of consciousness status was unknown versus moderate to severe. There's basically a dose effect here where as you go from more mild level of brain entry to more severe. The hazards ratios get greater further, if you look at this as a function of age. So, um again, we can see the black line here, this is those patients without TB exposure as you age as an increased cumulative incidence of dementia diagnosis. And then as you have mild TBI without loss of consciousness, the whole way up to moderate or severe TBI. There is a statistically significant increase. Now, it's important to note here from a research perspective, clearly there's an increase from a clinical perspective, We have to remember that there's a difference between the absolute versus the relative risk. So if we look here at the total numbers a total of 4698 veterans are about 2.6% without TB exposure developed dementia compared to about Almost 11,000 or 6.1% of those with TB exposure. So these are two of the primary um studies looking at this and if we look at some meta analysis, so There was a big dementia prevention intervention and care, the 2020 report of the Lancet Commission which was published and they did some meta analyses looking at the relative risk of all cause dementia as an association with all severity midlife traumatic brain injury. And if they looked here, there was a number of well done, high quality studies of which um the cumulative Risk ratio of all of these was 1.84 increased risk of developing dementia if you had a TV exposure in midlife. But again, this was all TB. So if we look at the most common which is just mild traumatic brain injury, there was another systematic review and meta analysis recently done and published in the Journal of Alzheimer's and dementia last year, Where they looked at five well done studies and they determined the overall odds ratio of about 1.9 to about two um of developing dementia after remote mild traumatic brain injury. Okay so with that background we're now going to look at, let's look at some of the evidence suggesting that cerebral microvascular pathology might be a common endo phenotype between TB and dementia. So again, we talked about 10 minutes ago about the fact that it's my belief that traumatic brain injury is a non specific diagnosis. So we're not looking at the actual end. Often a types here. And yes there's a lot of um variation. You could have subarachnoid subdural, you can have inter predictable hemorrhage. But the most common thing that you have is diffuse injury namely diffuse axonal injury and diffuse microvascular injury. So if we look at the few sex anal injury first um Sorry clinically when we're looking at a patient that might be still in the disorders of consciousness program that we're seeing that we're trying to figure out are they you know vegetative or minimally conscious um And there wasn't much bleeding but we get advanced M. R. I. So you know, what do we teach? The residents were getting advanced M. R. I. With susceptibility weighted and gradient echo sequences. So here you can see this was published a 17 year old female 10 days post a motor vehicle accident with a severe traumatic brain injury. And we're looking at all these black dots here. Okay. And this is MRI evidence this is a MRI susceptibility weighted imaging and clinically we're going to say aha this is evidence for diffuse axonal injury. If we look under the microscope and patients that succumbed to their injuries, the neuropathologist are looking for staining for the amyloid precursor protein or a P. P. This is the neuro pathological hallmark of diffuse sexual injury. Here's two cases. So one this is an 18 year old male that Um passed away 10 hours after an assault. And we can stand a higher high magnification here. You can clearly see the undulations in this axon as there was disruption to the micro tubules. And there was a backup of the amyloid precursor protein which is what we're standing for here. So all this brown staining is a PPD staining demonstrating a few sexual injury. Same thing here. This is a 22 year old female 22 hours post a motor vehicle accident. Same thing you have disruption of the micro tubules build up of a peep and you have nice staining here of this undulated accent of the few sex on injury. Now, About 25 years ago at the University of Pennsylvania Dr. Douglas Smith. Um Dave Meany and colleagues in neurosurgery and biomedical engineering developed a large animal swine model of diffuse axonal injury. So what happens is you have rapid rotational acceleration, deceleration. So there's no head impact, literally the heads moved from one side to the other in a split millisecond. It's like if you're you know, you're driving 60 mph down the highway in a car and you have to sleep out on and you slam on the brakes. Well what's going to happen? Your body is going to go against the seatbelt, right? Because your body has a different density than the car. So same thing sort of happens in your brain. You can think of it the same analogy you have white matter, you've got gray matter, you've got strip of spinal fluid. All of those things have a different density. So when you undergo rapid rotational acceleration deceleration, the different parts are going to accelerate and decelerate at different rates. And this is really what produces the stress and strain and causes the diffuse injury in a predictable pattern based on the level of where the force was coming and the trajectory of how the force was coming in. So they mapped this and we can do this in the coronal plane, the sagittal plane or the axial plane, mm hmm. And you're going to get very amount of pathology. If we look here at the gross pathology. So this was some of my colleagues dr Casey Cullen here, he is the director of R. V. A. Center for neuro trauma neuro degeneration and restoration that I'm a part of. So, okay, this is the gross pathology of some of the pig brains. So if we look at a sham control um that just underwent anesthesia didn't actually receive a traumatic brain injury when the brain is removed. You can see there's a pristine brain, there's no gross pathology there's no bleeding. If we do a coronal injury of about 190 radiance per second this is our model for concussion. There again there is no gross pathology. There's no gross bleeding or anything when the pigs come out of anesthesia. Um You know it's very hard to tell any clinical difference between the controls. Um It'll be a different story when we look under the microscope in a second as we increase the injury and the corona plane. Now we're starting to get into the more moderate range of brain injury where if this were human and we did advanced neuroimaging we would see some sub arachnoid hemorrhage here. You can see here the sub arachnoid blood and also down here in the brainstem region. If we go from the corona to the sagittal plane now um even at a lower acceleration here we can see much more subarachnoid hemorrhage. The bottom line is we can scale this the whole way from concussion up to severe brain injury disorders of consciousness. And one of my colleagues that pen now um just got a recent grant where they're doing um severe disorders of consciousness and their surviving the pigs long term to try to look at um long term outcomes which is more relevant to rehabilitation. So I mean the whole nine yards from you know there's a 24 hour E. G. And neurosurgery sweet and there the pigs have a bolt in their head and basically they're treated just like they are in neuro iCU um in a in a clinical setting. If we look under the microscope even in concussion or the mild end of the spectrum here where we had normal gross pathology you can see there's extensive diffuse axonal injury in the white matter tracks. So again we're standing for the amyloid precursor protein and panels A. And B. Are from the pig and panel C. And D. Are human. And if you're looking under the microscope high magnification of diffuse axonal injury you cannot tell the difference is identical. Um pathology between human versus these pigs. If we look at this um zoomed out. So now we're looking at a whole coronal section here and all of this blue staining is standing for A. Pp. So again we can see here you've got the lateral ventricle, you've got the white matter gray matter around it and you have most of the pathology and the leading hemisphere in the peri ventricular white matter where there is that significant difference of density between the cerebral spinal fluid and the white matter and again here high magnification of diffuse axonal injury. Okay so this is what we all learned about for the boards and you know when we think about diffuse injury we're always thinking about diffuse axonal injury. However let's go back to this MRI where we're looking at clinically the susceptibility weighted imaging. So again, we clinically say aha, this is evidence of diffuse axonal injury. But what we're really looking at is diffuse vascular injury, all of these black dots, Arnhem Assyrian deposits of microvascular injury. So we're looking at micro vascular injury and we're inferring the few sexual injury. This is a nice illustration from and two of my colleagues at penn looking at what happens to the micro vasculature in the brain when you have traumatic brain injury. So, again, most people on this call and society are probably pretty familiar with the concept of the blood brain barrier and the brain tightly regulates what can get in and out of the brain. Um So, you know, it's very hard to get drugs and different things from the blood into the brain, brain brain command when you have traumatic brain injury, there's multiple different disruptions of the different layers here of the neurovascular unit and the blood brain barrier. In the end, you get a dysfunctional blood brain barrier where you can have extra visitation of blood proteins into the brain prank mama, which causes a host of downstream effects Picture is worth 1000 words here. So this is a scanning electron micro graphs of two brains. So on the left we have a controlled brain. So we're just looking here. This is special technique where we're just looking at basically the arterial trees. So we have, you can think of it as you know, the bigger trunks and stuff to some of the branches, to the tiny tiny little branches as we go down into the brain parang coma. So this is a nice healthy brain microvascular chair where the person passed away from something other than traumatic brain injury. And if we look over here on the right, this is a person with a severe traumatic brain injury. And again, you can just look at the picture and see the vast difference between all the vascular structures here from the T. B. I. Patient versus the control. Yeah. So one of our colleagues and collaborators, dr Willie Stewart and colleagues over in the United Kingdom in Glasgow. They have one of the world's largest banks, brains of people that were exposed to traumatic brain injury, including moderate to severe brain injury and repetitive mild brain injury. And they didn't pass away at the time of their injury and they survived for several years where they were followed clinically and then when they passed away, their brain was donated to the bank. So They published a study, an autopsy study back in 2015 where they looked at a whole cohort of brains of long term survivors brain injury versus control. So again, If we look here, this is one example of a 20 year old male that survived two days post an assault and what we're looking at is standing for something called fibrinogen which is a a large protein that's in the blood which is normally confined to the blood and does not get into the brain when you have a healthy intact blood brain barrier when you have disruption to the blood brain barrier. Then the basically the blood contents are able to extract is eight into the brain parang coma without control. And that's what you're seeing here. All this brown staining is extensive Microvascular pathology in the brain. Two days post an assault in this 20 year old patient with severe brain injury On the right. We're looking at a 60 year old male from their archive that survived 18 years after a fall. So the person had a fall, had a moderate severe brain injury But survived lived 18 years died from another cause. And at autopsy you can see there's still extensive vascular pathology. Microvascular pathology with extra visitation of fiber into the brain prank throughout the brain. If we look here at sort of high magnification, you can see where my let me get it. My Laser pointer is right in the center of a blood vessel and you have extra visitation outwards 360° of fiber engine leaking through that vessel that has a disrupted blood brain barrier. So this is an autopsy. What if we look at some functional studies dr kim Kenny at the NIH and Eustace and Ramon Diaz Oresteia who is now at penn. They did ah a very interesting study. This is their preliminary results and they've now expanded it where they're looking at functional cerebral vascular reactivity in patients surviving a moderate or severe brain injury six months after their injury. So there's a special type of MRI called bold, which is blood oxygen I think A level dependent um M. R. I. And what what's done here is the patients are they have a mask on and the scientists can vary the concentration of carbon dioxide in the air that they're breathing. So if we look here at the right of this history graham, the sort of blue healthy control line shows what should normally happen as you alter the concentration of carbon dioxide, you're going to cause vaso constriction of vaso dilation and you're going to have changes in cerebral vascular reactivity. And so you see this nice healthy curve as they change the amount of carbon dioxide they're having vascular reactivity. The red is six months after moderate to severe brain injury. And like basically the gist is that there is a disruption of the ability of the micro vasculature to respond to that changing concentration of carbon dioxide. So there is a functional problem with the micro vasculature in the brain switching from moderate to severe brain injury to mild traumatic brain injury, concussion and from human to pigs. Um I showed you before, there was a ton of research done over the last 25 years looking at the future axonal injury in these pigs models. But recently doctor victoria, johnson and colleagues at penn published a paper In 2018 where they looked at the diffuse microvascular injury in mild traumatic brain injury in these pigs. Um And what we're looking at here, everything that's highlighted is the quantification of Freiburg region extra visitation into the brain prank and mark Up to three Days Post Single Concussion. So they did this at six hours, 24 hours, 40 hours and 72 hours. And were systematically looking through the brain. And they're looking at the widespread microvascular pathology again here, you can see, let's see, look here, see this is the low magnus is the leading hemisphere peri ventricular range. If you look at high magnification right? Where you have the border zone between the lateral ventricle and the surrounding period, ventricular white matter. You have a lot of the microvascular pathology here, if we look at this side by side in two serial sections. So a few microns apart from each other. So the first section was stained for fiber. Imagine looking at the future vascular injury and the second section was stained for a PP. Looking at diffuse axonal injury and the bottom line is there is overlap where you have the most mechanical forces in the period ventricular white matter based on this coronal input of the force of the pathology and you have the same corresponding microvascular injury. But you have injury profusely throughout the brain. Now my lab we were looking at this at quantifying this longer term going out to one year. So if we look on the left again, this is seven days after a concussion, we see a nice blood vessel here, there's disruption of the blood brain barrier and there's extra visitation fiber into the brain parang coma. And you can see several neurons are taking up this vibrant and they're being darkly stained. If we look here on the right, this is a technique that we did to systematically quantify the degree of um blood brain barrier disruption in a scientific manner where we can quantify and you know, be less biased. So you can see here here's gray matter, this is the corpus callosum. You can see the nice border zone. Now we're in the white matter. If we look here, here's a nice healthy blood vessel, I can't get there's a nice healthy blood vessel that's intact. All the blood and in this case by branches are contained within the blood vessel. Here's another one. But if we look here there's a blood vessel running through this field which has disruption of the blood brain barrier and there's a leak cloud of extra visitation of blood out if we quantify this. So now we're looking at low magnification all these purple dots are all the regions where there was extensive microvascular pathology. So if we quantify this, we replicated our colleagues initial results that in the acute phase up to three days post injury. Yes, there is a disruption of the blood brain barrier. But if we go out to one month, let alone one year there's been healing of the blood brain barrier. We cannot tell a statistically significant difference from the sham control animals. Going back to the philosophy of the principle that, you know, the body has the innate ability to heal itself and given the right conditions. So when you have a trauma instantaneously, the body is trying to heal. There might be some persistent pathology in a mild level of injury. But in a single mild injury it seems like there is repair the micro vasculature. I'm not presenting it here, but my some of my colleagues that were also doing the same thing in amyloid precursor protein A. Pp. And they're showing the same thing that when you have a single concussion. Yes, you're having a lot of diffuse sectional injury acutely. Um but you know, the pathological um hallmarks of that fade with time and by about one month post injury, it's very hard to tell the difference from the control animals. Okay, so that was a brief review of evidence suggesting that there's cerebral microvascular pathology in traumatic brain injury. Now let's look at dementia. So in the early 1900s, the view of dementia was Largely that it was a vascular phenomenon. And then the pendulum swung to the 1990s where it was all about, you know, it's pathological proteins like tau and amyloid. And then Over the past 2030 years the pendulum has really swung back to it. There's a ton of vascular pathology input to dementia. If not dementia dr I'm sorry microvascular pathology driving this dementia diagnosis. So there has been a multitude of pre clinical and clinical studies. Uh This is one review that was published in physiological physiology reviews about two years ago. This is a very well done um review. Looking at all the evidence that has accumulated to basically say when you have a cognitively normal person you have a healthy intact blood brain barrier. Once you start having a little bit of disruption in the blood brain barrier. What we're looking at advanced um you know imaging susceptibility weighted M. R. I. Just regular T. Two white matter hyper intensities. We're doing advanced things like dynamic contrast enhanced MRI with and without contrast where we're looking at breaches in the blood brain barrier versus maybe some people on this call have seen the beautiful pretty diffusion tensor imaging or track ta gra phy MRI's. Looking at all the white matter tracks. You know if we look at this advanced MRI's and functional MRI we're starting to see problems. This is around the pre clinical or mild cognitive impairment stage. And by the time you get to early dementia clinical diagnosis of early dementia there is extensive blood brain barrier pathology and finally in informant progressive alzheimer's and other dementias there is an extensive blood brain barrier pathology. If we look at one group. So um there's a big famous group out at U. C. L. A. By doctor as low Quebec. Um So his team has published a couple of landmark papers in the past couple of years and one of them they looked at dynamic contrast enhanced MRI. So this is MRI done with and without contrast and they're looking at three cohorts. So they're looking at I am non cognitively impaired or the young adults non cognitively impaired older adults, older adults who have been officially diagnosed with mild cognitive impairment and then a group of a control group that has multiple sclerosis without cognitive impairment. And then they're specifically looking at the hippocampus. And so they get these pretty maps here. They're looking at basically the permeability here of the blood brain barrier. And so blue is very little as you get towards more green, yellow red, you're having a lot more blood brain barrier pathology. If you quantify this, you can see there's a stepwise approach. So in in young non cognitively impaired individuals, they largely have an intact blood brain barrier as you get the older individuals that have normal cognition still just as a function of age or having increased permeability of the blood brain barrier in the hippocampus. And by the time you get to the official diagnosis of mild cognitive impairment, there is again a statistically significant increase in the permeability of the blood brain barrier in the hippocampus. So if we go back to our pigs and we look at some pre clinical models. So um I've been involved in the T. B. I. Uh pig work at penn but there's our colleagues um robert Wolinsky and colleagues at penn that our cardio cardiologists and cardiothoracic surgeons and they developed a diabetic hypercholesterolemia pig model. Now they specifically developed this to generate atherosclerosis. So they could do trials and stuff for um stents and cardiac drugs. So what they do is they take pigs that are six months old and they induce diabetes and then they give them a poor diet to give high cholesterol and hypertension. And after three months. So you can look here, here's one of the coronary arteries and you're starting to see a nice atherosclerotic plaque here By six months post injury. There's extensive atherosclerosis. So one of my collaborators um doctor robert Nagle and nemesis Acharya over at Rowan University in New Jersey. They initially got these brains and they looked at, okay well what's going on in the brain. So if we look here on the left, this is one of the pigs that was fed a normal diet and was not hyper cholesterol limit or diabetic and you can see this time instead of standing from fibrinogen, they're standing for I. G. But it's the same concept. All the I. G. Should be contained within the vasculature and you can see all these nice capillaries here in the brain and all the I. G. Standings within the vasculature there's no breach in the blood brain barrier and there's no interpreting caramel staining. However six months after being diabetic hypercholesterolemia you're already seeing breaching the blood brain barrier and extra visitation of these blood products into the brain. Um This next slide is unpublished data from my lab that we used for a grant we just submitted where we got some of these brains. And so panel A. Is we're looking at a single ah animal. This is one animal's brain that had a concussion, two concussions one week apart. So I had a mild traumatic brain injury or concussion seven days later had another mild traumatic brain injury, concussion, survived one month. And at one month we can still see there's a lot of microvascular pathology here um In this repeat mild TBI. I. Model panel B. Is six months after being diabetic hypercholesterolemia and see is healthy control where you have no tv no diabetes hypercholesterolemia. So in both cases whether you have poor modifiable cardiovascular risk factors or you have repetitive mild TBI. You're having reaching the blood brain barrier. It's a common endo phenotype. Okay so all of this is well and good but just like um in the clinical realm you know you can't really confirm alzheimer's or other dementias until death when the pathologist do an autopsy. So There was a lot of this. You know studies supporting the evidence that there was microvascular pathology in dementia. But it wasn't until about 2013 when a big large study was published from the National Alzheimer's Disease coordinating center where they looked at 4629 cases of Autopsy confirmed Alzheimer's disease. And they did a re analysis and they looked at these brains and they showed that 80% of all those patients that were pathologically confirmed to have Alzheimer's disease had co morbid vascular pathology in the brain. So taking this together um Again Kristine Yaffe and her group Back in 2014. They did a look at traumatic brain injury and the risk of dementia in older adults. And this time they did a retrospective cohort study looking at 188,000 U.S. veterans Age 55 or older who had at least one inpatient or outpatient visit during the baseline from 2000 2003 and also follow up between 2003 to 2012 periods and they did not have a dementia diagnosis at baseline. Um They Veterans had a mean age of 68 years old and during the nine year follow up 16% of those with T. B. I. developed dementia compared to only 10% without TB. But most importantly the biggest thing for this study is that there was an additive effect between the FBI and other conditions on the risk factor of dementia. So if we look here at the cumulative incidence of dementia in their cohort. The green line on the bottom is those patients without a history of TB exposure. And the red line is those with TB exposure. But importantly, if they look at cardiovascular disease also. So the green line on the bottom, this is no traumatic brain injury and no cerebral vascular disease. The red line is patients diagnosed with cerebral vascular disease only. This blue line is traumatic brain injury only. And then this dark rider maroon line is when you have a dual diagnosis of traumatic brain injury and cerebrovascular cardiovascular disease. Now you really significantly increase your risk for dementia diagnosis. Mhm. Okay, so with this background, you know, let's how are we exploring some of these future research and the scientific domains? So we have a grant in my lab that we just got a great score. We're anticipating getting funded here in the next couple of weeks. And our overall central hypothesis is that there is cerebral microvascular pathology is a common end of phenotype in both B and dementia. And while innate repair mechanisms may promote healing of traumatic microvascular pathology following TB exposure. The presence of a poor cardiovascular risk factor profile over the decades after this, it's going to promote progressive non traumatic microvascular pathology ultimately contributed to the significant increase risk of age related cognitive decline or dementia. So we're specifically looking at mild traumatic brain injury, but we think that there is an acute pathology But then there's largely some healing maybe not the base back to baseline. Obviously if you have multiple repetitive head injuries you're going to increase your risk more. But then really You know if you have head injuries when you're 20 or 30 well what's going on over those next 30 or 40 decades um are really what we think is going to be driving a lot of the pathology. Um Looking at a pre clinical study planning. Um Not for the grant I was talking about but for other grants were working on um both using pigs versus using special um mice. Um rodents don't have the same lipid profile as humans. So you have to use a genetically altered animal that's fed a bad diet so that you can induce um you know high cholesterol and things like this to get atherosclerosis. But we're looking at models where we can do um single versus repetitive mild traumatic brain injury and then induce either healthy cardiovascular risk factors versus poor cardiovascular risk factors over a period of at least 6 to 12 months and then look at from pathology to blood based biomarkers to neuro imaging. Um What I'm very hopeful that our our our grant is going to be funded is leveraging the Limbic Sensei database. They currently have 1600 patients enrolled. These are all combat veterans from Iraq and Afghanistan with mild traumatic brain injury only exposure. And um what we're going to be doing is looking at to advanced neuroimaging markers of cerebral microvascular pathology. A special type of white matter quantification versus a special type of diffusion MRI. And we're going to look at fixed risk factors versus age, sex and then their combat related mild TBI exposures versus a panel of modifiable cardiovascular risk factors including physical activity, sleep, smoking, alcohol, diabetes cholesterol, blood pressure and B. M. I. And the two neuroimaging methods. We're using the first one is this Bianca. It's a it's a method that basically combines T. One T. Two flair and the D. T. I. FAA. Or fractional anisotropy images to generate a probability map of white matter hyper intensities. And there was an initial study published in Jama, where I think this is very interesting. Although it's a preliminary study they took um 125 young adults that were seemingly healthy with no evidence of cardiovascular disease, no clinical evidence. And they looked at a um A variation of the American Heart Association's ideal cardiovascular health index. So we look here, this person was a little bit overweight, a little bit high cholesterol. You know, 21 year old male, a little bit overweight little high cholesterol, a little bit of high blood pressure. This is not exercise, it's just like acting graffiti and stuff. So about 14 hours per week of moderate activity, moderate to vigorous. The peak blood pressure exercise was 200 over 70. This person drank more than eight drinks per week. They were not a smoker. And already at age 21 they had over 31 White matter lesions measuring more than a millimeter. If we look at this person's brain, Look at the extensive white matter pathology already in this asymptomatic 21 year old. In contrast here we have a 24 year old female, that's normal body mass index. But you know, normal blood cholesterol, better ambulatory blood pressure, you know, 1.5 times the amount of moderate to vigorous activity per week is the person above peak blood pressure. And exercise is only 1 80/90 and drinks less than two drinks per week as a non smoker. And this person only had eight white matter lesions measuring more than one millimeter. Finally more sensitive than looking at white matter hyper intensities. Is looking at something called diffusion MRI based free water volume fraction analysis. So, this is a special technique um where we're looking at ah basically the free diffusion of water which is an indicator of microvascular injury. In addition to some other external pathology vs fractional anisotropy. This is the FAA. Which is what you normally see when you're reading MRI. Studies in mild traumatic brain injury or any brain injury. They're looking at, you know, diffusion tensor imaging that most of the time they're looking at the FAA. So here's a study that was done out of the Framingham heart study where they looked at um this measure of carotid ephemeral pulse wave velocity, a measure of arterial stiffness or cardiovascular disease. They look at the association of that versus free water um and F. A. Pathology in 2422 participants. And basically what you can see that just here is you're having an increase in free water and a decrease in FAA. So there's an increase in the free water and a decrease in fractional anisotropy. If we look at traumatic brain injury doing the same advanced neuro imaging on the left. This is a pilot study that was done In 40 patients in the nationwide tracked TB. I study two weeks after concussion. Same thing. We're seeing an increase in in free water and a decrease in fact in fractional anisotropy. So this is mild traumatic brain injury where we're seeing the same pattern though less extensive than in the cardiovascular disease above. And then here on the right again, this is the same uh neuro imaging modality. But now we're looking at moderate to severe traumatic brain injury, patients that presented to Moss rehab. So this is my collaborator dr Rajni verma slab that pen with john White from Moss rehab. So they looked at moderate to severe patients three months post injury. Same thing. They're seeing an extensive increase in a free water volume fraction in these patients brains. Okay, the last thing to sum this up, if we go back to the clinical realm besides research. So we still go back to the question of most of my patients are asking me, am I going to get dementia and you know, what can I do about it? And then just what I tell them now, based on the current best available balance of evidence is you cannot change the fact that you had a TB exposure, but you can change your modifiable, largely cardiovascular risk factor profile and being like in the beginning, I was a marine. So military personnel, military personnel in the V. A. I like to use this quote from the Chicago tribune from my veteran patients. That the idea of preventative medicine is faintly un american. It means first recognizing that the enemy is us. So I try to get them to incorporate secondary prevention, post TB exposure with a lifelong neuro rehabilitation based largely on the american college of lifestyle medicine, including nutrition, exercise, unwinding, restore and optimization of cognitive preserve. And I also point them to The recent 2020 Dementia Prevention Intervention and Care Report by the Lancet Commission Noting that there are at least 12 risk factors that a person can modify that might prevent or delay up to 40% of all dementias. And namely that yes, traumatic brain injury is on here, but it's really only 3-4 and all of these other things including smoking depression, social isolation, physical activity in activity, diabetes, hearing loss, all these other things, high blood pressure, obesity play a bigger role when you add it all up and these are what's in their control. So with that I'm going to stop um and take any questions. Mhm. Mhm. Are there any questions or it's a quiet group today? Sorry, maybe I went too fast or too much um If it's alright with you, I'm sorry, Sorry, that was accidental. I said we could share your contact information in case people need a little time to think it over and if they have questions they can reach out to you. Yeah, absolutely. I think that work you're doing is really um fascinating and also timely given all of the interesting stuff that's going on around brain injury and repeated injuries, especially over the past several years. Um Thank you for presenting today and for joining us virtually. Absolutely. It was my pleasure. Thank you so much. Yeah, I just want to say thank you very much, dr Swanson. Um This is Jessica angle from intern here. Um it was absolutely fascinating uh and you really incorporated so many things from you know, traumatic brain injury, to your military experience, to lifestyle medicine, which I think is becoming a huge, huge part of how we are practicing now as um as you know, as podiatrists and we were taught to treat the whole body and even you know, some of us even you know from the first day we started medical school in osteopathic medical school that as you said, the body has the ability to heal itself and I really appreciate this lectures absolutely phenomenal. And you hit it out of the park. Well thank you very much for your kind words. I think we have a lot Jessica I was gonna say I think we have a lot that we can we can we can help share with our patients um to make a difference even if they come in for something as small as a you know one joint musculoskeletal issue with that. We can even from this talk we can we can bring um as far as a lifestyle medicine component um and making a big difference for the for the rest of their lives and especially with the traumatic brain injury patients. This is great thank you. Yeah absolutely. Well it is 1:00 so thank you again. Um and we really appreciate you giving a presentation of all of your interesting work. Have a great day, everybody Created by Related Presenters
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