This presentation opens with introductions made by Dan Kelly, MD, and Scott Kaiser, MD., and Verna R. Porter, MD, FANA, presents an update on the prevention and treatment of Alzheimer's disease including trials, opportunities, and the challenges.
Good morning everyone. This is dr Daniel kelly, I'm the director and one of the co founders of pacific neuroscience Institute. We're very happy to welcome you all to our first and hopefully one of many symposia that centers around our pacific Brain Health Center. And the title of our symposium today is integrating lifestyle strategies into the care of neurologic disease. And I want to thank malita Petrosea in our course, director who directs our movement disorders center, and dr Scott Kaiser, who's our director of geriatric cognitive health, who are gonna he's gonna be moderating. So just a little background on pacific neuroscience where our home base is in santa Monica as many of you know. Um but we do have a fairly wide footprint up into the valley and and down somewhat into Orange County for some of our programs um R. P. And my mission is really about providing personalized precision, multidisciplinary patient care centered around um multiple centers of Excellence. We're trying to really advance the neuroscientist and promote brain health through novel research and innovative clinical trials. And you're going to hear quite a bit about that today. Were involved in training the next generation of clinicians and research scientists and we're really aimed at also educating patients in the community at large on on vital neuroscience issues. So when pacific neuroscience started we were we really were focused in this area around brain tumors and Pituitary iron skull base. And over the years we've really grown for all these different Centers of Excellence including the Brain Health Center. Um And we've grown from a relatively small group to now. 35 clinicians across 10 specialties. So quite a unique conglomeration of of specialist really to help us cover all of these different entities including stroke, a large stroke program, facial pain, hydrocephalus, spine care and then these other areas that are really involved in brain health Um of our of our 35 specialists and and across 10 specialties, you're gonna you're gonna be hearing from 10 of them today um highlighted here and and Dr Kaiser will introduce each one of them, but suffice it to say you're going to hear you're hearing from predominantly from our neurologist um are jerry attrition, which is dr Kaiser addiction medicine specialists um and our our psychiatrists and and 11 neurosurgeon, I'm a neurosurgeon, you're gonna be hearing from J. P. Land even as well. And so it's a it's a really nice diverse group and I think these are gonna be excellent talks. Um we've really focused a lot on this concept of centers of Excellence, that's how we build pacific neuroscience and and really what is a center of excellence. Well, it's a collaborative team of people that are using best practices around the focus area to optimize outcomes and really trying to expand expertise through ongoing education and training and advanced treatment through research and you're going to hear about a lot of that today and we've had a long experience with this for example in our pituitary Centers of Excellence. And this is an article we wrote almost a decade ago about this multidisciplinary team approach to pituitary tumor care and we think this is quite transferrable and applicable to the realm of brain health. And so when we created the pacific Brain Health Center in 2018 and started working on the concept in in 2017, we really visualized it uh and envisioned it as this uh multidisciplinary group working under one roof under one roof, and really applying evidence based therapies, but again trying to push the envelope and push the science forward to improve care for our patients. And so this is really what we've done with our Brain Health Center in santa Monica with all of these different specialists. Um and we've we've really had some remarkable success from from this great um team of clinicians and you're going to be hearing about this in great detail. So um are Brain Health Center is centered around several programs with a big focus on Alzheimer's and other types of dementia, as um I will mention that we've been very fortunate to receive a $40 million gift um from the Singleton family to help promote that, and we're very grateful for that. And with a big focus on cognitive fitness and healthy aging. Um We also have a great program with dr buxton and neuro muscular and neural diagnostics and fall prevention. You'll you'll hear from from him and then of course you will hear about movement disorders from uh dr Petrosian and Dr Diaz uh we have a unique psycho oncology program led by doctor going on thin um and really not just for patients with brain tumors but for all types of cancer patients. And this is I think a real area of need and help. And then our multiple sclerosis and autoimmune program led by Dr Barbara Kaiser, you'll you'll hear from her. And most recently we've we've been doing more in the realm of of addiction medicine and we've developed a psychedelic assisted therapy program. You're going to hear from Dr keith Hines, rolling on our clinical trials and and our ketamine program. Um A lot of there's a lot of overlap here. Depression and anxiety range through many of these issues. Dr Merrill, our our director of the Pacific Brain Health Center will be talking to you I think after dr Porter who's going to give you a nice talk on an overview on on dementia. And I think again, stressing the interconnectedness of these issues and how I think there's there's sort of the sum is greater than the individual parts and and we really are trying to practice that and and hopefully we'll demonstrate that to you today. So our course focus here, You've all seen the program. You know what's you know what's coming. Um I think we're going to have some some great talks that cover all of these issues and hopefully give you a fresh perspective on them. Um we really are trying this integrative approach with some of the foundational elements of good health which includes diet, exercise, sleep hygiene and cognitive stimulation, social engagement, um mindfulness and meditation. And I think as we go further and further we really do need to try to integrate all of these things into individuals lifestyles and hopefully with a really beneficial effect. So I'm really happy that we've put this program together, proud of all of our amazing faculty and I think it's gonna be a wonderful symposium and with that I'm going to turn it over to dr scott Kaiser who's going to be our moderator and our timekeeper, our time enforcer. Um and and scott is our Director of geriatric cognitive health. So scott thank you and take it away. Thank you dr kelly, thank you for that great overview and introduction. And again, just welcome to everybody. Thank you for joining us on a saturday morning. Uh Wonderful to be here with you. Uh just a little bit of housekeeping to begin with. Uh we want this to be interactive and so far as we want to hear from you, please ask questions. I believe there are two ways to submit questions. Uh there is a panel to the right of your video presentation in an area below where you can submit questions so please uh submit questions and we'll address those following each presentation. Uh also uh something that I'll mention throughout the day. There will be evaluations for you to complete uh you complete the evaluation, that's how you actually get your CMi credit. So I know you know we're all happy to be here on saturday morning but get that cmi Credit uh and so fill out the evaluation form to do that. Um But as dr kelly said, I think we've got a great lineup for today really and so forth. It's just that the breath the fact that we have all of these disciplines working together and that's really what we're about at P. And I. But the fact that there are all these disciplines working together and that there is this holistic whole person view to what we're talking about today and and really lifestyle is so critical when it comes to brain health, this is critical for patients and families and we want this to be a part of all of our practices. So we just think it's wonderful that you've come here today again, please ask questions. My job will be to keep the trains running on time. So I will make sure that there is time following every presentation for a Q. And a period and then we'll have a wrap up at the end of the day. So with that actually I'd like to kind of get us going a little bit ahead of schedule here, just a tad bit to give us a little cushion and I'd like to introduce dr vernon Porter, she is the director of dementia Alzheimer's disease and neurocognitive disorders. My colleague at the pacific Brain Health Center, she is a neurologist uh and uh just the ultimate expert when it comes to the diagnosis and management of Alzheimer's disease and related dementias. It's a real pleasure to call her a colleague and friend and she will be giving us an update on the prevention and treatment of Alzheimer's disease trials, opportunities and challenges and with that I hand it off to you dr Porter, thank you so much scott. It's my pleasure to be here this morning. Thank you for the opportunity to speak on what I think is a very important topic. First, to start with no faculty disclosures for me learning objectives. There are several things I'd like to achieve, its a relatively brief period of time. Today. We will go through quite a bit of information quickly but we do have some very specific learning objectives. The first is we want to develop an understanding of the clinical criteria for diagnosing Alzheimer's disease. The second is an understanding of important biomarkers of Alzheimer's disease in relation to the diagnosis and how that's evolving with time. Third is an understanding of current FDA approved treatments. Fourth is review of some notable clinical research strategies and really novel ways of attacking a d and looking at treatment intervention and what may be sort of the future where we're going to go with that. Fifth is really a discussion of challenges related to Alzheimer's disease. Clinical trials and research design. We all know that unfortunately, it's been a very long time since we've had a new FDA approved drug. Why is that? And let's look at some of the challenges with that. Right First. I just want to review what's the significance of Alzheimer's? Why is there so much energy, attention focused research on this particular topic? Well, the problem is really quite immense and it's exponentially increasing with time. In 2010 we had about 35.6 million people worldwide diagnosed with dementia. But by 2025, about 1.25 billion people or 22% of the world's population may in fact be affected by the dementia. The current cost of dementia care globally is huge. It's about one trillion and by 2030 will double to two trillion. So if we can do anything to postpone or delay the onset of Alzheimer's disease even by five years. It's been estimated to decrease this prevalence by up to 50% in 50 years. So that's quite notable in terms of diagnosing neurodegenerative dementias. Let's just talk about where alzheimer's sits among dementia as one of the ways I like to think about this is dementia is really an umbrella term. It's used to describe a range of symptoms associated with, cognitive impairment. Alzheimer's disease is by far and away. The most common form of dementia. It encompasses about 50 to 75% of dementia and that's one of the reasons that so much attention and focus is placed on Alzheimer's disease. But please bear in mind Alzheimer's six among a series of other dimensions. These are just four other examples. There are many others. So we really do have to think about differential diagnosis of dementia and realize that dementia itself has multiple causes that exist and frankly coexisting can co mingle. So when we think about neurodegenerative conditions we have to realize that neuro degeneration may co occur with other in particular problems such as vascular disease, post infectious states. I think we're becoming more aware of this in the covid era but also nutritional deficiencies are very relevant. Immune parameters are very relevant and then there's structural issues like normal pressure, hydrocephalus, trauma, external injury and so on. So it is something where we have to understand clearly what it is retreating how we got there and what the diagnosis of dementia or Alzheimer's disease means. So when we think about the D. S. M. Five criteria, what is dementia. First of all there's been a shift of the term, we now are using the term major neurocognitive disorder and the criteria by D. S. M. Five to establish a diagnosis of dementia is one or more acquired significant impairments defined by loss of independence in cognitive domains that can include memory, language, executive functioning, recognition or familiarity, visual spatial functioning, self control and management. But there are also other examples of other areas that may be affected mathematics, emotional expression, comprehension, writing and so on. So this again is the more global overview of how we diagnose dementia. Mhm. An important feature of this is cognitive deficits by definition interfere with independence in everyday activities. So at a minimum it requires that people are needing assistance with complex instrumental activities of daily living such as paying bills, managing medications, often driving and other things. How do we determine that? Typically what we're doing is we're approaching either a concerned individual who is approaching us with a subject of concern or knowledgeable informant, a caregiver spouse partner, also a clinician who has known the patient for a long period of time. Oftentimes were referred patients by primary care physicians who noticed significant decline in cognitive functioning. But overall the commonality is a substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or other qualified assessments such as the MSC, the Montreal cognitive assessment, among others who are wanting to objectively document this level of decline. Yeah, In 2011 there was sort of a paradigm shift that occurred and we began to develop new diagnostic criterion guidelines specifically for Alzheimer's. The guidelines were really intended to incorporate new scientific insights and technological advancements in the guidelines to improve current diagnosis, strengthen autopsy reporting of Alzheimer's changes and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy. Now three of the new guidelines focus on three distinct stages of alzheimer's there's dementia frank dementia due to Alzheimer's by D. S. M. Five criteria for example. But there's also mild cognitive impairment due to Alzheimer's and even pre clinical or pre symptomatic Alzheimer's the fourth is really focusing more on documenting reported alzheimer's related changes observed during autopsy. So with this N. I. A criteria this has been a shift from our more traditional N. I. N C. D. S. A D. R. D. A criteria which we used for decades really. And it's looking now at biomarkers as being a fundamental piece of having to define what is pre clinical Alzheimer's what is M. C. I. Or what is A. D. With dementia you'll notice that for example with preclinical phases it's normal cognition supported by the presence of biomarkers that actually support the presence of Alzheimer's pathology within the patient. M. C. I. Same thing, mild cognitive impairment. So not yet rising to the criteria of a dementia but with biomarker support. And finally dementia with biomarkers support. So what are these biomarkers? There are several and they're continuing to develop over time. Examples would be a CSF analysis with a beta and tau or pet amyloid imaging. We'll talk a little bit later about this in more depth and detail but also we're relying more heavily on structural imaging such as hippocampal volumetric analysis or cortical thickness. Also we continue to have access to other things like F. D. G. Pet scanning flora de oxy glucose pet as a means of assassin for different areas of hyper metabolism in the brain that would support on a biomarker level the presence of Alzheimer's changes. So as we begin to understand the relevance of a beta accumulation as a marker of this particular disease, were also understanding the utility of other future biomarkers such as tau proteins and how the relative ratios of these may help to inform the diagnosis with time. So if we think about Alzheimer's disease progression and how these different biomarkers work and how we actually use them in clinical medicine. What we're realizing is that if we can capture the disease not in the face of dementia where a person is already experiencing significant functional and cognitive decline but in more presymptomatic phases or even early mild cognitive impairment, then that would be the greatest opportunity to theoretically than the curve as it were or change the trajectory of the patient hopefully over time as we get disease modifying therapies that that diagnosis early becomes even more relevant. So you can see that even in presymptomatic phases of disease you have a rise of CSF a bit of 42 also paralleled paralleled by the amyloid imaging that occurs very early and presymptomatic phases then of course by the time you're an early emcee the F. D. G. Pet markers and other markers are becoming more relevant. But you can see that if we wait until we actually detect cognitive or functional decline in the patient, we're fairly well into the stages of dementia and by that point, the trouble is that the ability to intervene and actually change the trajectory, the patient becomes far less. So we want to be focused more on the earlier phases, detecting things early intervening quickly and aggressively to try to change the overall trajectory. We're also beginning to realize the utility of genetics. This is a rapidly expanding area for diagnosis. Uh we traditionally have thought of Alzheimer's disease as being in two different phases, if you will, the early onset being under the age of 65, later being over the age of 65. Traditionally, the early onset forms of Alzheimer's have been more familiarly related. They tend to oftentimes associated with auto, simple dominant genes. These are relatively large effect, or causative genes as opposed to late onset over the age of 65 which tends to rely more on sporadic Alzheimer's disease, where you have things like the epo. E genotype, which is a genetic risk factor gene, but not necessarily a determinant gene. So these are risk factor genes overall, they're smaller effects but nonetheless relevant in a comprehensive diagnosis. We're also beginning to rely more heavily and quantitative brain MRI imaging. So patients go into the brain scanner, we're now generating Euro reader reports, which actually generate a patient specific report that allows us to see a structural analysis of relative areas of atrophy or structural brain change. So, for example, with the neuro breeder volumetric analysis, you're actually given a readout and it will show you based on a bell shaped curve based on age and gender matched controls, where the patient falls on that bell shaped curve, With the normal range being generally between about the 25th and the 75th%ile and what it will show you is where your patient falls. And if there are areas that are falling less than lower than the 25th%ile for age and gender matched controls and then it allows a determination of whether or not there's certain patterns that are beginning to form, like for example, temporal parietal atrophy in a patient who may be developing very early Alzheimer's changes. So this becomes yet another modality of being able to assess brain change early quantitatively and structurally to assess for the possible disease development. Mhm. So this has really truly become a biomarker revolution. And the idea is that with time were beginning to develop more and more tools and biomarker strategies for detecting disease early. So if we look back just historically, in the late 19 nineties, we began to develop some of the Abeyta 42 Tau and phosphor related to technologies primarily through CSF analysis by the mid two thousands were beginning to use amyloid pet Imogene By the mid 2000 tens were starting to use some pet tau imaging which is still in development but is beginning to be used even in a clinical setting. And hopefully very soon we're going to start to see the emergence of clinical tools using blood based biomarkers for detection of disease. One very interesting study that really looked at what is the utility in clinical practice of using these sort of bio market tools was the ideas study. This was an imaging dementia evidence based study for Amyloid scanning and the results of this particular study were published in Jama in 2019. The ideas study essentially tested of amyloid pet imaging affected the management or the outcome of dementia care. What was found is that physicians change their treatment for a little over 60% of people based on the scan data, Which was interestingly well above the pre specified estimate of what they projected to be about 30%. So in participants to join the study with, for example, mild cognitive impairment and in whom brain scans revealed the presence of significant amyloid deposits. Clinicians were twice as likely to prescribe amyloid drugs following pet imaging. So this was about 40% priority Imogene versus about 82% following the imaging. So, what we're seeing is a shift in the way patients are treated in those with dimension significant amyloid build up on pet scans prescriptions for symptomatic drugs such as Donepezil, memantine, for example, Rose from 63% to 91% after the study. But here's the tricky part for CMS to cover the cost of an amyloid pet. It must be demonstrated to the results of a scan have an effect on patient outcomes, not just patient care process. And the trouble is in the absence of an actual disease modifying therapy, not a symptomatic therapy like Donepezil and memantine that slow the rate of progression but don't necessarily stop or fix or correct the disease. In the absence of true disease modifying therapy, that was a distinct challenge. It also led to a new ideas uh imaging study analysis that started in December of 2020 and this will go through 2020 for the goal is to enroll about 7000 patients. And the hope was also to increase the diversity of the patient population that was being considered and to really expand and be more racially and ethnically sensitive in terms of understanding the impact of this particular process on other patient populations, not just simply white caucasians or the more traditional areas that were studied. So this was really designed to be far more abroad, far more applicable for more comprehensive. So the idea was to evaluate the effects of having information from the brain amyloid pet scan and clinical care and health outcomes in a more diverse group of patients with dementia or mild cognitive impairment. All participants were receiving the amyloid pet scan and the results were shared both with the participant and their doctor participants returned at 30 days and 90 days after the pet scan. To meet with a doctor to discuss their care and the researchers are analyzing whether the participants. Medicare claims before and after scans are actually causing them to receive and result to receive the scans and then back to result in the care that's actually provided. So this will be an interesting study to see the impact. So in essence, the hope eventually is the use of multiple biomarkers to more accurately diagnosed and assessed disease and again allow earlier intervention. So whether you're dealing with a 75 year old with am nested multiple domain dementia or a 91 year old with severe dementia, we can be much more specific, much more solid in our diagnosis, understanding the relative contributions of even mixed Alzheimer's pathology such as Alzheimer's plus vascular but understanding it with biomarkers as being the basis of that disease and not simply a clinical assessment of functionality and cognitive decline. Let's talk for a few minutes about FDA approved drugs for Alzheimer's. These drugs have been unfortunately very ineffective in many ways because these are symptomatic drugs at best. The majority of our drugs for for really now the better part of several decades have really been symptomatic in slowing the rate of progression of disease. But they really haven't significantly affected the disease in a positive way. That's been something where you've seen true improvement in cognitive functioning in patients and for quite some time. These were the mainstay of our therapeutic arsenal for Alzheimer's disease. Recently In March of 2015 we begin to see some new research develop and Biogen announced positive results from a phase one clinical trial of attica Panama been aging patients. However, in March of 2019 an independent data monitoring committee determined that there was insufficient evidence to support the advocacy of Vatican a mob in treating the disease. So what happened is following the discontinuation of two large clinical trials emerge and engage Additional data from these studies became available. It was resulting in a larger data set which included a little over 3000 patients, slightly over 2000 of whom had had the opportunity to complete a full 18 months of treatment under the protocol. What they did is a larger, more extensive analysis of the data set and it showed a different outcome than predicted by the futility analysis and specifically what was found is that that in patients treated with high dose at a canter mob, they showed a significant reduction in clinical decline from a baseline. This is based on clinical dementia rating scale scores or C. D. R. S. B scores at 78 weeks. That was basically a reduction of about 22% versus placebo. So that was a measure that essentially looked at cognitive and functional impairment simultaneously. And that was essentially then beyond the original prediction from the futility analysis. So this sounds great. What's the problem. Well the problem really became that this was approved in sort of controversial move by the FDA. And I'm sure a lot of you have read about this even in the papers about just how controversial this particular approval has been. One of the concerns has been, Is this really applications? We're doing kind of almost data mining has been one of the arguments of a small dataset to look for particular patients who achieved some efficacy and benefit on the primary outcome. But is this really reliable data? And furthermore, we've got a problem in that we've got some very significant uh effects. Side effects from being on this drug. One of the most notable is amyloid related imaging abnormalities or aria. These are monitored by MRI imaging. And the most common side effects are aria e or a demon of the brain. That's seen. About. 35% of patients treated with this drug, versus 3% of patients treated with placebo. And the symptoms of that can include headaches, changes in mente shin confusion, vomiting, nausea, Tremor gait disturbance is not insignificant things and unfortunately much different than the sort of things that we have been accustomed to with symptomatic drugs, headaches become a problem. And then there's aria h, which is micro hemorrhaging or bleeding. That was seen in about 19% of patients treated versus 7% in controls. This again can result in headaches. There's even been unilateral weakness, vomiting, seizures really fairly significant problems. So the problem has become are these side effects? Tolerable. Is this justifiable in addition to other things, including imbalanced diarrhea, confusion, altered mental status. So this has unfortunately become a very controversial drug. So controversial that many health systems have actually said we're not going to use this. So there have been different groups that have come out providence right now is actually one of those groups that's holding on the use of this particular drug to try to get more data and see sort of post approval analysis. Is this really efficacious? Will this be valuable? Does this benefit our patients? And frankly, is it cost effective? Is this something that would be reasonable? This is an infusion all agent. This is not an oral medication. So just the structure of how we deliver it is very different. So maybe what we need to do is take a big step back because you know, when we look at our success rate for looking at these amyloid imaging or these amyloid drugs, rather, we have about a 99.6% failure rate over the course of a decade, we know that Alzheimer's disease features other things that features neuro February tangles that are composed of towel perhaps what we need to do is look at other potential targets for intervention, abnormal tau is actually present in a variety of conditions. Not just Alzheimer's, but it may be that looking at some of these other targets would be more efficacious because we've spent so much time focusing on amyloid. So this really leads us to prevention trials. There's primary prevention where we're looking at really delaying the onset of Alzheimer's their secondary with delay of onset of cognitive impairment and in tertiary, where unfortunately a lot of our drugs and treatments have been focused on delaying onset or progression of dementia. So we want to look at modifiable factors, We want to look at those things that we can really fix and change and modify early to potentially even decrease the risk of Alzheimer's. So if we looked at factors influencing cognitive decline across the lifespan, about a third of cases of Alzheimer's worldwide are attributable to seven modifiable factors including midlife hypertension, diabetes, obesity, depression, smoking and importantly physical in activity. Have you? So what we found is that the national academies, for example, came out in 2017 saying there's a lot of promising evidence that three basic things may really help in mitigating risk of patients eventually representing with dementia. blood pressure control, increased physical activity and memory training and dr Merrill will be talking a lot more in depth in detail about these in the next presentation. But these become interesting targets. So here at pacific brain health, one of the trials that we've been doing is called the prevention trial. This is a precision medicine approach to the disease And essentially what we're doing is we're taking 60 participants with cognitive impairment over the age of 50 and we're putting them through a precision medicine recommendation profile. We're looking at neurocognitive biomarkers were running clinical labs, neuro imaging. We're looking at genetics, microbiome and we're trying to intervene on diet, cognitive stimulation, exercise. We're trying to augment this through supportive brain health coaching and the study goal is to improve cognitive functioning after 12 months. The end game, the end goal is trying to improve using precision medicine prescriptions for the prevention of Alzheimer's disease. Again, trying to bend and change the trajectory. Another very interesting technique that's being used that's being studied here at our center at ST John's Cancer Institute is a study based on some pre clinical data demonstrating that intravenous administration of stem cells, mesenchymal stem cells resulted in a delay of accumulation of plaque formation in patients with Alzheimer's and also a reduction in plaque in animal models of alzheimer's. So the hope that studied conclusion is that will enhance our understanding first, whether this is efficacious versus placebo in patients with alzheimer's related dementia and whether there is actual evidence through neurologic functional and psychiatric endpoints of efficacy of this particular technique. What are some of the challenges to Alzheimer's disease. Clinical trial design. Well, as we've touched on a bit, there's a lot of heterogeneity of alzheimer's, there's concomitant vascular disease. Sometimes there are other infectious or inflammatory processes. Alzheimer's is oftentimes not a pure entity and we have to think about that in terms of our particular clinical trial design, Precision medicine is definitely a novel and very individualist way forward rather than simply taking a large, very heterogeneous group of people placing them on one particular intervention versus a group of individuals on placebo. Maybe we need to look at individuals as an end of one trying to intervene. Using precision medicine. We know we've had multiple failed trials targeting amyloid and already symptomatic patients. Maybe we need to take a different tactic and amyloid based interventions may be better actually in the preclinical phases of the disease. Perhaps it's too late into the disease trajectory. We want to look at risk factor reduction, looking at blood pressure, for example, or various other lifestyle factors that may reduce dementia emergence and prevention? And finally, we want to look at newer therapeutic targets such as tao that may actually prove more useful in treating symptomatic patients. So with that I'm going to stop. I know that was a bit of a whirlwind tour, but we'll go ahead and open it up for questions. Thank you so much. Great, thank you. Dr Porter. Yes. Uh looking at some questions that have come in here, um, the first question, so you were speaking a little bit about as you can um ab and the amyloid hypothesis and and somebody's asked, do you think that the failure of anti amyloid drugs means that the amyloid hypothesis is wrong. That's an excellent question. It may not be that the amyloid hypothesis is wrong. And maybe that amyloid is simply too far down the pathway, If you will of disease pathogenesis. Think of it this way, if your house were burning and you were focused on the bushes outside the house in terms of putting out the fire, but you didn't know what started the fire and you didn't know what was happening in the house and the house is burning down. It becomes a moot point. It's too far down the trajectory of what's happening. It may be simply that we're looking at an after effect of the actual disease itself rather than something that's truly the genesis of the disease. So we may need to be looking farther back at the genesis to understand when that happens and what that means? So, that would be a real argument for early detection uh, prevention. Because, I mean, the question that always comes to my mind is that idea. I mean, why bother? What? There are no drugs that that effectively um modify the disease course? Why all this effort? And you know, what are you accomplishing by uh screening and diagnosing dementia? Exactly. That's an excellent question. So that really does put even more emphasis on prevention in terms of really trying to understand again, what's the genesis, when does this start? What are the triggering factors? Is it genetic predisposition with compounded environmental factors? What are those environmental factors? How do we intervene? How to prevent that? That's what we need to understand better. And it may just simply be that we focus too far down the pipe too far into disease when sort of the heart of the horse is out of the barn in a sense and we need to back it up and really understand what can we do in terms of here we are with our next talk lifestyle strategies for prevention of dementia. Right right so we had a couple of things. Another question that came in here. Um you know you talked about a constellation of biomarkers, do you think for particularly for people who have mild cognitive impairment? M. C. I. What is the most reliable biomarker? Um You know if amyloid is maybe too far upstream for people of M. C. I. What is the most reliable biomarker to predict? Uh conversion to dementia? I think right now are probably our most reliable biomarkers are things like a beta 42 but also tao phosphor related towel. So I think we've got to focus a little bit more on tau and its significance in this particular setting. But over time we may understand that other things. For example, volume entry, looking at MRI imaging and volume entry is really much more important than we first realized. And it may in fact be a constellation like we talked about a different biomarkers that we look at to try to really say yes this is a person with mild cognitive changes or even pre symptomatic people who have enough biomarkers that they have a compelling evidence that they have compelling evidence of disease pathology early on. Or hopefully if we do get these disease modifying therapies in the next few years were able to utilize them very early and really truly change the trajectory. But I think these biomarkers are going to continue to evolve. Uh It's true amyloid may not be our final biomarker but right now it's probably one of our better ones combined with tao and I think the future is going to probably emerge through prevention and through precision medicine and defining really what those biomarkers are through precision medicine and seeing how people respond and what those biomarkers are. The change with these particular interventions like lifestyle. Excellent, excellent. And uh you mentioned some clinical trials going on at our center. Uh One audience member asked how do I enroll a patient in a trial? Uh do they need to come see you in the clinic first? Is it possible to refer individuals who'd like to be studied participants? Can you speak a little question. It is possible to refer patients. There are really several different portals of entry if you will. One is you're certainly welcome to refer to our physicians here for a clinical assessment and evaluation and determination their candidacy but also patients can be referred indirectly to the research team. We have a full research team at pacific brain health and we have an excellent research director Dr jennifer bremen. So that is another portal of entry. It does not have to be through the clinical route. Okay. And I know we're pushing up on time here but we started years a little early in. These questions coming in are just awesome. So I want to make sure I hit them all uh or a couple more of them. We can hit them all. But um any data on specific uh agents or specific classes of a blood pressure drugs, antihypertensive agents that seem to be better associated with slowing the progression of M. C. I. To dementia or is it just lowering blood pressure in general? That's an excellent question. And I have to say that I don't think that as a neurologist I probably have as much knowledge based on that as I as I could. So but I will I will say that I think in my opinion it's the lowering of the blood pressure. That's really the most critical. I know that there is data looking at various agents ace inhibitors and so on. Even beta blockers and their potential utility in this setting. But I think in my view it's really keeping people normal intensive is the most important factor overall rather than the specific agent that's utilized. Excellent. Excellent. And so apologies to those whose questions we did not get to. Hopefully we'll get to those throughout the day with other keep the great questions coming. These are awesome. Will file these away uh to address these. They're just great. Um but I think it's time for us to keep moving and we will move on. Thank you so much. Dr porter.
