PD Edu: Parkinson's Isn't What We Think— and a Solution In Sight

all right well let's go ahead and get started welcome everyone my name is Chris Gaffney I'm the executive director of Parkinson's support and wellness uh we are at organization based in uh the Greater Cincinnati greater Dayton Metroplex we provide uh services in the area of Education exercise and support groups for persons with Parkinson's in about a 32 County area and South West Ohio Southeast Indiana and Northern Kentucky one of our primary missions is education and throughout the year we have an educational seminar uh once a month we call them pdedus uh and we're kicking off this year with a very special presentation uh actually we have two members of our board uh Dr Alberto esbe is our medical director uh Maureen Gartner is our medical liaison and uh she will be introducing Dr espay in just a moment uh we've been going through some of the housekeeping but uh just so that you know uh everyone their your camera is is off and uh you are muted uh that's because we now have nearly 200 folks participating in this event this morning if you have any questions uh during the presentation uh and during our question and answer uh uh period later you can place your question in the Q a uh that uh you'll see an icon uh that has uh the opportunity to type out your question and we will recognize you at that time uh I want to let everybody know that we are recording this session and uh we will edit out these first few minutes so with the uh stuff that you don't want to hear and see uh but uh that uh recording will be available uh on our website Parkinson's support and wellness's website which is parkinsoncincinnati.org no ass after Parkinson so parkinsoncincinnati.org and uh I would invite you to visit our website and take a look at the various programs and services that we provide with that I'll hand it off to Maureen Gartner most of you probably know her but Maureen you'll get us started thank you Chris so I have the pleasure of introducing Dr espay this morning he and I have worked together for 18 years now he's currently the director and endowed chair of the James and Joan Gardener Center for Parkinson's Disease and movement disorders at the University of Cincinnati he completed medical school in Venezuela his internship at St Vincent Hospital in Indianapolis and his residency in neurology at the Indiana University School of Medicine from there he did a two-year Fellowship in Toronto with Dr Tony Lang and if any of you know about Dr Lang he's one of the most highly respected people in the in the movement disorder area I didn't best doctors in America six years in a row he has more Publications and research than we have time for I could never ever talk about them but what he does the other thing he does have is a real passion for research and it's not just research for science it's research to help people deal better with movement disorders and that's what he his passion is and he is all about it and does it well so Dr esbe thank you very much Marine I appreciate that introduction very much it's amazing to believe that we've we've been to even appreciate we've been together for as long as 18 years here in Cincinnati uh it is uh been a very important uh Journey for all of us and as you'll uh know very well you know very well and help our people hearing us well also uh it is clearly one where we have uh changed quite a bit in terms of that thing we call Parkinson's disease we I think have a very uh organized approach to uh saying to someone based on our expertise what you have is called Parkinson's disease but that quaint approach to the diagnosis Queen for the 19th century most of the 20th should not really apply to the 21st it cannot be that I or anyone in my position uh recognize uh all uh that needs to be recognized to call someone here's the disease you have sorry I cannot prove it to you but I'm an expert so part of all of what you're here in a moment and what we'll discuss thereafter is from the recognition that we Remain the last Bastion of neural of medicine Neurology in particular Neurology of diseases of brain aging in which we continue to Define diseases based on how they look to us we observe we ask questions we take a history we move people we do a pull tests we ask him to do finger tapping and then we say this is what this is based on our experience watching people and as you learn based on what it appears is on the proverbial ashes of the fire the so-called autopsy right so that's sort of how we came to Define this concept called Parkinson's disease so uh what I like to do and I think uh what I hope you'll find of interest is to go over uh my recently released Ted Talk which is going to go over the foundations of this and how we came to think about Parkinson's disease you get a bit of a taste of what's to come and these are going to be 15 minutes uh so it'll not be too long that's all that's considered a lecture for today and then we're gonna end at that point and open uh the session for a conversation about the meaning of it uh themes that are related but not touched upon at the Ted Talk and then what else is it that we are doing and propose to do for understanding the approach to Parkinson's as a different type of precision medicine and rescue medicine approaches which haven't been really um so far deployed in our field as they have in other fields of medicine so with that I'm going to ask Julie and Chris to start then the tedx presentation and as soon as that finishes I'll be here and I hope that you'll all join me for a conversation on what that means and what we're doing from there enjoy [Music] [Applause] everyone loves a story with the villain it holds our attention and it galvanizes us it gains a common enemy in the field of neural degenerative diseases which include Parkinson's Alzheimer's and others the victim is the brain and the villain is the abnormal proteins we have a name for it we call it proteinopathies diseases of the proteins and we have in fact accrual variety of strategies to get rid of this criminal to take it out of the brain of people that are suffering from neurodegenerative diseases and despite how well we've done this we haven't really been able to get much out of that effort so we've come out empty-handed and it is time to rethink The Narrative about the extent to which brain aging is accelerated by this abnormal proteins it may be that it is not about how much of these villains we have these abnormal proteins but rather how feel the normal proteins we have left before we delve into the research that is helping us Define what might be the most promising of all interventions let me back up a bit I'm a neurologist I study diseases of brain agent how do I diagnose conditions such as Parkinson's or Alzheimer's I do it by asking questions and observing patients I looked at individuals in terms of how they move how they talk how they behave for instance if someone is slow has a Tremor in one hand my Shuffle of foot when walking I would say you have Parkinson's disease I can't prove it until I have a biopsy or an autopsy but trust me I am an expert and I'm applying criteria that my expert forebears developed a while ago so how do I really get away with this how do we neurologists get away with just disclosing a diagnosis in a manner that requires Trust well it All Began in the early 1900s when our forebears had only one major technology at their disposal a microscope and what they did is that they used it on brain tissue of people who had died of impairment progressively in terms of memory well we perhaps now today call most often Alzheimer's or people who had Progressive slowness and other abnormalities seeing what we today call Parkinson's and what they did is that they apply the microscopic techniques as primitive as they may have been and when you are doing that as you can imagine positioning yourselves in their eyes they would see on the brain things that look like this this abnormal clums once of protein and they looked up normal and they look like they shouldn't be there so the part of the narrative that began at that point was in assuming that what they had encountered was the cause of the problem that somehow as the brain had these kinds of proteins there that it was the evidence that in fact gave rise to the abnormalities to the degenerations that ultimately created the problems for which the patients died but are they really the villains and let me explain how they in fact came to be normal proteins are in fact looking rather like this as you can see they are so flexible and light they can follow the table but as you can see what they ultimately are is so flexible and soluble that means dissolvable that they can perform functions is dissolved in water the solubility of it allows us to quantify in the liquid that surrounds the brain and that we can measure that through a spinal tap these proteins are all over the brain they are in fact so critical that the genes that code for them have been preserved since prehistoric genomes and that explains why they are all over the brain they are critical for the brain structure and ultimately to keep the neurons communicating one with another but what happens when we encounter in the brain something that shouldn't be there something that might be a virus for instance well these proteins then have something that will be the source for what we call a protein transformation from soluble they climbed into these very compact words and very similar to what you saw earlier and ultimately more than accumulate as you can see here and what happens therefore is that the normal proteins are becoming less and less common less and less in concentration but the source of the problem becomes invisible and what we end up with is a lot of this ultimately as you can imagine the normal proteins are now absolutely gone the uh aspect of this story that is important to realize is at the end very simple and that is that proteins are only able to function when they are normal when they are in this soluble functional state that the minute they clamped into something that they aren't uh normally in they no longer function and the process is universal across all neurodegenerative diseases it really is one in which when we ultimately see the transformation of these proteins into the clumps those proteins are ultimately so compact so tight that they are almost impossible to be toxic this is not unlike milk is ultimately if we leave it outside of the refrigerator is going to go bad it's undergoing soluble to insoluble phase transformation and that is ultimately what will make the milk curd now you can imagine trying to dissolve the curd but you cannot imagine bringing that curd back to normal milk you will never drink it the Paradox that has been greatest in our field is that we have in remarkably successful in eliminating this protein from the brain we've had the best part of two decades testing anti-protein treatments the amyloid the synuclein and more recently another protein called Tau and the Tau proteins and if you think of the feel of amyloids for instance there have been over 40 trials testing approximately 20 interventions that clear up the amyloid from the brain and 75 percent of these trials have shown that the reduction in this so if you just imagine that this is kind of coming down the brain is getting clean it's been so successful that you would think that if they are the villains somehow then our brains should return to normal and people should get back to state of normalcy not only has that now happened but in 40 of the trials those who were allocated to the experimental arm had the greatest reduction of amyloid worsened and in many cases their brains shrank further this is a problem we should be able to look at the data and falsify a hypothesis when the hypothesis fails to be confirmed in clinical trials so at this point we wish to resolve the Paradox in the literature and what we've done is we studied 600 people who already had plenty of amulet in their brains we can measure the amular in the brains by using something called a PET scan and ask the question of what is the difference between people who have these abnormal plums in their brains and remain normal versus people who have it but are already demented and we found that the difference is how much of this they're still in the brain so we actually can have plenty of them and we've actually now observe that it doesn't matter how much of this there is in the brain if the levels of the normal protein are high the individual will be normal so the the story and the narrative about where we are in terms of ours development holds on to the narrative that these proteins are toxic and it is not alike thinking that a forest ravished by a storm somehow would be restored back to health by simply cleaning up the broken up trees right reforestation will be needed there but just taking all the debris want so the story is as follows we now have a an enemy that we think of as necessary and sufficient for the development of diseases and in fact it isn't if it were all of us having these inner brains would have diseases of the brain and most of us don't as we've seen furthermore if these were the toxic elements in the brain and we were able to remove him as we've done then those who had a removal would be back to health and that is also not the case but there is a better way ahead one that actually thinks about the elements of the story so rather than insisting that these proteins Aggregate and this is the accumulation of the chunks of abnormal protein are actually going to create the difficulties in the brain we now have an opportunity and perhaps in our toolbox of future therapies to increase the levels in the brain such that it doesn't matter how much of this we may already have if we increase the levels of the proteins in the brain we can in fact get to levels where the brain can operate relatively normal now the way we're doing this is based on a couple of important developments the first is that the peptides are coming into a brain that's obviously fighting against something we don't know whether this part remains invisible in research we're saying if you have Parkinson's trust means adcs you have Alzheimer's trust me it's a disease it isn't it is a syndrome right so this is going to be the source of precision medicine but if we are able to bring the brain the levels of these normal proteins to elevate the levels to normal then it won't matter if we don't yet know what that is now the proteins would have a transformation that prevents them from turning into itself right so that hinge that makes that Clump appear would be change but the rest of the protein remains normal we have now demonstrated that above a certain threshold and the threshold is now well defined patients can be rescued so Precision medicine will require us to get to this and this is an individualized approach but rescue medicine would allow us to in fact use the opportunity to bring back what the brain is losing in the process of neural degeneration I'm working with a number of scientists very interested in moving us into this we're no longer testing the effects of removing the chunks of us or beginning in fact to test how to bring this to people affected with Parkinson's Alzheimer's and other conditions and as a neurologist I can tell you I have never been more hopeful thank you [Applause] building your business online all right Dr espay uh I I think your last word was maybe the most exciting hopeful yeah that's what's so it's what so many of us uh who are dealing with these diseases uh need so desperately that was exciting uh please uh please carry on and I'll remind everyone I can place your uh questions in the Q a and we'll be monitoring for those questions as they come up thank you very much Chris uh I appreciate the opportunity again uh what I will propose is uh for maybe Marine uh or Juliet to feel the questions as they come and uh and then we'll of course uh tackle them as they come um so I see one already what's the name of the peptide that is the villain uh well uh the peptide is the another name for a protein a collection of amino acids the most important peptide or protein in Parkinson's is called Alpha synuclein and Alpha synuclein is very important is all over the brain precisely because it is critical for a for the for a brain to react against a variety of exposures uh we age them more we're exposed to the more opportunities there may be for diseases of the brain in synuclein Alpha synuclein in particular can be very important now when it fights against something it transforms from its normal soluble State that's dissolved in water that's why it's called soluble into an insoluble State called the Lewy bodies the Lewy bodies we have held as the villain in the story and that's why in this dead talk I'm trying to make the case it isn't the villain it is not the cause of the problem is the consequence of the problem so when you chase a tail you get nothing that's why we have two trials already published for uh uh anti-synuclein antibodies and they are negative because that approach can't work it's not like oh if we have more patience if we do a larger study if we get those to be increased if we change the experimental partner none of that will will matter because the problem is not that that we're we're not doing enough of what we're doing is that we are doing something that isn't backed up by the evidence that we now have and so while the store that we created about these peptides is protein's been toxic had a lot of logic when it was first conceived ideas in science are false unto proven otherwise and we have not been able to prove them otherwise it doesn't matter how much of the Lewy bodies our brains have as I alluded to in the presentation it doesn't correlate with shrinking of the brain it doesn't correlate with the kinds of symptoms people have and therefore the Louis bodies cannot be the villains in the story they are indeed the victim so I hope that that concept came through that's the most important concept of this presentation because all of you are going to hear about new Trials of anti-synuclein therapies and we cannot continue doing them now when I say we I mean all of us but it turns out that we when I say neurologists or people like me we we have a conflict of interest it's an unfortunate a fortunate one to do to admit because a conflict of interest is that these trials are very very lucrative to institutions and so that has been one this incentive to move away from these trials because they bring income to institutions like ours fortunately the University of Cincinnati is not pushing us into taking this study simply because they are lucrative they recognize that we also assess the value of them to our patients and because we know there is no value to our patients and in fact much potential harm we don't do them so I hope that the answer that question uh appropriately Marine do you want me to go through it did you have been looking into which uh questions I am delighted that there is a lot of questions already pouring in this is exactly what I wanted um so there's a couple questions Alberto about how do we increase the good proteins or the peptides yes so uh that is uh going to require a what's called an analog an analog or a peptide analog which is essentially replicating the same string of amino acids that make this particular protein cone Alpha synuclein is a string of 140 amino acids put together but changing a part of the uh of the of the protein exactly the point in which it's uh acting as a hinge so you saw uh this in the presentation I actually brought another uh example of this you saw this and what happens is that there is a hinge around which then the protein begins to turn into what you then end up seeing as this in the presentation right that is no longer functioning that's not a functioning protein our narrative this is the villain this is replicating and spreading propagating no this is just simply becoming the result of the normal protein so how do we increase it we increase it by by uh creating an analog of this this is the exact same thing as our brain makes but it's only modified in a part of it that acts as the in the hinge around which then the folding occurs that transformation occurs we're working on this now uh we've been working on this for the last year and a half or so uh we are expecting an acceleration of this because uh the Michael defox is reviewing a a a a research program on this and also because I have colleagues at the Carolina Institute that are far smarter than I am and have very important resources in the pre-clinical state this is the this is trying to determine really how much the proteins added on to a model can in fact rescue the model how it makes sure that it's not toxic and then we have to Define such things as what's the best route of administration how much it gets to the brain how much the it stays in the brain how long this stays functional right because that defines how often replacement therapists will have to occur and so forth so so we are probably thinking that we're about two to I hope not three three I I think it's going to be under three years before we can make the shift to humans with the interest in these ideas it is possible that there will be more uh interest and that perhaps uh more funding will come from companies or foundations to help this be accelerated but we're very excited because it only makes sense uh and uh investigators in China has have actually learned of our studies in humans and decided to do a model that applies mostly to alzheimer's but it's exactly the same principle they they gave two models of Alzheimer's that have clumps instead of Louis bodies they're called Amino plaques and they gave him more of the stuff they created the one that's not modified so of course you have to then replenish more frequently because in a in a brain that is under stress then this quickly becomes this and you don't want that so they have already replicated a rescue the so the principle is is actually relatively simple I think of it as Occam's racer is really the easiest uh and most straightforward explanation uh for what happens to the proteins and what we can do for them so so not too long from now we're gonna have more more and more data but I'm I'm expecting that within a three year interval we'll be able to begin testing this in a phase one study in humans uh with Parkinson's disease there's a couple questions is this related at all to dopamine and levodopa production uh so uh yes to the extent indirectly the proteins that we have aren't directly themselves making the neurotransmitters but these are in many ways uh uh the soil on which the neurons that grow and they are the ones that create the the neurotransmitters uh uh is where they are so so this is sort of a way to keep those neurons healthy if you have not much of this uh the lower the levels the the the seeker of the brain is then the then the neurons cannot generate the dopamine that we know is deficient in Parkinson's so what we are doing with therapies currently and we've been doing it for 50 years is replenishing the levels of the dopamine used in levodopa because that's what the brain makes uh and what the brain isn't making enough of therefore the dopamine production is low but we need to go upstream and one level Upstream is precisely giving the brain what is missing which is the proteins that are transformed being transformed into Lewy bodies of course the ultimate approach as I mentioned is is to be able to get to a point where we address the cause of the problem these proteins are becoming transforming to Lewy bodies because something is triggered in the transformation we call it a a something is catalyzing this transformation it's a nucleation process and so I I talked about milk for instance that's one example of that transformation from from normal milk to curd um it happens in in nature in general from from water to ice from water glucose this is a phase transformation so that is very important to to Target because it doesn't require to know what is causing it now what's causing that though that's the source of precision medicine so we have rescue medicine which is the addition of these proteins into the brain that are being depleted that we can then rescue because we can bring those levels above the compensation threshold and then that is a universal approach that can apply to most people if not all Precision medicine is an individualized approach Precision medicine is to answer the question why James Parkinson's appeared and how is James Parkinson's different to Mary's and how is Mary is different from George and et cetera et cetera right that is what we're doing in the biomarker program uh of Aging called the ccbp in Cincinnati and that's a that's the highest level of medicine that's what happens in oncology where somebody is being told to have a specific cancer let's say breast cancer or prostate cancer or liver cancer and the the doctor immediately says but we don't know what that means we have to do this test this test this other thing and then and only then we know what to treat because then and only then we know what disease you actually have we skip all of that in our approach to Parkinson's and Alzheimer's and other diseases of brain aging we simply say this is your disease because I say so because I'm an expert and uh so that's the highest level so so we have symptomatic therapies which is what we've been doing for 50 years trying to replenish the the neurotransmitters that are not being produced enough we can go to rescue therapy which is what the Ted Talk was all about to trying to add the proteins that are being common depleted regardless of what the cause is and that's going to be a lightly uh powerful Universal approach to this condition and then we have Precision medicine at the Pinnacle which is actually really just very much finding the needles in a haystack trying to find out why each of our patients is unique we've said no two patients are alike but we've not done the research acting as if we minute now we are but that's of course a much longer term program although one that we have a strategy to to be able to begin deploying begin harnessing the successes of it before the decade is over so with that Precision medicine do you foresee a new patient getting a spinal tap to determine levels of normal and villain proteins for now I do on the uh however there are ongoing efforts to being able to measure the levels of the protein in blood and it's a very tricky situation because uh it's it's hard to find what about the blood levels of anything represent the brain levels of anything but it's something called exosomes they're very they're kind of like nanoparticles that come from the brain and are able to be measured in blood with very sophisticated newer techniques so in the future we may not need to do a spinal tap to measure these levels for now we do and we're in fact in one important study uh that is been undertaken in individuals who have synuclein duplication a genetic mutation in this in nuclein gene uh where we're measuring those levels in the spinal fluid because we're determining in those individuals what is the threshold for compensation because they will likely be the first beneficiaries of a synuclein replacement strategy foreign it was a good question here can you help us understand the relative mass of the good proteins versus the clumped proteins against the mass inside the skull is it a significant percentage or a tiny portion I like that question because that question is is so interesting so I'm gonna I'm gonna say that uh every story has has two sides right now in Parkinson's we've used only one side of the story which is which is the side of the of the clump proteins right they they they go up and and when you don't uh particularly uh think of where that comes from and just look at it of course is bad now if something goes up eventually you would imagine as it probably is the specific tone of this question that the brain is going to run out of a space going to have too much of it but in fact the brain is not having more the neurodegenerate degeneration is actually a problem or loss in Parkinson's the loss is not that clear on Imaging but there is a little change in the brain volume going down so how comes that this stuff goes up goes up goes up and the brain is going down that makes no sense well it's not that this goes up is that the measurable fraction of the protein which actually can only in its normal State can only be measured in spinal fluid uh once it gets accrued into a clump uh it just it just we just measure it now when it wasn't there the levels were zero when now we can measure it and now so far in Parkinson's we cannot use a pet scan we can only wait until somebody's brain tissues available which of course is an autopsy procedure to measure how much of this is in the brain now diffraction is high but it's not that the levels of the proteins are high and that's important concept it's not like proteins are growing this is not a cancer this is still a loss and the proteins in a total extent are becoming depleted we're losing proteins we're just measuring most of us so in a one-sided story we can always say that essentially this is going up going up going up right that's bad but what happens is that the levels of the proteins are going down going up now you have two sides of the story one side that goes up the other goes down in a process of degeneration what goes down is much more important what goes up may be reactive or in some cases even protective and what goes up as I mentioned is really a relative term it goes up in relationship to the fact that we cannot measure this in a normal state so uh I think that's so is there any intervention in Breaking that up breaking up those gloves yeah so no we already have accomplished this and uh one so so we're really great at getting rid of this stuff biotechnology has has delivered products and therapies that already are doing that and uh there are of the 72 trials in the pipeline for this modification in Parkinson's this is a full two-thirds so 63 or so are all therapies that now are in tested inter we're testing them in humans we Parkinson's that clean these up so we're really good at doing that I'm arguing that cleaning this up leads to nothing good that this is not but a sign of the problem not the source of the problem that this source of the problem is something we that we don't really know what it is I in my TED Talk I use this particular uh thing just something like a little ball like this and I say this is different in different people this is this is what creates a problem but it's mostly invisible now this is what makes proteins fold up right this let's say that this could be a virus uh it's very well demonstrated that herpes simplex virus type 1 can can actually get if if not treated can do this can get the proteins to Clump up form this right uh so that would be a cause of the problem but in most cases this is absent so essentially uh what we're dealing with is is the loss of the protein the accrual of the fraction of this so it looks like this is going up but really it isn't so um so I I hope that the answer to the question that you just pose is yes we've been talking this is a one-sided story this is going up and we have many therapies for this now recently there have been two trials that were just reported so a few months ago in the New England Journal of Medicine which is the most important journal in medicine and there were two anti-synulting trials that clean this up from the brain and uh in both cases there was no change no it was futile um uh in our narrative we've we felt that these trials weren't good enough that the dosage must have been something that perhaps needs to be worked on that the that the measurements we took were not sensitive enough and our favorite excuse is that the patients were already too advanced because they have symptoms imagine if our oncology colleagues would have come to any of their negative trials and say well no no we knew that this would have cured the cancer but the reason this trial was negative is because the trial was imperfect we need to do the same trial you know different molecules just keep on doing the same approach um until we finally get a result no oncology and other fields of medicine used negative trials to reject their hypothesis we do not reject hypothesis because we feel that they are perfect uh and and of course we've all grown up with the idea that this is the bad thing the Lewy bodies are the villain in the story and so yes we already have been able to do this but no we are not able to take that evidence and say all right well the hypothesis is incorrect we need to reject it we somehow cannot do it so Mike pledge to you all is that if you're invited to any study of disease modification if it's going to be anti-synuclein please say no it's not gonna work you have at best a chance of not being harmed and at worse you're going to be harmed is is definitely definitely no way can be beneficial there's just no no way right it's again in the the analogy of the milk it's like a trial that's gonna clean up the curd but you're not gonna drink that milk you're not gonna drink the milk so that's sort of where that comes from uh any any trial that's currently deceased modification should also ask the question why me right this is modification as I mentioned it's a it's a Precision medicine principle where a therapist to be matched to the biology of an individual so if you have a therapy that does something spectacular in animal models uh the disease is destroyed the animals are recovered you have to find out what about that therapy is applicable to you so when you're invited to a trial and the investigators say here I have something that's going to slow the progression of your disease uh the questions you need to ask is uh all right why me and if the answer is because you have early Parkinson's disease that's the wrong answer the the correct answer should be because this intervention acts by this specific mechanism of action and the biology that we've been able to determine about your condition is one that renders you suitable to benefit from this therapy as a candidate for this particular trial oh that will be the greatest uh uh explanation for why you should participate otherwise do not participate in those kinds of trials they are going to lead nowhere now for now there are many trials for symptomatic enhancements yes those are important for us to continue participating in because there is so much more that we can do to try to continue bringing therapies to to help with the symptoms but until we get it right in terms of disease modification which is a completely different animal compared to symptomatic therapies we should really not be continuing to just fit into those trials and actually unless patients say enough I'm not going to be doing this we're going to continue doing them so so there is a lot of power in patients and I hope that you'll exercise them so if you replace these peptides will that replace dopamine so if you replace these peptides you will nurture this uh fragile neurons back to health and those neurons will then be able to produce the dopamine and produce the other neurotransmitters Beyond dopamine that are associated with Parkinson's so dopamine is very important for motor function but there is not epinephrine for uh for other functions autonomic functions uh there is serotonin serotonin also affected for emotional function Etc et cetera so so the proteins will just get the conditions for the it's kind of like reforestation it's allowing the the neurons to then remain healthy and then those neurons are the ones that are going to make all these different neurotransmitters including dopamine so there's a question about Lark 2 and I have to go back and find it um Lark 2 shows mitochondrial fission how about reversing that too mitochondrial function Mark 2 shows mitochondrial fission is there a way to reverse that uh uh no and I'm not sure that uh I'm not sure actually even what mitochondrial fission actually means in this context Lark 2 as a gene when mutated create an increase in the in the kinase function which apparently is what's uh neurotoxic to it however all uh so large 2 generates a very wide range of potential presentations one of which is classic Parkinson's but it can generate all sorts of different things uh many of which we don't even call Parkinson's some of them are called from the temporal dementia some of them are called Progressive supernutral policy so they Parkinson's Gene that Lark 2 represents is actually not very clean and then the penetrance that is the extent to which it will actually Express is about 30 so most people with large two mutations don't ever develop Parkinson's now because this is so diverse because one gene is not an is not equal to one disease one gene can still give rise to many expressions of disease Each of which are biologically different one approach will not work for them particularly to to address the for instance the kinase Inhibitors which are the drugs used for large two are unlikely to work uh because they are chasing likely a common denominator of what the gene expression is and common denominators tend not to be the cause of the problem but rather the consequence of the problem so here the rescue with proteins could work because we don't need to necessarily understand at an individual level how Lark 2 is creating the brain kind of Parkinson's in the in the particular individual but the protein elevation will help so uh so the proteins will work here but it can work in other people without lard 2 just the same and do you think that there's any lifestyle changes that can increase the peptides and yes what impact would that have that's a great question and just I noticed that the question you asked me uh I I actually saw that and the first statement was of that particular question Lake Canim I've showed great efficacy with Alzheimer's how do you account for that I I don't want to miss that question because that that's an important question like anima is a drug that the FDA recently approved for the treatment of Alzheimer's and it it's medication that actually cleans up amulet from the brain so it gets rid of the clumps of proteins not called Lewy bodies they're called amyloplex but the principle is the same uh so how it comes the like anima is potentially efficacious now by the way the measure of efficacy is statistically significance but not clinically relevant it's uh in a scale of 0 to 18 this is uh 0.45 so it's less than a half a point one point and in some studies two points are required for the minimal difference that any patient can tell a difference on so this Falls below the resolution of what anyone can tell patients are still deteriorating but what makes lecanoma potentially abuse even though it's very harmful because one out of four patients actually get sicker with that it develops brain swelling Etc so it's it's a toxic thing to the brain but why is it that there seems to be at the end a margin of difference that favors for the first time a drug that has lowered this because this is not the first one that have been uh 15 other antibodies that have done the same thing have really very substantially eliminated this from the brain he said actually it increases in some people the levels of the normal proteins this thing goes up now because that's not part of the expected outcomes the investigators have relegated this very important piece of information to the supplementary material of the New England Journal of Medicine article were this like canimab study was published they mentioned nothing about it in the paper whatsoever and you find this information that this goes up uh there so so my hypothesis and I've hoped that ASI and Biogen the sponsors of Israel would actually get back to their data and find out if in fact those who benefit are precisely the ones that end up increasing their levels of the normal protein above the compensation threshold that we've defined already I don't know if they're going to take us up on that offer but that is an important question and they have the data to ask this particular question as to the one that you just asked me is there any there any anything that can be done to increase the levels of the normal protein it's a great question uh turns out yes and uh it's something I discovered recently you may have all heard of the ketogenic diet ketogenic diet is essentially a diet that is aimed at decreasing the processed carbohydrates as much as possible so very very low carbohydrates and all the diet based on uh protein and uh and uh and fat so it's kind of like a modified uh Atkins diet and the idea is that that will minimize the relative uh uh concentration of glucose which is not the best sugar in a brain under stress whereas ketones is Ketone is a much more uh useful in more uh efficient source of energy to brain under stress well it turns out that one of the things that ketogenic diet does and it's been demonstrated a couple years ago but it was just brought to my attention recently uh Publications have shown that the levels of the normal protein actually also go up and so that is fascinating because that might explain why people do get better it's just a very hard diet to to do and we are thinking already through a way of making a modified diet perhaps amplifying the ketogenesis by including the diet a ketogenic supplement so I think that's very interesting because if that can be accomplished as you can imagine that would be much better than any Fusion system right uh it would be a matter of ensuring that the dietary aspects to it are adhered to in the most uh strict possible a strict way just so that then this can happen but yeah so that's kind of interesting and I think that that could be one way in which uh you could all accomplish this we did a study of ketogenic ketogenic diet it was very hard to do because admittedly patients find it difficult it's difficult it's a difficult diet to be but if you can do it and maybe if you can not do it as stringently as we uh did it when Robert Krikorian our investigator here at the University of Cincinnati let it uh maybe with addition of a ketogenic supplement that could achieve enough of a ketogenesis to potentially Drive the levels up now we don't know if that is also going to get us with higher levels of the normal protein but it could be and so uh that's that's a fascinating question and I hope that we can answer it more definitively in the next couple of years and why does exercise slow the progression of Parkinson's disease why do we stress that so much so exercise is the only intervention that is multifacetic meaning uh it it it doesn't do one thing it does all sorts of different things and it it it ends up having an impact on the mitochondrial metabolism in the lysosomal function uh in the inflammatory uh response Etc it's just it has all sorts of things now what's interesting about exercise is it in addition of being uh just a very wide range of biological changes is that it tailors the changes to the individuals so that if you have two individuals doing the exact same type of exercise frequency intensity those two individuals will get different benefits they will benefit but they the the the underlying biological drivers of the benefits will be individualized no therapy can do that that we have and so that's why we think of exercise as the truly the only disease modified intervention we now have access to and that's why it's so important that's why we're stress is so heavily in each one of our visits because that's the one treatment that maybe maybe all of us have been hoping to get into a capsule uh but we cannot because this is what is really through Precision medicine in some level right is is adapting biological changes to the individuals that are doing the exercise we don't have a capsule can that can be so adaptable and probably never will uh so we have to recognize that it exercise is the one thing that that all of us cannot do without and as the recent research revealed anything about genetic versus environmental factors that lead to Parkinson's disease and which might be more of a factor okay so uh I hope that by this point uh in our discussion we know that when we say Parkinson's disease we don't mean here this is Parkinson's Disease uh everybody's different and so yes individually each of us have a genetic uh will not settlement abilities and an environmental set of exposures that combine to create the brand of Parkinson's we develop but what genetic and environmental exposures May apply to me would be very different to just about everyone else and so um we've so so that's so so the answer is yes we we know that at a population level there are all these very many different things that happen right exposure to pesticides exposure to well water increasing the risk uh exposure to smoke and decreasing the risk and you know also also but so we created a bit of a uh what what investigators have called the possible Parkinson's disease where it seems as if we just are uh very very close to finding the last couple of pieces to the puzzle Parkinson's disease so that we'll understand Parkinson's exactly as it is and that's hubris um so we've gotten to a point where we know so much about Parkinson's the disease construct in so little about how James Parkinson's came to be how Mary's Parkinson's came to be how Georgia sparkens right we know know so little about that and so I am now very mindful when questions like that come over I says well yeah we have we have a population based assessment of risks uh some some risks uh that are increasing the risk of parking some exposures that are decreasing the risks of Parkinson's but how many of them apply to you if any we don't we don't know uh for now I think it's important to emphasize the healthy lifestyle is largely good but it's so interesting that it's not exclusively good right so as I told you uh smoking coffee and red wine are are good and you would argue well those are surrogate markers uh of not the best possible life um so I don't know if that's cool I'm all about the red wine come on thank you thank you we need to defend the red wine so uh um I think that each of us is just a an individual and we should not continue on the the idea that here there is more studies to be to to be done to learn about Parkinson's disease is I'm no longer that interested in studies to advance our knowledge in Parkinson's disease I want to find out what about each individual effective Parkinson's is important to that individual uh in the past we would say please uh John coming to my study do you have Parkinson's anymore we study about you the more we learn about you the more we learn about Parkinson's disease I don't think that's the right approach we've been doing that for so long that you would think by now we would have figured this thing out if Parkinson's were one disease we would have conquered but it isn't it isn't what this is I wish it were because it'd be easier to some extent it's going to be hard but we just have to make the change uh it is it is unavoidable other fields of medicine have done it and that's why cancer was never cured but look at the progress done on individuals affected by cancer because they were looked upon as individuals not upon how is how is it that they fit into this model of of cancer so you know to kind of wrap this up Alberto there's as you stated in the beginning there's so many other neurodegenerative diseases besides parkinsonisms and Alzheimer's there's there's a little question on essential tremor but it also leads me to think about it what when Precision medicine comes about it's going to Target hopefully all these degenerative diseases right hopefully prion hopefully cjd hopefully frontotemporal dementias right yep maybe even the essential tremor because we don't know how essential tremors starts absolutely absolutely I think many of the labels that were used have made a lot of sense to us that's we created these boxes and in other fields of medicine they also created their boxes but then Technologies came and and then they were available for us to question those boxes and that's what other fields of medicine did we don't do that we said hey that guy James Parkinson's in 1817 when he first described six people with what he called the shaking policy it wasn't to something and we're about to prove that he was out to demonstrate a molecular biological concert no he was very astute for his time he was able to pick the few features were common across six different individuals six uh you know three or from off the street and three that he saw in his clinic and then the charcoal many years later say hey Parkinson's wasn't to something let's call this Parkinson's disease now we have Technologies to be able to question that all of these Concepts and in fact that's why I've written the book Brain fables because in in that book I just go through all the different Milestones that led us to where we are very important compelling logical stories that when you look at the data from which they come they don't support what we're saying we're just having all these technologies that we could have used to question that we're which we're calling it no matter we're calling uh and and we have not changed so all these terms as you're mentioning are in essential tremor from the temporal Dimension the menstrual everybody is all of them are are they are clinical pathologic constructs we created them because we figure hey look at the people look what the symptoms they have and let's see what the autopsy shows and then we make sense of them sometimes because oh well in retrospect because of this autopsy all these symptoms must have been due to the to what we see in the autopsy and I uh I find that this is just a primitive way of practicing medicine anymore it made a lot of sense sense but he doesn't anymore how often do you come to the scene of a crime in a forensic setting and what you see and what jumps that you uh is is the perpetrator of the crime it's almost never you get evidence to create a narrative about the crime but you rarely uncover the perpetrator just on what you see it gives you Clues to try to figure that out but it's not from what you see and yet in our forensic approach to Parkinson's which still dominates to today we continue to use the forensics to tell us what caused the problem they where which are the arsonists and and that is just an incredibly alluring but biologically false story and just one more quick idea to throw out there because there's been a couple questions what do you think about the stem cell approach to increasing the good proteins so a stem cell approach is an interesting approach that is falling under the category of neural restoration so it is kind of at rescue but not quite there because rescue approach we've talked about here is is going to sort of lift all boats so to speak stem cell therapy can lift one or two boats at a time because in stem cell therapy you're replenishing the a group of neurons or cells that would do something specific you cannot replant you cannot do a stem cell or therapy to the different regions of the brain that are affected only the real so stem cells is currently in Parkinson's been developed for the uh for replenishing the therapies that make up dopamine that could be good but we don't know how much more effective yet it will be if at all compared to say the burning stimulation or compared to say the newer dopamine Fusion system so these cells could be good they could avoid the need for Infusion systems but they might not we don't know yet but they can only replenish a specific region of the rain and that's what makes it tricky so far but I'm very interested in stem cell therapy though I think there is something there that we would need to understand better I just think that this scope of it at the moment is not going to be quite as as critical as uh as widely encompassing as as we think it might be the the idea sounds better than the practicalities of it well as Chris said and I don't know if you want to wrap it up Chris but my take away from this is always as I always tell my patients there's hope there is absolutely hope and we can never give up because we will always find some other way to help you

Channel: Parkinson Support and Wellness

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Id: IUhFmigB2ms

Length: 66min 11sec (3971 seconds)

Published: Thu Feb 09 2023