Parkinson's and Alzheimer's: The solution in sight | Dr. Alberto Espay | TEDxWrigleyville
URL: https://www.youtube.com/watch?v=a7oAoajBlHc Video ID: a7oAoajBlHc ============================================================ [Music] [Applause] everyone loves a story with a villain it holds our attention and it galvanizes us it gains a common enemy in the field of neurodegenerative diseases which include Parkinson's Alzheimer's and others the victim is the brain and the villain is the abnormal proteins okay we have a name for it we call it proteinopathies diseases of the proteins and we have in fact a crew a 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 Brave agent 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 might Shuffle or 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 in 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 clumps 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 uh soluble that means dissolvable that they can perform functions uh is dissolved in water the solubility of it allows us to quantify in the liquid that surrounds the brain and 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 clamped into these very compact words and very similar to what you saw earlier and ultimately more of them 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 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 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 a 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-protting 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 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 not 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 foreign 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 amulet 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 that 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 a like thinking that a forced 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 what that is 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's 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 it was we're 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] [Applause]