Ep 131 Parkinson’s Disease: Dopamine & discoveries

all on my left hand side. And then so I had mentioned this to my flatmate, who was also a doctor, and he told me that I needed to go see the GP, which is what I should have done a while ago.

for a while. And that happened for a couple of months, and then I noticed and people were commenting that I started limping with my left leg a little bit, and I noticed the one thing that was really really off was I couldn't slide my left foot into my crocs that I wore to go to operating theater. I couldn't wiggle my toes like normal. And at this point I was doing training for obgyn and then I had another

MRI again perfectly clear. Went back to the neuuralogist, and by that point he noticed that I had a reduced armswing in my left arm while walking, and he knew, and I knew my medical studies that that was pretty much a sign of Parkinson's city, something that we really hadn't considered at the time. By this point, I've been tested for pretty much everything under the sun. So then I was sent to a very specific type of neuralis motor movement disorder specialist who is still my neuralgists to

this day. And I had a scan called a dopamine of tape PET scan and that should reduce dopamine on my left side, and that was pretty much it.

opened because I was just absolutely overwhelmed. So I went and I worked all over Australia to job, still doing mostly but eat OBGN, but also doing emergency and some other kind of small town rural things all over Australia, and.

Mostly my main medication is dopamine, which is something helps me get through my day, or as Michael J. Fox says he called it, being on the bus, getting on the bus if you watched his documentary. I had one of the most advanced.

not helping enough people. But it took a while to realize I needed to help myself and nobody else was going to do it. Dealing with the Parkinson's diagnosis was the first time I saw a psychologist and psychiatrist, and it's been incredibly helpful and actually looking after my mental health, because the mental health side of Parkinson's is another thing that kind of gets overlooked depressions or part of the

whole package that is Parkinson's. And even as my medication wears off and I get into what we call an off period, I can feel my anxiety kind of wrenching

up sometimes. My biggest help in coming to terms with my diagnosis was actually listening to Michael J. Fox's biographies on audiobook and just having somebody who is from my same hometown diagnosed at the same age, and telling his story, which was very similar to mine, was incredibly helpful because having Parkinson's at this stage is incredibly lonely and it's very very different than the normal later onside Parkinson's, we

don't get symptoms quite as severe as quickly. We tend to progress slower, we tend not to have a dementia side of things. And if you've seen Michael J. Fox's most recent documentary, you can clearly see that he's still sharp as attack and incredibly wedding, which has helped me.

very like therapeutic in a way. But yeah, it's a.

a little bit of why that is. Parkinson's disease is really a clinical syndrome. It's diagnosed based on clinical findings, and what that means is that there isn't a point during one's life where a single or even a group of diagnostic tests can say this is Parkinson's disease period definitely. Instead, it's diagnosed based on this compilation of symptoms and a response to treatment that generally ends up with someone getting

a diagnosis of Parkinson's disease. And along those lines, there are actually a lot of other conditions that look and act much like Parkinson's disease, so much so that in fact, the suite of like motor findings especially that we'll talk about are called parkinsonism, and Parkinson's disease itself is the primary and most common cause of parkinsonism, but there are a lot of other conditions as well that fall under this Parkinsonism's umbrella.

someone has Parkinson's disease, Like how is this diagnosed? And then we'll get into our brains to actually understand what's happening that causes these symptoms, and then we can.

able to make rapid movements anymore. This Brady kinesia often goes along with rigidity, often what's called cog wheel rigidity. So the muscles are kind of tensed, but not all the time, if that makes sense, Like you can move a person's arm, for example, and it will like give a little and then be rigid again, and then give a little and be tense again and give a little.

I think a lot of people think of tremor when they think of Parkinson's and the tremor associated with Parkinson's disease is a resting tremor, which means when a person is at rest and relaxed, the tremor is present and it tends to get better with intentional movement, which is kind of the opposite of what we tend to see with something like an essential tremor, where you might have more of a tremor if you're trying to do intentional movement of some kind.

up the feet off the floor. And again all the movements are very slow and these two things, especially combined the trunkle instability and the shuffling gate, can put people at pretty high risk of falls. So falls tend to

be a common complication in Parkinson's disease. And because this can eventually also affect all of the muscles and not just like our skeletal muscles that control our arms and our legs, there can also eventually be things like dysphasia or difficulty eating and swallowing, and difficulty talking as well, So this can lead to an increased risk of things like aspiration, pneumonia and things like that down the line. So that's the motor half of Parkinson's disease. But then

there's a whole suite of non motor symptoms. And it turns out we know now that the non motor symptoms can and generally do tend to start quite a number of years earlier than the motor symptoms. And yet these motor symptoms are the kind of hallmarks of Parkinson's, and so it's not until these motor symptoms arise that the diagnosis is able to be made.

So these are things like constipation, very very common REM sleep disorders, which is honestly a entirely interesting probably worthy of its whole own category. I feel like we've talked about sleep and doing a lot of episodes on sleep. But REM sleep is your dream sleep, like it's your rapid eye. REM stands for rapid eye movement, and so this is when you're having a lot of dreams and normally during REM sleep, you don't really move, You're kind of a tonic. In REM sleep disorders, people are very

active during REM sleep. So this includes doing things like talking, moving, even going so far as acting out their dreams. And this of course can potentially actually be quite dangerous if people are getting up and moving and doing things during REM sleep as a part of a REM sleep disorder. Okay, yeah, this is not specific to Parkinson's, but very often seen in people who eventually are diagnosed with Parkinson's. Then there's

also things like depression, anxiety, or general mood changes. Sometimes we'll see things like hypotension or low blood pressure. Very interestingly, a diminishing of the sense of smell, so either like a complete loss of sense of smell or just your sense of smelln't isn't as good anymore. It's called hyposmia. Sometimes there'll be urinary symptoms like difficulty urinating or like

urinary retention that sort of thing, or erectile dysfunction. And then, same as with our motor symptoms, these non motor symptoms also progress over time and lead to things like fatigue, apathy.

Sometimes pain can become a pretty common symptom of Parkinson's, especially in the later stages that hypotension can progress to what's called dysautonomia, which is a very vague and general term, but it just means that your autonomic nervous system isn't regulating your blood pressure and your heart rate appropriately, So you can have drops in your blood pressure when it should be going up, you can have a high heart

rate when it should be going slow, et cetera. And then eventually Parkinson's leads to dementia and can even lead to psychosis. Parkinson's generally does not cause death outright, but Parkinson's, because of all of these findings, often leads to a significant amount of life lost in that people die much earlier than they otherwise would because of Parkinson's. So that's

the symptoms and what Parkinson's looks like. There are a couple of different things to talk about when it comes to the path of physiology.

result of Parkinson's. Sure, and so it's a little bit hard to tease out for some of these, some of them I think are a little bit more strongly associated with like Parkinson's, and only a few other things like the rum sleep disorders for example, so that you might be able to say, Okay, well this started, you know, three years before your Parkinson's diagnosis or something like that.

But in any case, all of these, especially the non motor prodromal symptoms, often start years before a Parkinson's diagnosis.

easy part, what is happening? And this is the part where I said, in some ways it's kind of straightforward to explain. Parkinson's disease results from destruction or degeneration of a specific set of neurons, A lot of neurons really, but predominantly neurons in a part of our brain that are called the substantia Niagara pars compacta or SNPC. Okay, I promise I'm not going to just name brain areas for this whole episode. So this is an area of

the brain. It's specifically this little cluster of neurons in our mid brain, which is part of our brain stem at the base of our brain, that happens to have a main function of being dopaminergic.

It helps with blood pressure maintenance, it's a precursor for other hormones and the rest of our body.

called the nigrostriadol pathway, gets degenerated. In the brains of people who have died with Parkinson's, this part of their brain is completely pale, which means that all of the neuromelanin that is supposed to be there is gone. It's just completely degenerated. So we see this degeneration. And the second thing that we see is the deposition of what

are called Louis bodies. Louis bodies are these aggregates of proteins, multiple misfolded proteins, but the primary one involved is called alpha sin nucleon, and this is a protein that we don't fully understand.

involved in Alzheimer's disease as well. Loui bodies are also present in another disorder called dementia with Loui bodies that's separate from Parkinson's but shares a lot of similarities. Rem sleep disorder is one of them, and in Parkinson's, these Loui bodies deposit in these areas we've already talked about, like the substantium niagara, but also in a variety of other brain regions as well, So now we know what

is happening. Neurons are being degenerated in the part of our brain that controls dopamine production, So now we don't have dopamine. If we don't have dopamine flowing, then our nerves can't fire. If our nerves can't fire, specifically, the nerves that are controlling our motor movements, we're going to have problems with those motor movements. Specifically, we're not going to be able to extend. Our muscles, going to become

fixed in certain positions. They're going to be rigid because our brain can't tell them no fire again, no fire again, or no relax again. Right, Because there's both positive and negative pathways that have to happen for us to be able to coordinate our movement smoothly. So that is why we see most of the predominant symptoms of Parkinson's. It's a lack of coordination of our muscle response.

It's not entirely clear. Is it that this protein alphasin nucleon starts to become misfolded for one reason or another and starts to deposit in our brain, and that is what causes the death of the neurons or is it inflammation because of either mitochondrial dysfunction and reactive oxygen species formation or because of other toxic insults to the brain over time that leads to the death of neurons and further inflammation which then leads to protein misfolding and alphasin nucleon deposition.

thought to be just genetic. It is definitely not. There are a few monogenic forms of Parkinson's disease, and much like what we talked about in our Migraine episode, which aaron I was like, how have we done so many brain episodes?

of Parkinson's disease. They are not the norm They are definitely not the most common types of Parkinson's disease, but they's still a very important part of the research of Parkinson's disease because not only are these forms of Parkinson's disease potentially good targets for things like gene therapy in terms of treatment, but it also tells us a lot about the underpinnings the basic pathophysiology of this disease, even for other forms.

really don't know when it comes to environmental factors. There's a few that have been identified as increasing risk of Parkinson's, like TBI or traumatic brain injury, or pesticide exposure, And I don't know what pesticides.

been linked in any of these cases. The cigarette smoking is really interesting because some of the theories are that it actually just has to do with how much dopamine you have in your brain, so it just like delays the onset of symptoms rather than actually delaying any disease process or something like that. Huh yeah, But in any case, we don't really know, but we know that it's not purely genetic. So there are in fact environmental factors that play a role in Parkinson's disease.

of simple. It's replacing dopamine. So we give this in general in the form of a combination of carbon dopa and leve doopa, which are like precursors to dopamine, so that they last longer in our body and actually make it into our brain rather than just staying in our bloodstream. And if someone has these motor symptoms consistent with parkinsonism, and they respond to dopamine like their symptoms improve usually drastically with treatment. That's when you can be pretty sure

that the diagnosis is Parkinson's disease. Technically, still, the only definitive diagnosis is made post mortem, with an autopsy of the brain that shows these very spific findings associated with Parkinson's disease.

are larger than just dopamine. So treating someone with dopamine isn't going to fix all of those symptoms, and we don't necessarily have great treatment for all of the rest of things aside from like treating depression if that is a symptom, or treating low blood pressure.

uncontrollable neck movements, or tongue movements. Some people might think of these as hallmarks of Parkinson's disease, but really they are an issue with the treatment for Parkinson's. It's replacing that dopamine. So we also see these type of symptoms in people who are on antipsychotics that are increasing the dopamine in their brains. They can have these same kind of symptoms. That's most of what I have for Parkinson's disease.

In terms of prognosis, It's hard to give an exact one because despite this being very specific brain findings, it's a very variable disease. In some of the literature, people have started to try to classify Parkinson's into different subgroups because of how variable the presentation can be, and there's a few different ways that it's been done, depending on

which literature you read. One common way is to separate it into kind of mild motor predominant, an intermediate group, and then what's called a diffuse malignant group, or you can think of it as very severe and very rapid onset group. And in all of these three groups, the prognosis is going to be very different. The duration of disease in terms of how long you go from very mild symptoms that are very easy to deal with to not being able to swallow safely or not being able

to move at all. It's really highly variable. If we think of probably the most well known individual with Parkinson's, Michael J. Fawx, he was diagnosed at age twenty nine, which is incredibly young. It's a very early onset form of Parkinson's disease. He's now over sixty and still very functional.

of these Parkinson's symptoms. So there's a huge amount of variability, which makes it really difficult not only to study, but also to understand what is going on and how can it be so different in different individuals.

strong placebo effect. And I just didn't know if you had read anything about that or like what what that could mean, or because like some of just the little things about Parkinson's I find so fascinating, where in terms of walking, sometimes people with Parkinson's can freeze, but then if an obstacle is placed in front of them, then they can step over it and then continue on. Like what causes this sort of start and stop.

still exists in the brain. So what determines how much dopamine makes it all the way to the places that it's supposed to bind And what other systems does our brain have as backup to be able to keep us functioning and moving the way that we're supposed to if there isn't enough dopamine for those signals.

but the coordination of those messages is messed up. Okay, that's my me, not being a brain person the way I think about it.

are also going to be helpful. And it's interesting that was what I thought of when you were saying that the placebo e fact seems very strong in.

disease naturally, like it can be induced in animal models. Interesting, and maybe people have hypothesized that that's due to our pretty good longevity. We have pretty long, long longevity, as suggesting that Parkinson's disease is more or less mostly a disease of aging. But what about like blue whales or giant tortoises, other creatures that have longevity. Yeah, sea turtles

live like undreds of years man. Yeah, and as far as I have read, they have not been observed to develop Parkinson's, So maybe it's something to do with our human brain. I did come across one paper that refutes the more like widely accepted preon kind of misfolded protein model for Parkinson's, and the authors instead suggest that it has to do with how during early human evolution, our brain expanded in certain ways that left other parts behind.

So like the olfactory part of our brain is smaller relative to other primates, for instance, and those areas that didn't expand during human brain evolution maybe are more susceptible to like neuron loss. I don't know. I also did come across that humans have relatively fewer dopamine neurons than

other animals as a function of size. So the example that I came across was that a mouse has roughly twenty thousand dopamine neurons, while an average human has around four hundred thousand, So it's only twenty times more than a mouse, despite humans being well more than twenty times the size of a mouse. Okay, interesting, I don't know. And part of the reason I don't know and no one seems to really know is that the driver's and precise path of physiology of Parkinson's disease have not been

fully worked out right. But don't worry, there is still so so much more to talk about in terms of the history of Parkinson's disease, and so for now, let's head back to the ancient world to see whether people recognize the disease long ago. Did they? Did they? Yes, of course they did. Hah. There's an ancient Egyptian papyrus that describes excessive drooling in an elderly king. There are ancient Indian texts that describe a chronic progressive condition, including

tremor and lack of movement. There are ancient Chinese teps that describe tremor and stiffness, and one of our frequent mentions, the ancient Greek physician Galen wrote of resting and action tremors. What's really fascinating is that in some of the ancient Indian and ancient Chinese texts, treatment was recommended in the form of various herbal concoctions, often containing seeds or extracts

from seeds. And it turns out that some of those seeds, when analyzed, you know, in the twentieth century, contain LEVDOPA or have anti colinergic and dopaminergic properties. Is that kind of really? I just love that, Like it probably worked. Yeah. Yeah. There are also a handful of possible references to Parkinson's

that pop up throughout the centuries. Leonardo da Vinci wrote about people quote whose soul cannot control their movements in spite of the fact that their extremities are shaking continuously end quote. There's a possible reference to Parkinson's disease in Shakespeare's Henry the sixth Part two. Dick the butcher asks why dost thou quiver man, and Lord say replies, the palsy and not fear provokes me. And philosopher Thomas Hobbes, who lived in the seventeenth century, is thought to have

had it. Quote he had the shaking palsy in his hands, which began in France before the year sixteen fifty, when he was aged sixty two, and has grown upon him by degrees ever since, so that he has not been able to write very legibly since sixteen fifty five or sixteen sixty six. So people have clearly recognized Parkinson's disease for a long time, But how would it get its name, like?

Who was Parkinson? Essentially? James Parkinson was born in seventeen fifty five in London, England, and decided to follow in his father's footsteps, training as a surgeon and apothecary, but also becoming in the meantime a political pamphleteer, a member of secret societies, a pacifist, a campaigner for social welfare, involved in like mysterious plots, a paleontologist and geologist. I'm sorry, yeah,

I don't know how he had all this time. Yeah, to also possibly be the first to describe appendicitis maybe, and was, of course the namesake of Parkinson's disease.

that you just saw walking around the neighborhood. I know it's I it's amazing to me that this is the paper and one of it, like one of the case descriptions is literally like I did not have a chance to talk to this person, but this is what they looked like from AFAR. So you know, okay, eighteen seventeen publishing standards. Yeah, no, IRB, that's for sure. No, no. So I'm going to read a little quote from this quote.

So slight and nearly imperceptible are the inroads of this malady, and so extremely slow its progress that the patient cannot recall the onset. The first symptoms perceived are a slight sense of weakness with a proneness to trembling, most commonly in one of the hands and arms. As the disease proceeds, the hand fails to answer the dictates of the will. Walking becomes a task which cannot be performed with how considerable attention care is necessary to prevent falls, difficulties increase.

Writing can now be hardly at all accomplished, and reading from the tremulous motion is accomplished with some difficulty. End quote. I really just liked that phrase. The hand fails to answer the dictates of the will. Yeah.

the final stages of disease. Parkinson also laid out some of the ideas that he had about what caused the disease, which he thought originated in like the spinal cord or brainstem you know, yeah, not far off, yeah, as well as possible treatments, mostly relating to bloodletting, but ultimately acknowledged that nothing had an effect and said that he hoped that that would change one day if enough people, you know, put their attention to this, put their focus on this disease.

And at the time that it was published, the essay didn't really make much of a splash, and he died in eighteen twenty four, seven years after it was published, never knowing just how famous his name would become. Wow. And in fact, we might today call the disease by a completely different name if it weren't for Jean Martin Scharco. I've definitely mentioned Charco several times on the podcast before. Very famous dude. Yeah, and he at least makes an

appearance in our episodes on multiple sclerosis and endometriosis. I think probably other ones as well, epilepsi. I don't know. Charco was a famous, famous medical scientist, both in his time as well as today, and his primary interest was in diseases of the nerves. People came from all over to watch him lecture at the public hospital where he worked in Paris, and the list of diseases he recognized or described, or that have been named after him, it's

a long list. It's a very long list. Yeah. Almost fifty years after Parkinson's essay was published, Sharko got his hands on a copy and immediately recognized that many of his patients seemed to have the condition that Parkinson was describing, and so he went about systematically characterizing the disease as

he had done with other conditions. He listed the most common symptoms tremor, rigidity, slowness, or poverty of movement, and postural instability, all of which Parkinson had pointed out, and then he added two more small handwriting and facial masking. Oh yeah, facial masking. Yeah, Aaron, could you give us a quick definition of facial masking.

distinct symptom. Quote in some of the various patients I showed you, you can easily recognize how difficult it is for them to do things, even though rigidity or tremor is not the limiting feature. Instead, even a cursory exam demonstrates that their problem relates more to slowness in execution of movement rather than to real weakness end quote. Charco's contributions to Parkinson's disease went beyond adding to its description or raising awareness of the condition among the medical community.

He also tried out all sorts of experimental therapies, medicines such as hiosiamine derived from Jimson weed, belladonna, cannabis, arsenic opium, and hemlo, as well as non pharmaceutical interventions like his quote unquote shaking chair and shaking helmet. Dear. So, he observed that symptoms sometimes got better after long carriage rides or horseback rides, and so he thought that shaking would help. It didn't. He did run trials and there were some benefits,

but it was due to placebo effect. And when his shaking chair and shaking helmet didn't work, he also tried electrical stimulation SPA treatments, even some horrible sounding contraption that was supposed to stretch the spinal cord. Oh, dear did nothing. That's a torture device. Yeah, I think really nothing seemed to have an effect, and so you know, he reasoned maybe if the cause of the disease were to be discovered,

then more effective treatments could be developed. So to try to identify the physical basis of Parkinson's disease, he was going to need to do a lot of autopsies, and fortunately the hospital where he worked had no shortage of opportunities for that since it took in many wards of the state. Ultimately, it wasn't Sharko himself but a couple of his students who would end up finding a hazelnut sized lump in the right side of the midbrain, close to the substantia nigra, and this was in a thirty

eight year old patient with Parkinson's. Wow, so maybe the substantia nigra was where Parkinson's originated. Seemed like a reasonable hypothesis, but no one really did anything about it for twenty five years or so until nineteen nineteen. That was the year that a Russian graduate student named Konstantine Tretiakov who was working in Paris, published his findings from fifty four

autopsied brains. All of the nine from people with Parkinson's had extensive damage to the substantia nigra, and none of the other brains did even more compelling was his finding of neuronal inclusions in the brains of people with Parkinson's and that was the same finding that Fritz Louis had

previously made aka Louis Bodies Louie buddies. Okay, And this narrowing in on what changed physiologically or physically in Parkinson's disease really helped researchers to focus their efforts on possible treatments, because if they knew what was actually changing and how those changes were associated with the signs of Parkinson's disease, then maybe they could develop a treatment to slow the progress or at the very least alleviate the symptoms of

the condition. And that's where we find ourselves with dopamine and eldopa. The story begins in nineteen ten. That year, dopamine was first synthesized by researchers Burger and Ewan, who I think were more or less just casting a wide net for chemicals that had an effect on the sympathetic nervous system. Seemed like a very hot time for that kind of research, Like I couldn't get at why they were looking at dopamine, or how they found dopamine, or

what they were looking for when they found it. Okay, that's as far as I could discern. But at the time of this publication and for decades after, dopamine was not really considered anything more than an intermediate compound in the production of adrenaline and nor adrenaline. It was just sort of like, nah, this is unimportant by itself, right, Yeah.

therapeutic promise. Oh wow, yeah, like, why would anyone want to take this? It has this horrible side effect? And then in nineteen thirty eight, I swear we're getting there. It's just like a lot of steps along this stree.

I love this, Okay. Researcher Peter Holtz and colleagues discovered the enzyme dopa decarboxylase, which converts el dopa to dopamine, and that revealed how dopamine could be created in the brain if you gave someone el dopa, Because well, dopamine cannot cross the blood brain barrier on its own, el dopa can. Yeah, And by the nineteen fifties, people were starting to suspect that maybe dopamine was actually important as just an individual molecule.

Carlson suggested that maybe the drug was blocking the uptake of an essential neurotransmitter in the brain and thought that maybe if they injected the rabbits with el dopa, then maybe the balance of neurotransmitters like adrenaline and ner adrenaline or epinephrin and nora openephrin would be restored. And sure enough, the el dopa worked almost like magic. The rabbits woke up and were moving around in no time. But was it because because the balance had been restored or was

something else going on? When Carlson took a closer look at the chemical makeup in the rabbit's brains. He found that the el dopa didn't convert into adrenaline and nor adrenaline as he had expected, but rather this supposedly unimportant molecule dopamine. Wow, it was like, Okay, this is kind

of revolutionary. And then then not long after, researcher Kathleen Montague demonstrated the presence of dopamine in the brain of humans, and that was later confirmed by Carlson's lab, and they had developed assays to measure like the amount of dopamine in different parts of the body and different parts of the brain, which also was like whoa, yeah, more here

going on than we thought. And so all of this together led Carlson to suggest that dopamine was essential for normal brain function and the control of movement, and that adop deficiency maybe at the root of Parkinson's disease, and that just so.

answer here. And so since the symptoms in the rabbits were very similar to Parkinson's disease, dopamine Parkinson's and then we're almost getting there. I love it. We're so close. And it's now the nineteen sixties. You said, nineteen fifty eight is when he presented this hypothesis at the first International Catacholamine Symposium.

not just in Parkinson's but in general. And there were also many other laughs along the way, because while this hypothesis is probably not the best way to say that, but while this hypothesis was widely rejected, it wasn't unanimously rejected.

Two Austrian researchers I apologized for my poor pronunciation. Ole Hornikowitz and Herbert Arainger were intrigued by this idea, and they decided to dig a bit deeper, which involved examining some brain samples from people who had died with Parkinson's, and sure enough, they found that the neurons in the region of the brain that was critical for movement, they were depleted of dopamine. Further, the substantia nigra region was

also completely missing dopamine. So finally a dopamine centered framework of Parkinson's disease was coming to together, which was exciting on its own because it was like, oh, my gosh,

finally we're understanding how these pieces are fitting together. But it was also potentially revolutionary because it promised hope for effective treatment, right because they already did the el dopa in the rabbits exactly and at this point treatment didn't exist, right, and so it was like it was an uncontrollable progression and that was the state of Parkinson's at the time. Maybe el dopa was the long awaited answer, and it

seemed so, at least initially. In nineteen sixty one, researchers Walter Burkmeyer and Ole Hornikowitz administered small doses of el dopa to twenty patients with advanced Parkinson's disease. Hornikowitz later remembered the scene quote, it was a spectacular moment to see the patients who could not walk, could not get up from bed, could not stand up when seated, start walking.

They all performed these activities like normal. Speech became better, they started laughing and actually crying with joy end quote wow. And even though Hornikowitz filmed this transformation, there were still doubters,

and rightfully so. The dosages that they had given these patients were relatively small, and only a small proportion of el dopa is known to cross the blood brain barrier, and so some people suggested that it was largely due to placebo effect, which we talked about does happen, and

a double blind study supported this doubt. In some ways, el dopa was found to be no more effective in relieving symptoms than saline, and it was beginning to be recognized to cause serious side effects like high blood pressure and nausea. But the Parkinson's field wasn't ready to give up quite yet. Maybe it was just a matter of

finding the sweet spot for dosage. George Ktesias made a major breakthrough when he tried scaling up the dose, so starting out small and then gradually increasing, and this helped to limit the adverse side effects seen early on with the early big doses, but still allowed to build up those doses to more effective levels. Another big step forward was the addition of carbon doopa, which allowed more of the el dopa to pass through the blood brain barrier.

Researcher Roger Duvoissen described what happened when he gave a patient this combo in nineteen sixty seven. Quote the effect was so dramatic, I couldn't believe it. Patients were so improved that they didn't look like they had Parkinson's anymore. End quote. The dramatic transformation that eldopa had on people

with Parkinson's disease and Parkinson's like disease. If you remember from our encephalitis lethargica episode from way back or the slash movie Awakenings by Oliver Sachs, which we talked about in that episode, the difference was so stark, the improvement was so great that this was really something that had rarely been seen before and has rarely been seen since in the history of medicine. Truly, Like the only other things that came to mind to me in terms of

like near instant improvement are antibiotics and insulin. Yeah, just like immediate holy cow reversal, What is happening like or complete elimination of symptoms.

remember from r encephalitis lethargic episode. After a month or two of taking it, people began to experience severe side effects, including problem like you mentioned Aaron with involuntary movement, and as time went on, people developed a tolerance for the drug, which meant that higher and higher doses had to be given, leading to more and more side effects like confusion, agitation, paranoia,

and hallucinations. And occasionally the drug would just randomly stop working, almost like a switch was flipped from on to off. There's no denying that el dopa is an incredible drug, but it also does come at a cost, and that's one that must be carefully weighed by people with Parkinson's disease and their medical providers in terms of like when

to start and so on. And the trade offs inherent with el dopa have also led people to search for alternative therapies, from surgeries and deep brain stimulation to neural graphs, neuroprotective treatments like MAO inhibitors which prevent the degradation of dopamine even phase therapy. I saw mentioned Oh interesting, I meant to read more about that. Each of those treatments has a story, and I know that there are probably eight million more on the horizon that you're going to

talk about, which is amazing. Not to mention, there's the whole part about how we learned more about the genetic and potential environmental causes of Parkinson's. But so this doesn't turn into a million hour episode. I'm not going to go down those rabbit holes today. I do, however, have one more story to tell before turning it over to you. So I told the story just now of l DOPA and how it revolutionized treatment, and this next story is

another revolution, but of a slightly different kind. I'm thrilled. One of the biggest challenges for many diseases that are specific to humans is not having an appropriate animal model. We've talked about this a bunch on the podcast. It makes it much more difficult to test out new treatments or conduct experiments to understand the mechanism of disease. Until the nineteen eighties or so, there were a couple of Parkinson's animal models, so like using the plant extract medication resurpene,

which I mentioned earlier in the Eldapa story. But apparently that drug blocks more neurotransmitters than just dopamines, so it wasn't It's not perfect for that, and that lack of really good animal models did severely limit Parkinson's disease research, especially before genetic models of disease were developed, and so researchers were always on the hunt for better tools, and they stumbled upon one in an unexpected place, the San

Jose County Jail OHKAY. In July nineteen eighty two, George Correo, who was in the San Jose County Jail on drug charges, woke up one morning unable to talk or move, but with his senses fully intact. He was admitted to the emergency room after his condition got worse and the doctors could not find out what was wrong. Reflex hammer no response, blunt pressure to fingernails, no response, ammonium sulfate smelling salts no response. Eventually he was transferred to the psychiatric ward

and diagnosed with catatonic schizophrenia. This was a diagnosis that stirred up some controversy among the hospital's doctors, with the neurologists arguing that it was a psychiatric disorder and the psychiatrists insisting insisting that it was neurologic. I have been in the middle of one of these debates. That's cool.

And then it was the head of neurology, Bill Langston, that got involved and decided to run a few more tests, the results of which convinced him that they were actually dealing with a mysterious neurological problem, so he had George transferred to the neurobehavior unit. After a few days there, a doctor noticed the slightest of movements from George's fingers, and so he placed a pencil in his hands with

a notepad underneath. After about thirty minutes, George had written his name along with quote, I'm not sure what is happening to me. I only know I can't function normally. I can't move right. I know what I want to do, it just won't come out right. And he wrote all of that. It took it took a while, but yeah, wow, yeah.

And so with this path of communication open, the doctors began taking a detailed, or as detailed as they could, medical history, which is how they learned that George had taken heroin, and that he had been with his girlfriend Juaniita Lopez before he had gotten sick. And when they found her, because they were like okay, you know, they were going to find out first of all if she was okay, but also what she knew, they found that she was in pretty much the same state that George

was in, motionless and rigid m hm. So then they cast a wider net around the town around the area and found more cases of people who were mysteriously frozen, six in total, including George and Juanita, and one of whom was a young woman who was diagnosed with hysterical paralysis. Wow. Yeah, The link between all of them was that they had

all taken heroin or what they thought was heroin. Okay, Testing of the substance that they had found in the apartment of one of these patients revealed that it wasn't actually heroin, but a designer drug synthesized in an underground lab and sold as heroin, And somehow this substance had induced the symptoms of Parkinson's disease in these young people in a matter of hours. What and because it looked

like Parkinson's, why not try al dopa. When they were given al dopa, they improved almost like almost immediately, gaining full control over their bodies, at least until the side effects started. But this improvement, sort of the treatment as part of the diagnosis, showed that something in that designer drug had crossed the blood brain barrier and destroyed the substantia nigra. How wow, what was this thing that did this?

The answer came from yet another unexpected source, a strange case study from the nineteen seventies, where a college student had used a home chemistry set to make his own drugs, namely MPPP, which, like, if I were to tell you what that stood for, it would be a lot of chemical names that don't mean anything to us, well probably to some listeners out there, but yeah not us. Yeah, give it a Google. But MPPP, in theory, gives a

heroin like high. And apparently this college student's experiments worked, or at least the first few batches did. A few months after starting, he injected himself with a batch and immediately felt a burning sensation and within a few days lost complete movement, becoming completely immobile and unable to speak.

And I don't know what happened to this guy, whether he eventually received any treatment, but his case eventually made it to the NIH, where they discovered that instead of making MPPP, he had made something called MPTP, which I can name this one out because I have written here one methyl for phenal one two three six tetra hydropyridine.

So yeah, MPTP. Turns out, the chemists that had made that designer drug in the nineteen eighties that had paralyzed those six people had also been trying to make MPPP but instead made MPTP. Okay, those individuals would never be the same, never fully recovering from the drug and struggling with motor complications for the rest of their lives, many of which were shortened. And it's an incredibly tragic story.

But if one good thing came out of it, it was that this situation ended up being a revolution for the field of Parkinson's disease research, because with the discovery of the effects of MPTP on the brain, researchers now had a potential cause for the condition, or could at least outline how an environmental contaminant such as an herbicide or pesticide could cross the blood brain barrier and cause

the disease. Secondly, and this is the huge part that I started this section with, they could now use MPTP to create the first animal models for Parkinson's disease, which could be used to test out treatments, study mechanisms, examine potential causes. The possibilities were endless. Wow. Yeah. Since the discovery of the effects of MPTP, the field of Parkinson's

disease research has come a tremendously long way. We've learned so much more about this disease and how to treat it, and this disease has also taught us so much about our own brains, unlocking movement pathways and reflexive actions by

looking at how they break down. We're also in the process of reframing this disease by incorporating symptoms that aren't movement related, something that is about as we've gotten better at diagnosing Parkinson's before the movement symptoms begin, which has also allowed people to conduct more precise and accurate clinical trials. We're expanding treatment options beyond the narrow dopamine focus, and

I'm super excited to learn more about those. But I think another huge aspect that has really grown in the past few decades is the incredible advocacy work done by people like Michael J. Fox. There can be such a stigma around neurodegenerative diseases, a huge one, including Parkinson's, and people like Michael J. Fox and the providers of our first hand account who share their experience and are open about it, have really done an immeasurable amount of good

in terms of humanizing this disease. And there's really just like so much more that we could talk about in terms of Parkinson's. So erin why don't you just cut me off here and tell me where we are today with this disease.

given time. It makes sense that prevalence is increasing because we're living longer. We're an aging global population, and Parkinson's disease is predominantly a disease of age. But the incidents, or the number of new cases that are diagnosed year after year, is also on the rise.

as the second most common neurodegenerative disorder after Alzheimer's disease. Okay, so it's like Alzheimer's disease and Parkinson's as like the two most common neurodegenerative dementia causing diseases. Parkinson's is, of course found across the globe. Prevalence is perhaps higher in Europe, North America, South America when compared to Africa, Asia, and

countries in the Middle East. It's really difficult, I think, in cases like this to really get a sense of like, how true is this versus are places that tend to be higher income better at diagnosing this disease unlear But overall, this is a disease that is affecting millions and millions

of people. And like we mentioned in the biology section, while Parkinson's disease is not causing death outright, it does significantly reduce the length of a person's life, and the degree to which that is true varies a lot by

the time course of the illness. So if we think back to dividing Parkinson's into maybe three different subtypes, the kind of worse or diffuse malignant group, the intermediate group, and the kind of mild motor predominant group, the median survival after diagnosis in the diffuse malignant group in some studies is only eight years, which is really short, compared to thirteen years for the intermediate subtype and twenty for

a mild motor predominant subtype. Often, when we look at just all Parkinson's altogether, the median survival after diagnosis is between like six and fourteen years. The good news is that there is a lot being done about this disease, so much so one of the big hurdles right now in Parkinson's disease that we've mentioned a lot is that, because this is a clinical diagnosis, you have to have these signs and symptoms present, at least some of them

before somebody can be diagnosed. And these predominantly motor signs that are used are not the first signs of neurodegeneration.

released a few months ago. In the year twenty twenty three, a paper came out in Lancet Neurology that was the result of this really massive longitudinal study funded in large part by the Michael J. Fox Foundation for Parkinson's Research, does a huge amount of funding for Parkinson's research, that in fact identified a potential biomarker of Parkinson's.

But this is the kind of breakthroughs in research that leads to the potential for these early diagnoses that can someday maybe even lead to screening tools that could be available, which is incredible. But then with this knowledge, this knowledge without a disease modifying therapy doesn't really do anything right. So the next step has to be disease modifying therapy because otherwise you're diagnosing something very early with nothing that you can do to treat it.

There are even studies looking into using GLP one agonists, which are the drugs that are all the rage right now. They were developed as treatment for diabetes. They're also being used for weight loss. They're like the drugs that everyone's heard of.

for Parkinson's. Not all of these are drug trials, but over twenty three hundred of them are interventional trials of some kind, so it's a lot and the third avenue of research, in addition to biomarkers identifying disease early and disease treatment like changing the course of disease or slowing progression of disease, the third very interesting avenue of research that is separate but very closely related, is better following

this disease in terms of clinical progression. So Aarin, you sent me an article that was about wearable devices that can be used to track the movement of people with Parkinson's disease. So these devices in combination with machine learning

give us better resolution on progression of disease. There's other ones that look at speech pattern recognition and deep learning and AI machine learning things to be able to track the progression of Parkinson's disease in a very nuanced way, which is going to be a very important tool when we're trying to find disease modifying therapy because if we can better parse out what's working and what's not by better tracking the progression of this disease, then we're going

to be able to get a lot better data on what's working and what isn't and.

being done in terms of treatment. We will post the list of sources from this episode in all of our episodes on our website This podcast will Kill You dot Com under the episode's tab.