Speaker 1: My name is Stacey.
Speaker 2: I'm thirty five years old and at the age of
Speaker 2: twenty nine, I was diagnosed with Parkinson's disease, specifically something
Speaker 2: called young onset Parkinson's disease. I'm a doctor living in
Speaker 2: Australia and my first symptoms were a trimmer in my
Speaker 2: left hand, and I remember very clearly one day I
Speaker 2: was just finishing up a case in the operating theater
Speaker 2: and my consultant commented that my left hand was a
Speaker 2: little bit shakier than usual and had asked if I
Speaker 2: had extra coffee that day.
Speaker 1: I didn't really think anything of it, and then a
Speaker 1: couple of weeks later.
Speaker 2: I remember getting the odd weird muscle twitch and again
Speaker 2: not really thinking anything of it. And then one day
Speaker 2: I just couldn't tie surgical knots with my left hand,
Speaker 2: which was something I had spent a lot of time
Speaker 2: trying to learn and had been able to do just
Speaker 2: as well as my right hand. And suddenly, all of
Speaker 2: a sudden, I became quite clumsy. And then over time
Speaker 2: I started getting just a little bit more symptoms, a
Speaker 2: little bit more twitching, getting cramps on and off and
Speaker 2: all on my left hand side. And then so I
Speaker 2: had mentioned this to my flatmate, who was also a doctor,
Speaker 2: and he told me that I needed to go see
Speaker 2: the GP, which is what I should have done a
Speaker 2: while ago.
Speaker 1: But I finally went and I.
Speaker 2: Got referred to neuralgists and de Neeral just said it's
Speaker 2: likely MS given the fact your female and young.
Speaker 1: And so I was sent.
Speaker 2: For an m R on and I had an m
Speaker 2: OR I think a week or two later, and then
Speaker 2: went to see the neuralist again and the MRI I
Speaker 2: was perfectly clear. Theenerali just wasn't sure what was going on,
Speaker 2: thought it might be an essential chremor so start me
Speaker 2: on a bita blocker called penel and it got better
Speaker 2: for a while. And that happened for a couple of months,
Speaker 2: and then I noticed and people were commenting that I
Speaker 2: started limping with my left leg a little bit, and
Speaker 2: I noticed the one thing that was really really off
Speaker 2: was I couldn't slide my left foot into my crocs
Speaker 2: that I wore to go to operating theater. I couldn't
Speaker 2: wiggle my toes like normal. And at this point I
Speaker 2: was doing training for obgyn and then I had another
Speaker 2: MRI again perfectly clear. Went back to the neuuralogist, and
Speaker 2: by that point he noticed that I had a reduced
Speaker 2: armswing in my left arm while walking, and he knew,
Speaker 2: and I knew my medical studies that that was pretty
Speaker 2: much a sign of Parkinson's city, something that we really
Speaker 2: hadn't considered at the time. By this point, I've been
Speaker 2: tested for pretty much everything under the sun. So then
Speaker 2: I was sent to a very specific type of neuralis
Speaker 2: motor movement disorder specialist who is still my neuralgists to
Speaker 2: this day. And I had a scan called a dopamine
Speaker 2: of tape PET scan and that should reduce dopamine on
Speaker 2: my left side, and that was pretty much it.
Speaker 1: So my neuralogist was lovely. He walked me at the
Speaker 1: back door, knowing that I'd probably know people at the hospital,
Speaker 1: and he told me to take two.
Speaker 2: Weeks off, which is something that I really really struggled
Speaker 2: with and said, no, I can't.
Speaker 1: I can't stop working. I was supposed to start a
Speaker 1: new job.
Speaker 2: Soon, and by this point I had very few symptoms
Speaker 2: and very very intimatetent symptoms, but my world just kind
Speaker 2: of came crashing down and I went from working sixty
Speaker 2: hours to working nothing. I ended up quitting the job
Speaker 2: that I never started, and took a couple months off
Speaker 2: how to basically deal with APPRA, which in Australia is
Speaker 2: our regulatory body, and just make sure I was able
Speaker 2: to safely work again and what I was able to
Speaker 2: do and not do. And then I went and I
Speaker 2: opened because I was just absolutely overwhelmed. So I went
Speaker 2: and I worked all over Australia to job, still doing
Speaker 2: mostly but eat OBGN, but also doing emergency and some
Speaker 2: other kind of small town rural things all over Australia, and.
Speaker 1: Also took the opportunity to travel.
Speaker 2: All over the world, which was great, especially because my
Speaker 2: last trip ended up being February twenty twenty and was
Speaker 2: in Western Australia at the time that COVID broke, which
Speaker 2: was Australia lockdown during COVID completely but Western Australia the
Speaker 2: state was the absolute strictest of them all and I
Speaker 2: was able.
Speaker 1: To get up before the borders closed.
Speaker 2: During the time, I started messaging my now husband, so
Speaker 2: that worked out well. But then I found myself into
Speaker 2: a research job working on COVID vaccine trials and actually
Speaker 2: we're seeing patients undergoing those trials and then somehow from there,
Speaker 2: I've found my way into friends with medicine, where I
Speaker 2: am now and absolutely loving it. During the time I've
Speaker 2: been on I can't even tell you how many medications.
Speaker 2: Mostly my main medication is dopamine, which is something helps
Speaker 2: me get through my day, or as Michael J. Fox
Speaker 2: says he called it, being on the bus, getting on
Speaker 2: the bus if you watched his documentary. I had one
Speaker 2: of the most advanced.
Speaker 1: Treatments for deep brain stimulation two years ago, and I
Speaker 1: have two elect roads.
Speaker 2: Implanted in my brain and a battery in my chest,
Speaker 2: and those electrodes sent a continuous current to my brain.
Speaker 2: And I'm able to change this and modify it with
Speaker 2: an app on my phone, which is pretty crazy.
Speaker 1: But the surgery itself was absolutely.
Speaker 2: Terrifying for me. It was my first time in an
Speaker 2: operating peter about.
Speaker 1: Eighteen months at that point.
Speaker 2: And it was like coming home and away but then
Speaker 2: getting a massive metal halo and being bolted to an
Speaker 2: operating table and then having your skull drilled into when
Speaker 2: you were awhite when I was a white.
Speaker 1: Which was absolutely terrifying.
Speaker 2: But I'm incredibly glad I did. It helped my symptoms
Speaker 2: a lot. It's helped me reduce my medication and kind
Speaker 2: of continue to have a really normal life. I still
Speaker 2: work pretty much full time, but normal hours instead of
Speaker 2: the crazy sixty day eighty hour weeks that I was
Speaker 2: doing before. And I've had to learn how to take
Speaker 2: care of myself, which was something that was really hard
Speaker 2: to do. And I still struggle with the guilt and
Speaker 2: feeling that I'm not doing enough as a doctor and
Speaker 2: not helping enough people. But it took a while to
Speaker 2: realize I needed to help myself and nobody else was
Speaker 2: going to do it. Dealing with the Parkinson's diagnosis was
Speaker 2: the first time I saw a psychologist and psychiatrist, and
Speaker 2: it's been incredibly helpful and actually looking after my mental health,
Speaker 2: because the mental health side of Parkinson's is another thing
Speaker 2: that kind of gets overlooked depressions or part of the
Speaker 2: whole package that is Parkinson's. And even as my medication
Speaker 2: wears off and I get into what we call an
Speaker 2: off period, I can feel my anxiety kind of wrenching
Speaker 2: up sometimes. My biggest help in coming to terms with
Speaker 2: my diagnosis was actually listening to Michael J. Fox's biographies
Speaker 2: on audiobook and just having somebody who is from my
Speaker 2: same hometown diagnosed at the same age, and telling his story,
Speaker 2: which was very similar to mine, was incredibly helpful because
Speaker 2: having Parkinson's at this stage is incredibly lonely and it's
Speaker 2: very very different than the normal later onside Parkinson's, we
Speaker 2: don't get symptoms quite as severe as quickly. We tend
Speaker 2: to progress slower, we tend not to have a dementia
Speaker 2: side of things. And if you've seen Michael J. Fox's
Speaker 2: most recent documentary, you can clearly see that he's still
Speaker 2: sharp as attack and incredibly wedding, which has helped me.
Speaker 1: A lot in my kind of mental health journey as well.
Speaker 2: I have a great team behind me and I'm really
Speaker 2: really grateful for that and great family.
Speaker 1: And yeah, that's pretty much it.
Speaker 3: Thank you so much for sharing your story with us,
Speaker 3: like it's it's really we appreciate it so much. I
Speaker 3: don't have the words. Yeah, thank you. Yeah.
Speaker 4: Hi, I'm Aaron Welsh and I'm Erin Allman Updike.
Speaker 3: And this is this podcast will kill you.
Speaker 4: Welcome to this episode about Parkinson's disease.
Speaker 3: Yeah, big episode on our list for a while. The
Speaker 3: usual things that I say, but true every time. This was.
Speaker 3: This was a hard one to do. Yeah, yeah, it was.
Speaker 3: It was I found myself my grandpa had Parkinson's, died
Speaker 3: of complications with Parkinson's, and I it was just when
Speaker 3: I started to read, I immediately was like I have
Speaker 3: to stop and take a step away from this and
Speaker 3: then come back to it kind of like and then
Speaker 3: and then I think by the end of it, especially
Speaker 3: with some of the sources that I read, it became
Speaker 3: very like therapeutic in a way. But yeah, it's a.
Speaker 4: Lot, Yeah that makes sense. It hits very close to home.
Speaker 3: Yeah.
Speaker 4: Yeah, it's also a big one. It is as per
Speaker 4: usual this season, yeah, every season.
Speaker 5: Yeah, true, And because they're so so very much to cover,
Speaker 5: I guess we should just sort of like get started
Speaker 5: with things as soon as possible.
Speaker 3: We should.
Speaker 4: It's definitely quarantiny.
Speaker 3: Time, it is. What are we drinking this week?
Speaker 4: Well, nothing other than the Dopamini.
Speaker 3: Teeny apologies for the name. I think it's pretty good.
Speaker 3: It's pretty good. I love it it. And the Jopamini
Speaker 3: tini is kind of exactly what it sounds like. It's
Speaker 3: a martini, so really, you can choose your own adventure
Speaker 3: for this martini. And any martini you ever do. We
Speaker 3: are choosing to go with gin or a non alcoholic gin.
Speaker 3: There are tons of options out there, and some sweet
Speaker 3: vermouth changing it up a bit, and some Marishino lecre It's.
Speaker 3: It's fantastic. What a great option it is. We'll post
Speaker 3: the full.
Speaker 4: Recipe for that quarantini as well as our non alcoholic
Speaker 4: plus e burrita on our website, this podcast wiki you
Speaker 4: dot com.
Speaker 3: We certainly will. On our website you can find all
Speaker 3: sorts of things, transcripts, bookshop dot org, and goodreads list,
Speaker 3: merch Patreon sources for each and every one of our episodes.
Speaker 3: It's just more things.
Speaker 4: It's just all the things this podcast. Okay you dot
Speaker 4: com check it out.
Speaker 3: Yeah, I think I would have something like memorized, but
Speaker 3: we say.
Speaker 4: That literally every time, and it never will happen.
Speaker 3: And it won't. At this point we know ourselves. Yeah,
Speaker 3: that's fine. Should we get started on this topic. We should.
Speaker 4: Let's take a break and get into the biology of Parkinson's.
Speaker 4: One thing that is interesting about Parkinson's disease is that
Speaker 4: it is, on the one hand, kind of a very
Speaker 4: specific thing, and yet it is a highly variable disease.
Speaker 4: So what that means for this episode is that it's
Speaker 4: actually really simple and straightforward to explain on the one hand,
Speaker 4: while also being a very classic TPWKY scenario, where as
Speaker 4: soon as you start asking me questions, my answer is
Speaker 4: going to be I don't know. So let me explain
Speaker 4: a little bit of why that is. Parkinson's disease is
Speaker 4: really a clinical syndrome. It's diagnosed based on clinical findings,
Speaker 4: and what that means is that there isn't a point
Speaker 4: during one's life where a single or even a group
Speaker 4: of diagnostic tests can say this is Parkinson's disease period definitely. Instead,
Speaker 4: it's diagnosed based on this compilation of symptoms and a
Speaker 4: response to treatment that generally ends up with someone getting
Speaker 4: a diagnosis of Parkinson's disease. And along those lines, there
Speaker 4: are actually a lot of other conditions that look and
Speaker 4: act much like Parkinson's disease, so much so that in fact,
Speaker 4: the suite of like motor findings especially that we'll talk
Speaker 4: about are called parkinsonism, and Parkinson's disease itself is the
Speaker 4: primary and most common cause of parkinsonism, but there are
Speaker 4: a lot of other conditions as well that fall under
Speaker 4: this Parkinsonism's umbrella.
Speaker 3: Right, like many different roads leading to one destination kind.
Speaker 4: Of exactly exactly, and that is the nature of something
Speaker 4: that's diagnosed based on like clinical signs and symptoms. Sure,
Speaker 4: but we're going to focus on capital P Parkinson's disease
Speaker 4: today and then if you ask questions, maybe we'll talk
Speaker 4: about the other ones too, since again they do have
Speaker 4: very overlapping symptoms and in some cases similar causes but
Speaker 4: in different ways. So the way that I split up
Speaker 4: this biology section is will go over first off, like
Speaker 4: what are those symptoms, what does it look like if
Speaker 4: someone has Parkinson's disease, Like how is this diagnosed? And
Speaker 4: then we'll get into our brains to actually understand what's
Speaker 4: happening that causes these symptoms, and then we can.
Speaker 3: Talk about how we treat it.
Speaker 4: So the symptoms that characterize Parkinson's disease can be divided
Speaker 4: into motor symptoms and non motor symptoms. The motor symptoms
Speaker 4: means movement symptoms, and these are kind of the hallmark
Speaker 4: of Parkinson's disease. The first and one that has to
Speaker 4: be present to be able to end up with a
Speaker 4: diagnosis of Parkinson's is Brady kinesia, Brady means slow and
Speaker 4: kind is like in kinesiology it means movement, So this
Speaker 4: is a slowing of movement, meaning that people are not
Speaker 4: able to make rapid movements anymore. This Brady kinesia often
Speaker 4: goes along with rigidity, often what's called cog wheel rigidity.
Speaker 4: So the muscles are kind of tensed, but not all
Speaker 4: the time, if that makes sense, Like you can move
Speaker 4: a person's arm, for example, and it will like give
Speaker 4: a little and then be rigid again, and then give
Speaker 4: a little and be tense again and give a little.
Speaker 3: Does that kind of make sense? Yeah, Okay, it's like.
Speaker 4: The way like the wheels on a cog like turning right.
Speaker 4: That's why I got that description.
Speaker 3: I don't know.
Speaker 4: Yeah, So Brady kinesia, rigidity and a tremor and the tremor.
Speaker 4: I think it's a lot of the press in Parkinson's.
Speaker 4: I think a lot of people think of tremor when
Speaker 4: they think of Parkinson's and the tremor associated with Parkinson's
Speaker 4: disease is a resting tremor, which means when a person
Speaker 4: is at rest and relaxed, the tremor is present and
Speaker 4: it tends to get better with intentional movement, which is
Speaker 4: kind of the opposite of what we tend to see
Speaker 4: with something like an essential tremor, where you might have
Speaker 4: more of a tremor if you're trying to do intentional
Speaker 4: movement of some kind.
Speaker 3: Yeah, okay, I won't. I'm I'm suppressing.
Speaker 4: The why is that there's so many right, Yeah, we'll
Speaker 4: get there.
Speaker 3: We'll get there, We'll get there. Okay.
Speaker 4: As these motor symptoms, those are the three big hallmarks
Speaker 4: Brady kinesia, so slowing of the movements, rigidity, and tremor.
Speaker 3: They don't all have to be present.
Speaker 4: They often are all present, but Brady kinesia plus at
Speaker 4: least one of the others is the kind of motor symptoms.
Speaker 4: As these progress, they lead to things like trunkle instability,
Speaker 4: so that means like your top half of your body
Speaker 4: when you try to walk is unstable, or even if
Speaker 4: you're just standing, you're kind of unstable and not able
Speaker 4: to control the muscles in your trunk very well. And
Speaker 4: then changes in the gate, which is often called a
Speaker 4: kind of shuffling gait because it becomes difficult to pick
Speaker 4: up the feet off the floor. And again all the
Speaker 4: movements are very slow and these two things, especially combined
Speaker 4: the trunkle instability and the shuffling gate, can put people
Speaker 4: at pretty high risk of falls. So falls tend to
Speaker 4: be a common complication in Parkinson's disease. And because this
Speaker 4: can eventually also affect all of the muscles and not
Speaker 4: just like our skeletal muscles that control our arms and
Speaker 4: our legs, there can also eventually be things like dysphasia
Speaker 4: or difficulty eating and swallowing, and difficulty talking as well,
Speaker 4: So this can lead to an increased risk of things
Speaker 4: like aspiration, pneumonia and things like that down the line.
Speaker 4: So that's the motor half of Parkinson's disease. But then
Speaker 4: there's a whole suite of non motor symptoms. And it
Speaker 4: turns out we know now that the non motor symptoms
Speaker 4: can and generally do tend to start quite a number
Speaker 4: of years earlier than the motor symptoms. And yet these
Speaker 4: motor symptoms are the kind of hallmarks of Parkinson's, and
Speaker 4: so it's not until these motor symptoms arise that the
Speaker 4: diagnosis is able to be made.
Speaker 3: I read something really interesting about that in how like
Speaker 3: diagnostic criteria are kind of undergoing a little bit of
Speaker 3: a transformation right now, or people are trying to incorporate
Speaker 3: more of the non motor symptoms, because often when the
Speaker 3: motor symptoms arise, it's just like you said, it's like
Speaker 3: in later stages, and so clinical trials might be targeting
Speaker 3: things that aren't possible to target in those later stages,
Speaker 3: and so.
Speaker 4: On, Ooh, Aaron will get there in the event section.
Speaker 4: Don't you worry? But one hundred percent yes, But so
Speaker 4: what are some of these symptoms? Some of these are
Speaker 4: considered kind of prodromal symptoms where they might be present
Speaker 4: but very nonspecific at this point, so you might never
Speaker 4: associate them with Parkinson's until hindsight, until many years later
Speaker 4: and you realize, oh, these were actually symptoms of your Parkinson's.
Speaker 4: So these are things like constipation, very very common REM
Speaker 4: sleep disorders, which is honestly a entirely interesting probably worthy
Speaker 4: of its whole own category. I feel like we've talked
Speaker 4: about sleep and doing a lot of episodes on sleep.
Speaker 4: But REM sleep is your dream sleep, like it's your
Speaker 4: rapid eye. REM stands for rapid eye movement, and so
Speaker 4: this is when you're having a lot of dreams and
Speaker 4: normally during REM sleep, you don't really move, You're kind
Speaker 4: of a tonic. In REM sleep disorders, people are very
Speaker 4: active during REM sleep. So this includes doing things like talking, moving,
Speaker 4: even going so far as acting out their dreams. And
Speaker 4: this of course can potentially actually be quite dangerous if
Speaker 4: people are getting up and moving and doing things during
Speaker 4: REM sleep as a part of a REM sleep disorder. Okay, yeah,
Speaker 4: this is not specific to Parkinson's, but very often seen
Speaker 4: in people who eventually are diagnosed with Parkinson's. Then there's
Speaker 4: also things like depression, anxiety, or general mood changes. Sometimes
Speaker 4: we'll see things like hypotension or low blood pressure. Very interestingly,
Speaker 4: a diminishing of the sense of smell, so either like
Speaker 4: a complete loss of sense of smell or just your
Speaker 4: sense of smelln't isn't as good anymore. It's called hyposmia.
Speaker 4: Sometimes there'll be urinary symptoms like difficulty urinating or like
Speaker 4: urinary retention that sort of thing, or erectile dysfunction. And then,
Speaker 4: same as with our motor symptoms, these non motor symptoms
Speaker 4: also progress over time and lead to things like fatigue, apathy.
Speaker 4: Sometimes pain can become a pretty common symptom of Parkinson's,
Speaker 4: especially in the later stages that hypotension can progress to
Speaker 4: what's called dysautonomia, which is a very vague and general term,
Speaker 4: but it just means that your autonomic nervous system isn't
Speaker 4: regulating your blood pressure and your heart rate appropriately, So
Speaker 4: you can have drops in your blood pressure when it
Speaker 4: should be going up, you can have a high heart
Speaker 4: rate when it should be going slow, et cetera. And
Speaker 4: then eventually Parkinson's leads to dementia and can even lead
Speaker 4: to psychosis. Parkinson's generally does not cause death outright, but Parkinson's,
Speaker 4: because of all of these findings, often leads to a
Speaker 4: significant amount of life lost in that people die much
Speaker 4: earlier than they otherwise would because of Parkinson's. So that's
Speaker 4: the symptoms and what Parkinson's looks like. There are a
Speaker 4: couple of different things to talk about when it comes
Speaker 4: to the path of physiology.
Speaker 3: What the heck is going on?
Speaker 1: Wait?
Speaker 3: Can I ask a question first? Sure, So you said
Speaker 3: that the non motor symptoms tend to show up earlier.
Speaker 3: If I ask the question, how much earlier is the answer?
Speaker 3: It depends?
Speaker 4: It varies, You know me so well, it definitely is
Speaker 4: that it depends. But it's often years, like okay, I
Speaker 4: mean it could be on the order of several years.
Speaker 4: It could be on the order of a decade or more.
Speaker 3: Oh my gosh.
Speaker 4: Yeah, And it's it's hard right now, like because this
Speaker 4: is not something that we have a diagnostic.
Speaker 3: Test for at all.
Speaker 4: Constipation that's a very vague symptom, right, even depression, anxiety.
Speaker 4: These are things that could be manifest that are entirely
Speaker 4: unrelated to Parkinson's or they could be there as a
Speaker 4: result of Parkinson's. Sure, and so it's a little bit
Speaker 4: hard to tease out for some of these, some of
Speaker 4: them I think are a little bit more strongly associated
Speaker 4: with like Parkinson's, and only a few other things like
Speaker 4: the rum sleep disorders for example, so that you might
Speaker 4: be able to say, Okay, well this started, you know,
Speaker 4: three years before your Parkinson's diagnosis or something like that.
Speaker 4: But in any case, all of these, especially the non
Speaker 4: motor prodromal symptoms, often start years before a Parkinson's diagnosis.
Speaker 3: Okay. So there's two.
Speaker 4: Things to talk about when it comes to the kind
Speaker 4: of path of physiology of what's going on in our brain.
Speaker 4: There's what has happened and what is happening in the
Speaker 4: brain of someone with Parkinson's and why that finding what's
Speaker 4: happening in the brain leads to these symptoms that we
Speaker 4: just described. And then there's our favorite question on this podcast,
Speaker 4: how does this happen? Or as you often ask Aaron,
Speaker 4: why my favorite question? So first let me answer the
Speaker 4: easy part, what is happening? And this is the part
Speaker 4: where I said, in some ways it's kind of straightforward
Speaker 4: to explain. Parkinson's disease results from destruction or degeneration of
Speaker 4: a specific set of neurons, A lot of neurons really,
Speaker 4: but predominantly neurons in a part of our brain that
Speaker 4: are called the substantia Niagara pars compacta or SNPC. Okay,
Speaker 4: I promise I'm not going to just name brain areas
Speaker 4: for this whole episode. So this is an area of
Speaker 4: the brain. It's specifically this little cluster of neurons in
Speaker 4: our mid brain, which is part of our brain stem
Speaker 4: at the base of our brain, that happens to have
Speaker 4: a main function of being dopaminergic.
Speaker 3: What does that mean.
Speaker 4: It means these neurons are making dopamine. Dopamine, of course,
Speaker 4: is one of our neurotransmitters. Most people have probably heard
Speaker 4: of dopamine because it gets a lot of press. It
Speaker 4: does a lot in our brain. It's one of our
Speaker 4: happy hormones, right. This is a neurotransmitter that affects actions
Speaker 4: in our brain. It happens to have a huge role
Speaker 4: to play in motor control, cognition, learning, and reward, all
Speaker 4: happening in our brain. It also does a lot of
Speaker 4: other stuff in our GI tract, like modulating GI motility.
Speaker 4: It helps with blood pressure maintenance, it's a precursor for
Speaker 4: other hormones and the rest of our body.
Speaker 3: It does a lot. I just I find it so
Speaker 3: fascinating that it's involved in GI motility.
Speaker 4: Have you heard aaron of like the gut brain axis? Oh? Yeah,
Speaker 4: we should do a whole episode on that, because like dopamine, serotonin,
Speaker 4: these things that are acting more in our guts than
Speaker 4: our brains.
Speaker 3: And I love it. Okay, I am, I'm writing this
Speaker 3: down for sure. We're doing this.
Speaker 4: Okay, cool, Okay, But back to Parkinson's Yes, yes, So,
Speaker 4: these neurons in the SNPC.
Speaker 3: Make dopamine.
Speaker 4: They shuttle that dopamine through the nerve axons to another
Speaker 4: part of our brain. Called the putamen, which is a
Speaker 4: part of our basil ganglia.
Speaker 3: It's deep in.
Speaker 4: Our brain, and this area in our brain is very
Speaker 4: specifically involved in motor control. It coordinates a huge amount,
Speaker 4: if not almost all of our motor functions and also learning,
Speaker 4: also speech articulation, language function, cognitive function. A lot of
Speaker 4: different things have to pass through this basil ganglia via
Speaker 4: these axons. So what we see in Parkinson's is that
Speaker 4: this area of the brain and these axons, specifically what's
Speaker 4: called the nigrostriadol pathway, gets degenerated. In the brains of
Speaker 4: people who have died with Parkinson's, this part of their
Speaker 4: brain is completely pale, which means that all of the
Speaker 4: neuromelanin that is supposed to be there is gone. It's
Speaker 4: just completely degenerated. So we see this degeneration. And the
Speaker 4: second thing that we see is the deposition of what
Speaker 4: are called Louis bodies. Louis bodies are these aggregates of proteins,
Speaker 4: multiple misfolded proteins, but the primary one involved is called
Speaker 4: alpha sin nucleon, and this is a protein that we
Speaker 4: don't fully understand.
Speaker 3: In our brain.
Speaker 4: There's a lot of proteins in our brain that we
Speaker 4: don't fully understand, and when it becomes misfolded in a
Speaker 4: variety of different ways, it can accumulate in our neurons
Speaker 4: and lead to further neuronal damage like Preon style, Like
Speaker 4: Preon style, Yes, like Preon style. You can find Louis
Speaker 4: bodies in people with Parkinson's, but also in people with Alzheimer's,
Speaker 4: and of course there are other misfolded proteins that are
Speaker 4: involved in Alzheimer's disease as well. Loui bodies are also
Speaker 4: present in another disorder called dementia with Loui bodies that's
Speaker 4: separate from Parkinson's but shares a lot of similarities. Rem
Speaker 4: sleep disorder is one of them, and in Parkinson's, these
Speaker 4: Loui bodies deposit in these areas we've already talked about,
Speaker 4: like the substantium niagara, but also in a variety of
Speaker 4: other brain regions as well, So now we know what
Speaker 4: is happening. Neurons are being degenerated in the part of
Speaker 4: our brain that controls dopamine production, So now we don't
Speaker 4: have dopamine. If we don't have dopamine flowing, then our
Speaker 4: nerves can't fire. If our nerves can't fire, specifically, the
Speaker 4: nerves that are controlling our motor movements, we're going to
Speaker 4: have problems with those motor movements. Specifically, we're not going
Speaker 4: to be able to extend. Our muscles, going to become
Speaker 4: fixed in certain positions. They're going to be rigid because
Speaker 4: our brain can't tell them no fire again, no fire again,
Speaker 4: or no relax again. Right, Because there's both positive and
Speaker 4: negative pathways that have to happen for us to be
Speaker 4: able to coordinate our movement smoothly. So that is why
Speaker 4: we see most of the predominant symptoms of Parkinson's. It's
Speaker 4: a lack of coordination of our muscle response.
Speaker 1: Right.
Speaker 3: But now the question is how and why and why?
Speaker 4: And that is a question that we still don't know,
Speaker 4: and it's a very highly debated topic and highly researched question.
Speaker 3: Yeah, we know the what.
Speaker 4: We know that alphas and nucleon and these lowy bodies
Speaker 4: are very involved. We know that neurodegeneration is happening. But
Speaker 4: exactly how how this process happens and the order in
Speaker 4: which it happens is still very much up for debate.
Speaker 4: It's not entirely clear. Is it that this protein alphasin
Speaker 4: nucleon starts to become misfolded for one reason or another
Speaker 4: and starts to deposit in our brain, and that is
Speaker 4: what causes the death of the neurons or is it
Speaker 4: inflammation because of either mitochondrial dysfunction and reactive oxygen species
Speaker 4: formation or because of other toxic insults to the brain
Speaker 4: over time that leads to the death of neurons and
Speaker 4: further inflammation which then leads to protein misfolding and alphasin
Speaker 4: nucleon deposition.
Speaker 3: We don't know I mean, or is it are those
Speaker 3: two things mutually exclusive? Where you know what I mean?
Speaker 3: Like if the end result is the same there exactly?
Speaker 4: And like I said, this is a disease that can
Speaker 4: be highly variable in presentation, in time course. And there
Speaker 4: are a lot of other disorders that are classified as
Speaker 4: parkinsonism because they share a lot of similar features, but
Speaker 4: not necessarily all these same hallmarks on autopsy of the brain. Right,
Speaker 4: so there is a lot of pathways to end to
Speaker 4: the same result. Yeah, so we don't fully know as
Speaker 4: usual on this podcast, but we at least know a
Speaker 4: lot of the major players that are involved.
Speaker 3: Does that make sense? Yeah, I still want to know
Speaker 3: why does it happen in those regions of the brain
Speaker 3: that it happens, Why does it tend to be associated
Speaker 3: with older age? But yet, like what happens with early
Speaker 3: on set Parkinson's disease, what environmental Like there's been associations
Speaker 3: with pesticides and so on, Like, what is happening? Why
Speaker 3: is that happening?
Speaker 4: Yeah, so there's kind of it's interesting. So Parkinson's is
Speaker 4: an age related disease most definitely, But like you said,
Speaker 4: it does not mean that everyone who gets it is
Speaker 4: old at the time of diagnosis, or even middle age
Speaker 4: at the time of diagnosis. Twenty five percent of people
Speaker 4: are diagnosed under age sixty five. Five to ten percent
Speaker 4: of people who are diagnosed are under age fifty.
Speaker 3: Wow.
Speaker 4: And the time course can really vary because, like I said,
Speaker 4: the prodromal symptoms can start years before the diagnosis actually happens.
Speaker 4: Right in general, aside from age, which is like considered
Speaker 4: the main risk factor just because the majority of people
Speaker 4: diagnosed are over age sixty five, the two big determinants
Speaker 4: of Parkinson's disease are genetics and environmental factors, and then
Speaker 4: their interaction. There was a time in which it was
Speaker 4: thought to be just genetic. It is definitely not. There
Speaker 4: are a few monogenic forms of Parkinson's disease, and much
Speaker 4: like what we talked about in our Migraine episode, which
Speaker 4: aaron I was like, how have we done so many
Speaker 4: brain episodes?
Speaker 2: We have done that.
Speaker 3: We did epilepsy this season, didn't we We.
Speaker 4: Did we do epilepsy this season? Our last season, I
Speaker 4: don't remember. We've done a lot, Yeah, we have. But
Speaker 4: like in our Migraine episode, there are these monogenic forms
Speaker 4: of Parkinson's disease. They are not the norm They are
Speaker 4: definitely not the most common types of Parkinson's disease, but
Speaker 4: they's still a very important part of the research of
Speaker 4: Parkinson's disease because not only are these forms of Parkinson's
Speaker 4: disease potentially good targets for things like gene therapy in
Speaker 4: terms of treatment, but it also tells us a lot
Speaker 4: about the underpinnings the basic pathophysiology of this disease, even
Speaker 4: for other forms.
Speaker 3: Right. Yeah, So there's a number.
Speaker 4: Of specific single gene mutations, a variety of different mutations
Speaker 4: therein that have been linked to the development of Parkinson's disease.
Speaker 4: Some of them are related to our good friend alphas
Speaker 4: and nucleon Some of them are related to mitochondrial dysfunction,
Speaker 4: but it's really kind of a wide variety, so there's
Speaker 4: not still like a clear cut answer from the genetic
Speaker 4: side of things. You asked about environmental factors, and we
Speaker 4: really don't know when it comes to environmental factors. There's
Speaker 4: a few that have been identified as increasing risk of Parkinson's,
Speaker 4: like TBI or traumatic brain injury, or pesticide exposure, And
Speaker 4: I don't know what pesticides.
Speaker 3: Because that's just like very variable, I know, and everything
Speaker 3: I saw was just pesticide. And I also, to be fair,
Speaker 3: I didn't look up Parkinson's and specific pesticides, but like
Speaker 3: it was just like pesticides. Well, because it's also.
Speaker 4: Been linked to working in an agriculture environment, so I
Speaker 4: think it might be like a variety of different pesticides
Speaker 4: have been quote unquote linked to an increased risk. There
Speaker 4: are also some exposures that seem to be related to
Speaker 4: a decreased risk of Parkinson's, including interestingly, cigarette smoking and
Speaker 4: coffee drinking, but there is no causal relationship that has
Speaker 4: been linked in any of these cases. The cigarette smoking
Speaker 4: is really interesting because some of the theories are that
Speaker 4: it actually just has to do with how much dopamine
Speaker 4: you have in your brain, so it just like delays
Speaker 4: the onset of symptoms rather than actually delaying any disease
Speaker 4: process or something like that. Huh yeah, But in any case,
Speaker 4: we don't really know, but we know that it's not
Speaker 4: purely genetic. So there are in fact environmental factors that
Speaker 4: play a role in Parkinson's disease.
Speaker 3: And then there's treatment.
Speaker 4: And I mentioned at the top that the treatment for
Speaker 4: Parkinson's disease is actually in some ways part of the
Speaker 4: diagnosis of Parkinson's disease, at least at this point, because
Speaker 4: since Parkinson's disease is at its core a disruption in
Speaker 4: our ability to produce dopamine in our brains, like that
Speaker 4: is what's happening in our brains. The treatment is kind
Speaker 4: of simple. It's replacing dopamine. So we give this in
Speaker 4: general in the form of a combination of carbon dopa
Speaker 4: and leve doopa, which are like precursors to dopamine, so
Speaker 4: that they last longer in our body and actually make
Speaker 4: it into our brain rather than just staying in our bloodstream.
Speaker 4: And if someone has these motor symptoms consistent with parkinsonism,
Speaker 4: and they respond to dopamine like their symptoms improve usually
Speaker 4: drastically with treatment. That's when you can be pretty sure
Speaker 4: that the diagnosis is Parkinson's disease. Technically, still, the only
Speaker 4: definitive diagnosis is made post mortem, with an autopsy of
Speaker 4: the brain that shows these very spific findings associated with
Speaker 4: Parkinson's disease.
Speaker 3: It's really interesting to think about treatment as part of
Speaker 3: the diagnostic criteria, like I had never that had never
Speaker 3: occurred to me. Yeah, but it makes complete sense, like, yeah,
Speaker 3: if you don't respond to dopamine, something else is happening,
Speaker 3: exactly exactly.
Speaker 4: The problem is that even in Parkinson's disease, something else
Speaker 4: is also happening. While the substantia Niagara pars compacta and
Speaker 4: the dopaminergic neurons therein are the primary part of our
Speaker 4: brain that is subject to neurodegeneration in Parkinson's, it is
Speaker 4: not the only one.
Speaker 3: And it's not.
Speaker 4: Only these dopamine producing neurons. We also see effect on
Speaker 4: a lot of other neurons that produce things like acetylcholine
Speaker 4: and norepinephrine and all of our other neurotransmitters, which is
Speaker 4: part of why we see symptoms that aren't purely dopamine related. Right,
Speaker 4: There's a lot of other symptoms associated with Parkinson's that
Speaker 4: are larger than just dopamine. So treating someone with dopamine
Speaker 4: isn't going to fix all of those symptoms, and we
Speaker 4: don't necessarily have great treatment for all of the rest
Speaker 4: of things aside from like treating depression if that is
Speaker 4: a symptom, or treating low blood pressure.
Speaker 3: If that is a symptom kind of a thing.
Speaker 4: What we don't have at all right now are any
Speaker 4: disease modifying therapies. So even treating someone with dopamine doesn't
Speaker 4: change the course of disease. It improves symptoms, it improves
Speaker 4: quality of life, but it does not change the underlying problem,
Speaker 4: and it doesn't change the course of disease.
Speaker 1: Right.
Speaker 4: In addition, both Parkinson's disease itself as it progresses and
Speaker 4: replacing that dopamine externally can actually lead to its own problems.
Speaker 4: The side effects of this dopamine administration are called diskenesia's tardiv.
Speaker 4: Discinesia is one of the main ones, and these are
Speaker 4: the erratic or uncontrollable movements of the limbs or the
Speaker 4: trunk or in tardiv diskinesia the face, things like eye blinking,
Speaker 4: uncontrollable neck movements, or tongue movements. Some people might think
Speaker 4: of these as hallmarks of Parkinson's disease, but really they
Speaker 4: are an issue with the treatment for Parkinson's. It's replacing
Speaker 4: that dopamine. So we also see these type of symptoms
Speaker 4: in people who are on antipsychotics that are increasing the
Speaker 4: dopamine in their brains. They can have these same kind
Speaker 4: of symptoms. That's most of what I have for Parkinson's disease.
Speaker 4: In terms of prognosis, It's hard to give an exact
Speaker 4: one because despite this being very specific brain findings, it's
Speaker 4: a very variable disease. In some of the literature, people
Speaker 4: have started to try to classify Parkinson's into different subgroups
Speaker 4: because of how variable the presentation can be, and there's
Speaker 4: a few different ways that it's been done, depending on
Speaker 4: which literature you read. One common way is to separate
Speaker 4: it into kind of mild motor predominant, an intermediate group,
Speaker 4: and then what's called a diffuse malignant group, or you
Speaker 4: can think of it as very severe and very rapid
Speaker 4: onset group. And in all of these three groups, the
Speaker 4: prognosis is going to be very different. The duration of
Speaker 4: disease in terms of how long you go from very
Speaker 4: mild symptoms that are very easy to deal with to
Speaker 4: not being able to swallow safely or not being able
Speaker 4: to move at all. It's really highly variable. If we
Speaker 4: think of probably the most well known individual with Parkinson's,
Speaker 4: Michael J. Fawx, he was diagnosed at age twenty nine,
Speaker 4: which is incredibly young. It's a very early onset form
Speaker 4: of Parkinson's disease. He's now over sixty and still very functional.
Speaker 3: Right.
Speaker 4: On the other hand, there are forms of Parkinson's that
Speaker 4: sometimes aren't ever distinguished from Parkinson's disease or one of
Speaker 4: these other more atypical Parkinsonisms that can progress incredibly rapidly.
Speaker 4: I had a patient that I cared for in medical
Speaker 4: school who in the course of a few months, like
Speaker 4: under a year, went from being someone who could kayak
Speaker 4: and go for hikes to passing away as a result
Speaker 4: of these Parkinson's symptoms. So there's a huge amount of variability,
Speaker 4: which makes it really difficult not only to study, but
Speaker 4: also to understand what is going on and how can
Speaker 4: it be so different in different individuals.
Speaker 3: Right like just trying to tease apart individual factors from
Speaker 3: is it the same disease progression like everything. Yeah.
Speaker 1: Yeah.
Speaker 3: One thing I came across was the placebo effect and
Speaker 3: how this seems to be kind of an interesting field
Speaker 3: for Parkinson's disease research where a lot of the times
Speaker 3: in like a very positive way, where there'll be a
Speaker 3: clinical trial for a certain new type of drug or
Speaker 3: something like that, and it turns out that both the
Speaker 3: treatment and non treatment groups improve equally, Like there's a
Speaker 3: strong placebo effect. And I just didn't know if you
Speaker 3: had read anything about that or like what what that
Speaker 3: could mean, or because like some of just the little
Speaker 3: things about Parkinson's I find so fascinating, where in terms
Speaker 3: of walking, sometimes people with Parkinson's can freeze, but then
Speaker 3: if an obstacle is placed in front of them, then
Speaker 3: they can step over it and then continue on. Like
Speaker 3: what causes this sort of start and stop.
Speaker 4: Start and stop? Yeah, I don't have a good answer
Speaker 4: for that. It's really interesting.
Speaker 3: Yeah.
Speaker 4: I imagine it's in part because until you get very
Speaker 4: very very late in the course of disease, it's not
Speaker 4: like you have no dopamine whatsoever, right, and even late
Speaker 4: in the course of disease, you have some dopamine that
Speaker 4: still exists in the brain. So what determines how much
Speaker 4: dopamine makes it all the way to the places that
Speaker 4: it's supposed to bind And what other systems does our
Speaker 4: brain have as backup to be able to keep us
Speaker 4: functioning and moving the way that we're supposed to if
Speaker 4: there isn't enough dopamine for those signals.
Speaker 3: To get sent. Mm hmm, right.
Speaker 4: I think part of what it comes back to is
Speaker 4: that it's this is affecting the part of our brain
Speaker 4: that is coordinating and controlling things. It's not acting directly
Speaker 4: the motor cortex of our brain or our spinal cord
Speaker 4: where the nerves are actually exiting and directly contracting or
Speaker 4: relaxing muscles. Right, So the motor cortex of our brain
Speaker 4: is what is directly sending signals to the nerves that
Speaker 4: go to our muscles that say contract or release.
Speaker 3: So like the messaging is messed up. All of the
Speaker 3: systems are in place except for the control center to
Speaker 3: carry out those actions, but like the messages stop going
Speaker 3: out except for a few It's yes.
Speaker 4: It's like if you think of like a nineteen fifty's
Speaker 4: call center. You know those switchboard Yeah, yeah, people who
Speaker 4: would be like bloop blop bloop blop boop, and like
Speaker 4: sending messages to the right place. That part isn't working well.
Speaker 4: But down the line, all the phone cords are still connected, right,
Speaker 4: so some signals are going to get through and some
Speaker 4: calls are still going to make it to the right place,
Speaker 4: but the coordination of those messages is messed up. Okay,
Speaker 4: that's my me, not being a brain person the way
Speaker 4: I think about it.
Speaker 3: Yeah, Beyond el dopa, there are other options, right, like
Speaker 3: deep brain stimulation, exercise or like physical therapy and stuff
Speaker 3: like that.
Speaker 4: Absolutely, yeah, yeah, deep brain stimulation is one that I
Speaker 4: don't know very much about, but definitely exists as an option,
Speaker 4: especially for when el dopa stops working very well and
Speaker 4: like later in the course of disease. And then there
Speaker 4: are a lot of other things physical therapy not only
Speaker 4: for just like muscles fall prevention, but also physical activity
Speaker 4: increases our dopamine levels, So things that are increasing dopamine
Speaker 4: are also going to be helpful. And it's interesting that
Speaker 4: was what I thought of when you were saying that
Speaker 4: the placebo e fact seems very strong in.
Speaker 3: People with Parkinson's.
Speaker 4: And I do wonder because we don't understand the Placino effect.
Speaker 4: I mean, anyone can have a Placbo effect. Pacibo effect
Speaker 4: is awesome. We have.
Speaker 3: It's pretty cool.
Speaker 4: It's fascinating and very cool, and I wonder, like how
Speaker 4: much is it it is? It is our neurotransmitters, most
Speaker 4: likely because our brain is controlling so much. Is it
Speaker 4: that we think that something is working and so we
Speaker 4: are producing more dopamine and that is part of what's
Speaker 4: telling us that something is working and serotonin and whatever else.
Speaker 3: Ah, yeah, I mean I don't know, but I'm I'm
Speaker 3: right now as we speak adding it to our list
Speaker 3: of episodes topic placebo effect. That's a good one. So
Speaker 3: that's Parkinson's disease. You're right, it's like very fairly straightforward.
Speaker 3: But also we don't know what the heck is going
Speaker 3: on in our brain.
Speaker 4: Yeah, well, like we know what's going on in our brain,
Speaker 4: we just don't know why.
Speaker 3: Yeah yeah, And we like why does the swinging arms
Speaker 3: when walking? Why does that stop? Like yeah? Why? Yeah?
Speaker 4: I mean probably just too much this is me guessing,
Speaker 4: but like too many things to coordinate, right.
Speaker 3: Yeah, yeah, it's fascinating.
Speaker 1: Yeah.
Speaker 3: Yeah, well, Aaron, can I ask you.
Speaker 4: How did we get here? Where did Parkinson's come from?
Speaker 4: Besides our brain or maybe our environment?
Speaker 3: I don't know. Yeah, lots of questions there. Let's take
Speaker 3: a break and then I'll see what I can do. Aaron,
Speaker 3: you asked, where did this come from? You know I'm
Speaker 3: not going to be able to answer that question unfortunately. No,
Speaker 3: And I think at this point it's not a question
Speaker 3: that anyone can answer, at least with any level of certainty.
Speaker 3: Humans seem to be the only species that develops Parkinson's
Speaker 3: disease naturally, like it can be induced in animal models. Interesting,
Speaker 3: and maybe people have hypothesized that that's due to our
Speaker 3: pretty good longevity. We have pretty long, long longevity, as
Speaker 3: suggesting that Parkinson's disease is more or less mostly a
Speaker 3: disease of aging. But what about like blue whales or
Speaker 3: giant tortoises, other creatures that have longevity. Yeah, sea turtles
Speaker 3: live like undreds of years man. Yeah, and as far
Speaker 3: as I have read, they have not been observed to
Speaker 3: develop Parkinson's, So maybe it's something to do with our
Speaker 3: human brain. I did come across one paper that refutes
Speaker 3: the more like widely accepted preon kind of misfolded protein
Speaker 3: model for Parkinson's, and the authors instead suggest that it
Speaker 3: has to do with how during early human evolution, our
Speaker 3: brain expanded in certain ways that left other parts behind.
Speaker 3: So like the olfactory part of our brain is smaller
Speaker 3: relative to other primates, for instance, and those areas that
Speaker 3: didn't expand during human brain evolution maybe are more susceptible
Speaker 3: to like neuron loss. I don't know. I also did
Speaker 3: come across that humans have relatively fewer dopamine neurons than
Speaker 3: other animals as a function of size. So the example
Speaker 3: that I came across was that a mouse has roughly
Speaker 3: twenty thousand dopamine neurons, while an average human has around
Speaker 3: four hundred thousand, So it's only twenty times more than
Speaker 3: a mouse, despite humans being well more than twenty times
Speaker 3: the size of a mouse. Okay, interesting, I don't know.
Speaker 3: And part of the reason I don't know and no
Speaker 3: one seems to really know is that the driver's and
Speaker 3: precise path of physiology of Parkinson's disease have not been
Speaker 3: fully worked out right. But don't worry, there is still
Speaker 3: so so much more to talk about in terms of
Speaker 3: the history of Parkinson's disease, and so for now, let's
Speaker 3: head back to the ancient world to see whether people
Speaker 3: recognize the disease long ago. Did they? Did they? Yes,
Speaker 3: of course they did. Hah. There's an ancient Egyptian papyrus
Speaker 3: that describes excessive drooling in an elderly king. There are
Speaker 3: ancient Indian texts that describe a chronic progressive condition, including
Speaker 3: tremor and lack of movement. There are ancient Chinese teps
Speaker 3: that describe tremor and stiffness, and one of our frequent mentions,
Speaker 3: the ancient Greek physician Galen wrote of resting and action tremors.
Speaker 3: What's really fascinating is that in some of the ancient
Speaker 3: Indian and ancient Chinese texts, treatment was recommended in the
Speaker 3: form of various herbal concoctions, often containing seeds or extracts
Speaker 3: from seeds. And it turns out that some of those seeds,
Speaker 3: when analyzed, you know, in the twentieth century, contain LEVDOPA
Speaker 3: or have anti colinergic and dopaminergic properties. Is that kind
Speaker 3: of really? I just love that, Like it probably worked. Yeah. Yeah.
Speaker 3: There are also a handful of possible references to Parkinson's
Speaker 3: that pop up throughout the centuries. Leonardo da Vinci wrote
Speaker 3: about people quote whose soul cannot control their movements in
Speaker 3: spite of the fact that their extremities are shaking continuously
Speaker 3: end quote. There's a possible reference to Parkinson's disease in
Speaker 3: Shakespeare's Henry the sixth Part two. Dick the butcher asks
Speaker 3: why dost thou quiver man, and Lord say replies, the
Speaker 3: palsy and not fear provokes me. And philosopher Thomas Hobbes,
Speaker 3: who lived in the seventeenth century, is thought to have
Speaker 3: had it. Quote he had the shaking palsy in his hands,
Speaker 3: which began in France before the year sixteen fifty, when
Speaker 3: he was aged sixty two, and has grown upon him
Speaker 3: by degrees ever since, so that he has not been
Speaker 3: able to write very legibly since sixteen fifty five or
Speaker 3: sixteen sixty six. So people have clearly recognized Parkinson's disease
Speaker 3: for a long time, But how would it get its name, like?
Speaker 3: Who was Parkinson? Essentially? James Parkinson was born in seventeen
Speaker 3: fifty five in London, England, and decided to follow in
Speaker 3: his father's footsteps, training as a surgeon and apothecary, but
Speaker 3: also becoming in the meantime a political pamphleteer, a member
Speaker 3: of secret societies, a pacifist, a campaigner for social welfare,
Speaker 3: involved in like mysterious plots, a paleontologist and geologist. I'm sorry, yeah,
Speaker 3: I don't know how he had all this time. Yeah,
Speaker 3: to also possibly be the first to describe appendicitis maybe,
Speaker 3: and was, of course the namesake of Parkinson's disease.
Speaker 4: Sorry, I can't get over the paleontologist too, Like what Yeah?
Speaker 3: I think that was one of his most famous publications
Speaker 3: was on like paleontology slash geology.
Speaker 4: I am envious, right, I'm one of jack of all
Speaker 4: trades that well, I mean.
Speaker 3: Gosh, I mean I feel like you do. Thanks appreciate that.
Speaker 3: You just have to start publishing pamphlets. Now, there you go.
Speaker 3: I could do a pamphlet, pamphlet, will create a secret
Speaker 3: society and then check done anyway. In eighteen seventeen, Parkinson
Speaker 3: published a paper titled Essay on the Shaking Palsy, in
Speaker 3: which he described six cases a combination of patients that
Speaker 3: he had personally examined, as well as one or two
Speaker 3: that you just saw walking around the neighborhood. I know
Speaker 3: it's I it's amazing to me that this is the
Speaker 3: paper and one of it, like one of the case
Speaker 3: descriptions is literally like I did not have a chance
Speaker 3: to talk to this person, but this is what they
Speaker 3: looked like from AFAR. So you know, okay, eighteen seventeen
Speaker 3: publishing standards. Yeah, no, IRB, that's for sure. No, no.
Speaker 3: So I'm going to read a little quote from this quote.
Speaker 3: So slight and nearly imperceptible are the inroads of this malady,
Speaker 3: and so extremely slow its progress that the patient cannot
Speaker 3: recall the onset. The first symptoms perceived are a slight
Speaker 3: sense of weakness with a proneness to trembling, most commonly
Speaker 3: in one of the hands and arms. As the disease proceeds,
Speaker 3: the hand fails to answer the dictates of the will.
Speaker 3: Walking becomes a task which cannot be performed with how
Speaker 3: considerable attention care is necessary to prevent falls, difficulties increase.
Speaker 3: Writing can now be hardly at all accomplished, and reading
Speaker 3: from the tremulous motion is accomplished with some difficulty. End quote.
Speaker 3: I really just liked that phrase. The hand fails to
Speaker 3: answer the dictates of the will. Yeah.
Speaker 4: Yeah, I feel like that's a very good descriptor of what's.
Speaker 3: Going on in the brain. Yeah. It uses way fewer
Speaker 3: words than what we did trying to talk about the
Speaker 3: control tower, and it took me like forty minutes to
Speaker 3: like the hand can't do it. And then Parkinson's in
Speaker 3: this essay goes on to describe changes in walking, the
Speaker 3: tendency for constipation to be a frequent symptom, and then
Speaker 3: the final stages of disease. Parkinson also laid out some
Speaker 3: of the ideas that he had about what caused the disease,
Speaker 3: which he thought originated in like the spinal cord or
Speaker 3: brainstem you know, yeah, not far off, yeah, as well
Speaker 3: as possible treatments, mostly relating to bloodletting, but ultimately acknowledged
Speaker 3: that nothing had an effect and said that he hoped
Speaker 3: that that would change one day if enough people, you know,
Speaker 3: put their attention to this, put their focus on this disease.
Speaker 3: And at the time that it was published, the essay
Speaker 3: didn't really make much of a splash, and he died
Speaker 3: in eighteen twenty four, seven years after it was published,
Speaker 3: never knowing just how famous his name would become. Wow.
Speaker 3: And in fact, we might today call the disease by
Speaker 3: a completely different name if it weren't for Jean Martin Scharco.
Speaker 3: I've definitely mentioned Charco several times on the podcast before.
Speaker 3: Very famous dude. Yeah, and he at least makes an
Speaker 3: appearance in our episodes on multiple sclerosis and endometriosis. I
Speaker 3: think probably other ones as well, epilepsi. I don't know.
Speaker 3: Charco was a famous, famous medical scientist, both in his
Speaker 3: time as well as today, and his primary interest was
Speaker 3: in diseases of the nerves. People came from all over
Speaker 3: to watch him lecture at the public hospital where he
Speaker 3: worked in Paris, and the list of diseases he recognized
Speaker 3: or described, or that have been named after him, it's
Speaker 3: a long list. It's a very long list. Yeah. Almost
Speaker 3: fifty years after Parkinson's essay was published, Sharko got his
Speaker 3: hands on a copy and immediately recognized that many of
Speaker 3: his patients seemed to have the condition that Parkinson was describing,
Speaker 3: and so he went about systematically characterizing the disease as
Speaker 3: he had done with other conditions. He listed the most
Speaker 3: common symptoms tremor, rigidity, slowness, or poverty of movement, and
Speaker 3: postural instability, all of which Parkinson had pointed out, and
Speaker 3: then he added two more small handwriting and facial masking.
Speaker 3: Oh yeah, facial masking. Yeah, Aaron, could you give us
Speaker 3: a quick definition of facial masking.
Speaker 4: Yeah, a mask faces or facial masking means like a
Speaker 4: face that's not really able to make expression. So it's
Speaker 4: a very expressionless face, which is really common in Parkinson's disease,
Speaker 4: especially later in the disease.
Speaker 3: Okay, thank you, that's what I thought it was, but
Speaker 3: I wasn't confident enough to give a definition. Yeah, appreciate it.
Speaker 3: Charcot also noted that tremor wasn't a consistently present symptom
Speaker 3: and argued that because of that, the condition shouldn't be
Speaker 3: called shaking palsy, but rather Parkinson's disease. Wow, so he
Speaker 3: named Parkinson's disease. Charco also described brady kinesia as a
Speaker 3: distinct symptom. Quote in some of the various patients I
Speaker 3: showed you, you can easily recognize how difficult it is
Speaker 3: for them to do things, even though rigidity or tremor
Speaker 3: is not the limiting feature. Instead, even a cursory exam
Speaker 3: demonstrates that their problem relates more to slowness in execution
Speaker 3: of movement rather than to real weakness end quote. Charco's
Speaker 3: contributions to Parkinson's disease went beyond adding to its description
Speaker 3: or raising awareness of the condition among the medical community.
Speaker 3: He also tried out all sorts of experimental therapies, medicines
Speaker 3: such as hiosiamine derived from Jimson weed, belladonna, cannabis, arsenic opium,
Speaker 3: and hemlo, as well as non pharmaceutical interventions like his
Speaker 3: quote unquote shaking chair and shaking helmet. Dear. So, he
Speaker 3: observed that symptoms sometimes got better after long carriage rides
Speaker 3: or horseback rides, and so he thought that shaking would help.
Speaker 3: It didn't. He did run trials and there were some benefits,
Speaker 3: but it was due to placebo effect. And when his
Speaker 3: shaking chair and shaking helmet didn't work, he also tried
Speaker 3: electrical stimulation SPA treatments, even some horrible sounding contraption that
Speaker 3: was supposed to stretch the spinal cord. Oh, dear did nothing.
Speaker 3: That's a torture device. Yeah, I think really nothing seemed
Speaker 3: to have an effect, and so you know, he reasoned
Speaker 3: maybe if the cause of the disease were to be discovered,
Speaker 3: then more effective treatments could be developed. So to try
Speaker 3: to identify the physical basis of Parkinson's disease, he was
Speaker 3: going to need to do a lot of autopsies, and
Speaker 3: fortunately the hospital where he worked had no shortage of
Speaker 3: opportunities for that since it took in many wards of
Speaker 3: the state. Ultimately, it wasn't Sharko himself but a couple
Speaker 3: of his students who would end up finding a hazelnut
Speaker 3: sized lump in the right side of the midbrain, close
Speaker 3: to the substantia nigra, and this was in a thirty
Speaker 3: eight year old patient with Parkinson's. Wow, so maybe the
Speaker 3: substantia nigra was where Parkinson's originated. Seemed like a reasonable hypothesis,
Speaker 3: but no one really did anything about it for twenty
Speaker 3: five years or so until nineteen nineteen. That was the
Speaker 3: year that a Russian graduate student named Konstantine Tretiakov who
Speaker 3: was working in Paris, published his findings from fifty four
Speaker 3: autopsied brains. All of the nine from people with Parkinson's
Speaker 3: had extensive damage to the substantia nigra, and none of
Speaker 3: the other brains did even more compelling was his finding
Speaker 3: of neuronal inclusions in the brains of people with Parkinson's
Speaker 3: and that was the same finding that Fritz Louis had
Speaker 3: previously made aka Louis Bodies Louie buddies. Okay, And this
Speaker 3: narrowing in on what changed physiologically or physically in Parkinson's
Speaker 3: disease really helped researchers to focus their efforts on possible treatments,
Speaker 3: because if they knew what was actually changing and how
Speaker 3: those changes were associated with the signs of Parkinson's disease,
Speaker 3: then maybe they could develop a treatment to slow the
Speaker 3: progress or at the very least alleviate the symptoms of
Speaker 3: the condition. And that's where we find ourselves with dopamine
Speaker 3: and eldopa. The story begins in nineteen ten. That year,
Speaker 3: dopamine was first synthesized by researchers Burger and Ewan, who
Speaker 3: I think were more or less just casting a wide
Speaker 3: net for chemicals that had an effect on the sympathetic
Speaker 3: nervous system. Seemed like a very hot time for that
Speaker 3: kind of research, Like I couldn't get at why they
Speaker 3: were looking at dopamine, or how they found dopamine, or
Speaker 3: what they were looking for when they found it. Okay,
Speaker 3: that's as far as I could discern. But at the
Speaker 3: time of this publication and for decades after, dopamine was
Speaker 3: not really considered anything more than an intermediate compound in
Speaker 3: the production of adrenaline and nor adrenaline. It was just
Speaker 3: sort of like, nah, this is unimportant by itself, right, Yeah.
Speaker 4: Also, no, adrenaline and adrenaline are also called epinefrinin nor
Speaker 4: epinephrine today today, Yeah, I feel like that's important because
Speaker 4: I said nor epineffyrin earlier, so.
Speaker 3: I know, well, and that's what like. I may have
Speaker 3: changed it, but I think I had them both in here.
Speaker 3: They're both so they're both correct.
Speaker 2: Yeah.
Speaker 3: Yeah. A year after this paper came out, d L dopa,
Speaker 3: so like another form of el dopa, was first synthesized
Speaker 3: by Casimir Funk, who this is a good TPWKY trivia question.
Speaker 3: Does his name sounds familiar to you? Yeah? It does.
Speaker 4: Oh, I feel like it's one of our chemical episodes
Speaker 4: and it's not tilan all, is it.
Speaker 3: No? Well maybe, I mean I don't I don't know.
Speaker 3: I would not have gotten this. I had to search.
Speaker 3: He coined the word vitamin. Oh. Yeah, because they're vital. Okay,
Speaker 3: vital I mean yeah yeah. And a couple of years
Speaker 3: after that, another researcher, Marcus Guggenheim, isolated el dopa from
Speaker 3: fava beans, decided to try it out why don't know,
Speaker 3: and quickly discovered its tendency to induce vomiting, but he
Speaker 3: didn't notice any other effect, and so he just wrote
Speaker 3: it off as a naturally occurring molecule with no real
Speaker 3: therapeutic promise. Oh wow, yeah, like, why would anyone want
Speaker 3: to take this? It has this horrible side effect? And
Speaker 3: then in nineteen thirty eight, I swear we're getting there.
Speaker 3: It's just like a lot of steps along this stree.
Speaker 3: I love this, Okay. Researcher Peter Holtz and colleagues discovered
Speaker 3: the enzyme dopa decarboxylase, which converts el dopa to dopamine,
Speaker 3: and that revealed how dopamine could be created in the
Speaker 3: brain if you gave someone el dopa, Because well, dopamine
Speaker 3: cannot cross the blood brain barrier on its own, el
Speaker 3: dopa can. Yeah, And by the nineteen fifties, people were
Speaker 3: starting to suspect that maybe dopamine was actually important as
Speaker 3: just an individual molecule.
Speaker 4: Wow, nineteen fifties, nineteen fifty and maybe even more than important.
Speaker 3: It was essential huh yeah. One of the most prominent
Speaker 3: names associated with this reframing of dopamine was a Swedish
Speaker 3: researcher named Arvid Carlson, who in the late nineteen fifties
Speaker 3: was leading a team researching the effects of the recently
Speaker 3: introduced to antipsychotic drug resurpene or resurpine I'm not sure.
Speaker 3: They gave rabbits various doses and found that at higher
Speaker 3: doses of recurpene the rabbits became paralyzed with Parkinson's like symptoms.
Speaker 3: Carlson suggested that maybe the drug was blocking the uptake
Speaker 3: of an essential neurotransmitter in the brain and thought that
Speaker 3: maybe if they injected the rabbits with el dopa, then
Speaker 3: maybe the balance of neurotransmitters like adrenaline and ner adrenaline
Speaker 3: or epinephrin and nora openephrin would be restored. And sure enough,
Speaker 3: the el dopa worked almost like magic. The rabbits woke
Speaker 3: up and were moving around in no time. But was
Speaker 3: it because because the balance had been restored or was
Speaker 3: something else going on? When Carlson took a closer look
Speaker 3: at the chemical makeup in the rabbit's brains. He found
Speaker 3: that the el dopa didn't convert into adrenaline and nor
Speaker 3: adrenaline as he had expected, but rather this supposedly unimportant
Speaker 3: molecule dopamine. Wow, it was like, Okay, this is kind
Speaker 3: of revolutionary. And then then not long after, researcher Kathleen
Speaker 3: Montague demonstrated the presence of dopamine in the brain of humans,
Speaker 3: and that was later confirmed by Carlson's lab, and they
Speaker 3: had developed assays to measure like the amount of dopamine
Speaker 3: in different parts of the body and different parts of
Speaker 3: the brain, which also was like whoa, yeah, more here
Speaker 3: going on than we thought. And so all of this
Speaker 3: together led Carlson to suggest that dopamine was essential for
Speaker 3: normal brain function and the control of movement, and that
Speaker 3: adop deficiency maybe at the root of Parkinson's disease, and
Speaker 3: that just so.
Speaker 4: That I understand, they are like reasoning behind it was
Speaker 4: because of the symptoms that they saw in animals who
Speaker 4: were dopamine deficient, or that they blocked their dopamine receptors,
Speaker 4: but not yet necessarily because they made the connection between
Speaker 4: the neurons in the part of the brain that they
Speaker 4: already knew were involved right from way back when that
Speaker 4: those also happened to be the dopo energic neurons.
Speaker 3: Right, there was still that sort of connection. So they saw, Okay,
Speaker 3: there is something that this drug is doing to prevent
Speaker 3: movement that's probably related to a neurotransmitter. We don't know
Speaker 3: that it's dopamine. Okay, So then what if we gave
Speaker 3: this neurotransmitter precursor aka L dopa dopa to the rabbits,
Speaker 3: Maybe that'll help fix things up. Yep, it worked way
Speaker 3: better than anticipated, and so then they took a closer look.
Speaker 3: They were like, hey, dopamine. Dopamine seems to be the
Speaker 3: answer here. And so since the symptoms in the rabbits
Speaker 3: were very similar to Parkinson's disease, dopamine Parkinson's and then
Speaker 3: we're almost getting there. I love it. We're so close.
Speaker 3: And it's now the nineteen sixties. You said, nineteen fifty
Speaker 3: eight is when he presented this hypothesis at the first
Speaker 3: International Catacholamine Symposium.
Speaker 4: Okay, I love this. What a symposium to be at, right.
Speaker 3: It was completely rejected His hypothesis morale, his hypothesis.
Speaker 4: Sid dopamine was involved in Parkinson's based on these findings.
Speaker 3: Yep, yeah, fascinating. Okay, okay, yeah. They were like more data, bro,
Speaker 3: They were like, you need more data. Also, stop with dopamine.
Speaker 3: Dopamine's never going to happen. It doesn't have a future.
Speaker 3: Oh my gosh, fetch that's exactly what I was thinking of.
Speaker 3: But Carlson would get the very last laugh when he
Speaker 3: was awarded first of all, the Nobel Prize in Physiology
Speaker 3: or Medicine in two thousand for his revolutionary work on dopamine,
Speaker 3: not just in Parkinson's but in general. And there were
Speaker 3: also many other laughs along the way, because while this
Speaker 3: hypothesis is probably not the best way to say that,
Speaker 3: but while this hypothesis was widely rejected, it wasn't unanimously rejected.
Speaker 3: Two Austrian researchers I apologized for my poor pronunciation. Ole
Speaker 3: Hornikowitz and Herbert Arainger were intrigued by this idea, and
Speaker 3: they decided to dig a bit deeper, which involved examining
Speaker 3: some brain samples from people who had died with Parkinson's,
Speaker 3: and sure enough, they found that the neurons in the
Speaker 3: region of the brain that was critical for movement, they
Speaker 3: were depleted of dopamine. Further, the substantia nigra region was
Speaker 3: also completely missing dopamine. So finally a dopamine centered framework
Speaker 3: of Parkinson's disease was coming to together, which was exciting
Speaker 3: on its own because it was like, oh, my gosh,
Speaker 3: finally we're understanding how these pieces are fitting together. But
Speaker 3: it was also potentially revolutionary because it promised hope for
Speaker 3: effective treatment, right because they already did the el dopa
Speaker 3: in the rabbits exactly and at this point treatment didn't exist, right,
Speaker 3: and so it was like it was an uncontrollable progression
Speaker 3: and that was the state of Parkinson's at the time.
Speaker 3: Maybe el dopa was the long awaited answer, and it
Speaker 3: seemed so, at least initially. In nineteen sixty one, researchers
Speaker 3: Walter Burkmeyer and Ole Hornikowitz administered small doses of el
Speaker 3: dopa to twenty patients with advanced Parkinson's disease. Hornikowitz later
Speaker 3: remembered the scene quote, it was a spectacular moment to
Speaker 3: see the patients who could not walk, could not get
Speaker 3: up from bed, could not stand up when seated, start walking.
Speaker 3: They all performed these activities like normal. Speech became better,
Speaker 3: they started laughing and actually crying with joy end quote wow.
Speaker 3: And even though Hornikowitz filmed this transformation, there were still doubters,
Speaker 3: and rightfully so. The dosages that they had given these
Speaker 3: patients were relatively small, and only a small proportion of
Speaker 3: el dopa is known to cross the blood brain barrier,
Speaker 3: and so some people suggested that it was largely due
Speaker 3: to placebo effect, which we talked about does happen, and
Speaker 3: a double blind study supported this doubt. In some ways,
Speaker 3: el dopa was found to be no more effective in
Speaker 3: relieving symptoms than saline, and it was beginning to be
Speaker 3: recognized to cause serious side effects like high blood pressure
Speaker 3: and nausea. But the Parkinson's field wasn't ready to give
Speaker 3: up quite yet. Maybe it was just a matter of
Speaker 3: finding the sweet spot for dosage. George Ktesias made a
Speaker 3: major breakthrough when he tried scaling up the dose, so
Speaker 3: starting out small and then gradually increasing, and this helped
Speaker 3: to limit the adverse side effects seen early on with
Speaker 3: the early big doses, but still allowed to build up
Speaker 3: those doses to more effective levels. Another big step forward
Speaker 3: was the addition of carbon doopa, which allowed more of
Speaker 3: the el dopa to pass through the blood brain barrier.
Speaker 3: Researcher Roger Duvoissen described what happened when he gave a
Speaker 3: patient this combo in nineteen sixty seven. Quote the effect
Speaker 3: was so dramatic, I couldn't believe it. Patients were so
Speaker 3: improved that they didn't look like they had Parkinson's anymore.
Speaker 3: End quote. The dramatic transformation that eldopa had on people
Speaker 3: with Parkinson's disease and Parkinson's like disease. If you remember
Speaker 3: from our encephalitis lethargica episode from way back or the
Speaker 3: slash movie Awakenings by Oliver Sachs, which we talked about
Speaker 3: in that episode, the difference was so stark, the improvement
Speaker 3: was so great that this was really something that had
Speaker 3: rarely been seen before and has rarely been seen since
Speaker 3: in the history of medicine. Truly, Like the only other
Speaker 3: things that came to mind to me in terms of
Speaker 3: like near instant improvement are antibiotics and insulin. Yeah, just
Speaker 3: like immediate holy cow reversal, What is happening like or
Speaker 3: complete elimination of symptoms.
Speaker 4: Like changing lives immediately immediately.
Speaker 3: Yeah, and I'm sure there are others, but the introduction
Speaker 3: of el dopa it was absolutely revolutionary, and of course
Speaker 3: it wasn't Sunshine and Roses Forever, which you also may
Speaker 3: remember from r encephalitis lethargic episode. After a month or
Speaker 3: two of taking it, people began to experience severe side effects,
Speaker 3: including problem like you mentioned Aaron with involuntary movement, and
Speaker 3: as time went on, people developed a tolerance for the drug,
Speaker 3: which meant that higher and higher doses had to be given,
Speaker 3: leading to more and more side effects like confusion, agitation, paranoia,
Speaker 3: and hallucinations. And occasionally the drug would just randomly stop working,
Speaker 3: almost like a switch was flipped from on to off.
Speaker 3: There's no denying that el dopa is an incredible drug,
Speaker 3: but it also does come at a cost, and that's
Speaker 3: one that must be carefully weighed by people with Parkinson's
Speaker 3: disease and their medical providers in terms of like when
Speaker 3: to start and so on. And the trade offs inherent
Speaker 3: with el dopa have also led people to search for
Speaker 3: alternative therapies, from surgeries and deep brain stimulation to neural graphs,
Speaker 3: neuroprotective treatments like MAO inhibitors which prevent the degradation of
Speaker 3: dopamine even phase therapy. I saw mentioned Oh interesting, I
Speaker 3: meant to read more about that. Each of those treatments
Speaker 3: has a story, and I know that there are probably
Speaker 3: eight million more on the horizon that you're going to
Speaker 3: talk about, which is amazing. Not to mention, there's the
Speaker 3: whole part about how we learned more about the genetic
Speaker 3: and potential environmental causes of Parkinson's. But so this doesn't
Speaker 3: turn into a million hour episode. I'm not going to
Speaker 3: go down those rabbit holes today. I do, however, have
Speaker 3: one more story to tell before turning it over to you.
Speaker 3: So I told the story just now of l DOPA
Speaker 3: and how it revolutionized treatment, and this next story is
Speaker 3: another revolution, but of a slightly different kind. I'm thrilled.
Speaker 3: One of the biggest challenges for many diseases that are
Speaker 3: specific to humans is not having an appropriate animal model.
Speaker 3: We've talked about this a bunch on the podcast. It
Speaker 3: makes it much more difficult to test out new treatments
Speaker 3: or conduct experiments to understand the mechanism of disease. Until
Speaker 3: the nineteen eighties or so, there were a couple of
Speaker 3: Parkinson's animal models, so like using the plant extract medication resurpene,
Speaker 3: which I mentioned earlier in the Eldapa story. But apparently
Speaker 3: that drug blocks more neurotransmitters than just dopamines, so it
Speaker 3: wasn't It's not perfect for that, and that lack of
Speaker 3: really good animal models did severely limit Parkinson's disease research,
Speaker 3: especially before genetic models of disease were developed, and so
Speaker 3: researchers were always on the hunt for better tools, and
Speaker 3: they stumbled upon one in an unexpected place, the San
Speaker 3: Jose County Jail OHKAY. In July nineteen eighty two, George Correo,
Speaker 3: who was in the San Jose County Jail on drug charges,
Speaker 3: woke up one morning unable to talk or move, but
Speaker 3: with his senses fully intact. He was admitted to the
Speaker 3: emergency room after his condition got worse and the doctors
Speaker 3: could not find out what was wrong. Reflex hammer no response,
Speaker 3: blunt pressure to fingernails, no response, ammonium sulfate smelling salts
Speaker 3: no response. Eventually he was transferred to the psychiatric ward
Speaker 3: and diagnosed with catatonic schizophrenia. This was a diagnosis that
Speaker 3: stirred up some controversy among the hospital's doctors, with the
Speaker 3: neurologists arguing that it was a psychiatric disorder and the
Speaker 3: psychiatrists insisting insisting that it was neurologic. I have been
Speaker 3: in the middle of one of these debates. That's cool.
Speaker 3: And then it was the head of neurology, Bill Langston,
Speaker 3: that got involved and decided to run a few more tests,
Speaker 3: the results of which convinced him that they were actually
Speaker 3: dealing with a mysterious neurological problem, so he had George
Speaker 3: transferred to the neurobehavior unit. After a few days there,
Speaker 3: a doctor noticed the slightest of movements from George's fingers,
Speaker 3: and so he placed a pencil in his hands with
Speaker 3: a notepad underneath. After about thirty minutes, George had written
Speaker 3: his name along with quote, I'm not sure what is
Speaker 3: happening to me. I only know I can't function normally.
Speaker 3: I can't move right. I know what I want to do,
Speaker 3: it just won't come out right. And he wrote all
Speaker 3: of that. It took it took a while, but yeah, wow, yeah.
Speaker 3: And so with this path of communication open, the doctors
Speaker 3: began taking a detailed, or as detailed as they could,
Speaker 3: medical history, which is how they learned that George had
Speaker 3: taken heroin, and that he had been with his girlfriend
Speaker 3: Juaniita Lopez before he had gotten sick. And when they
Speaker 3: found her, because they were like okay, you know, they
Speaker 3: were going to find out first of all if she
Speaker 3: was okay, but also what she knew, they found that
Speaker 3: she was in pretty much the same state that George
Speaker 3: was in, motionless and rigid m hm. So then they
Speaker 3: cast a wider net around the town around the area
Speaker 3: and found more cases of people who were mysteriously frozen,
Speaker 3: six in total, including George and Juanita, and one of
Speaker 3: whom was a young woman who was diagnosed with hysterical paralysis. Wow. Yeah,
Speaker 3: The link between all of them was that they had
Speaker 3: all taken heroin or what they thought was heroin. Okay,
Speaker 3: Testing of the substance that they had found in the
Speaker 3: apartment of one of these patients revealed that it wasn't
Speaker 3: actually heroin, but a designer drug synthesized in an underground
Speaker 3: lab and sold as heroin, And somehow this substance had
Speaker 3: induced the symptoms of Parkinson's disease in these young people
Speaker 3: in a matter of hours. What and because it looked
Speaker 3: like Parkinson's, why not try al dopa. When they were
Speaker 3: given al dopa, they improved almost like almost immediately, gaining
Speaker 3: full control over their bodies, at least until the side
Speaker 3: effects started. But this improvement, sort of the treatment as
Speaker 3: part of the diagnosis, showed that something in that designer
Speaker 3: drug had crossed the blood brain barrier and destroyed the
Speaker 3: substantia nigra. How wow, what was this thing that did this?
Speaker 3: The answer came from yet another unexpected source, a strange
Speaker 3: case study from the nineteen seventies, where a college student
Speaker 3: had used a home chemistry set to make his own drugs,
Speaker 3: namely MPPP, which, like, if I were to tell you
Speaker 3: what that stood for, it would be a lot of
Speaker 3: chemical names that don't mean anything to us, well probably
Speaker 3: to some listeners out there, but yeah not us. Yeah,
Speaker 3: give it a Google. But MPPP, in theory, gives a
Speaker 3: heroin like high. And apparently this college student's experiments worked,
Speaker 3: or at least the first few batches did. A few
Speaker 3: months after starting, he injected himself with a batch and
Speaker 3: immediately felt a burning sensation and within a few days
Speaker 3: lost complete movement, becoming completely immobile and unable to speak.
Speaker 3: And I don't know what happened to this guy, whether
Speaker 3: he eventually received any treatment, but his case eventually made
Speaker 3: it to the NIH, where they discovered that instead of
Speaker 3: making MPPP, he had made something called MPTP, which I
Speaker 3: can name this one out because I have written here
Speaker 3: one methyl for phenal one two three six tetra hydropyridine.
Speaker 3: So yeah, MPTP. Turns out, the chemists that had made
Speaker 3: that designer drug in the nineteen eighties that had paralyzed
Speaker 3: those six people had also been trying to make MPPP
Speaker 3: but instead made MPTP. Okay, those individuals would never be
Speaker 3: the same, never fully recovering from the drug and struggling
Speaker 3: with motor complications for the rest of their lives, many
Speaker 3: of which were shortened. And it's an incredibly tragic story.
Speaker 3: But if one good thing came out of it, it
Speaker 3: was that this situation ended up being a revolution for
Speaker 3: the field of Parkinson's disease research, because with the discovery
Speaker 3: of the effects of MPTP on the brain, researchers now
Speaker 3: had a potential cause for the condition, or could at
Speaker 3: least outline how an environmental contaminant such as an herbicide
Speaker 3: or pesticide could cross the blood brain barrier and cause
Speaker 3: the disease. Secondly, and this is the huge part that
Speaker 3: I started this section with, they could now use MPTP
Speaker 3: to create the first animal models for Parkinson's disease, which
Speaker 3: could be used to test out treatments, study mechanisms, examine
Speaker 3: potential causes. The possibilities were endless. Wow. Yeah. Since the
Speaker 3: discovery of the effects of MPTP, the field of Parkinson's
Speaker 3: disease research has come a tremendously long way. We've learned
Speaker 3: so much more about this disease and how to treat it,
Speaker 3: and this disease has also taught us so much about
Speaker 3: our own brains, unlocking movement pathways and reflexive actions by
Speaker 3: looking at how they break down. We're also in the
Speaker 3: process of reframing this disease by incorporating symptoms that aren't
Speaker 3: movement related, something that is about as we've gotten better
Speaker 3: at diagnosing Parkinson's before the movement symptoms begin, which has
Speaker 3: also allowed people to conduct more precise and accurate clinical trials.
Speaker 3: We're expanding treatment options beyond the narrow dopamine focus, and
Speaker 3: I'm super excited to learn more about those. But I
Speaker 3: think another huge aspect that has really grown in the
Speaker 3: past few decades is the incredible advocacy work done by
Speaker 3: people like Michael J. Fox. There can be such a
Speaker 3: stigma around neurodegenerative diseases, a huge one, including Parkinson's, and
Speaker 3: people like Michael J. Fox and the providers of our
Speaker 3: first hand account who share their experience and are open
Speaker 3: about it, have really done an immeasurable amount of good
Speaker 3: in terms of humanizing this disease. And there's really just
Speaker 3: like so much more that we could talk about in
Speaker 3: terms of Parkinson's. So erin why don't you just cut
Speaker 3: me off here and tell me where we are today
Speaker 3: with this disease.
Speaker 4: I will try to do just that right after this break.
Speaker 4: Parkinson's disease is incredibly common, It is a chronic condition,
Speaker 4: and it is very much on the rise. Yes, both
Speaker 4: the incidents and the prevalence have been increasing across the
Speaker 4: globe for the last several decades. And prevalence listeners may
Speaker 4: or may not recall. I feel like we throw this
Speaker 4: word around a lot. Prevalence is just how many people
Speaker 4: in a population are living with the disease at a
Speaker 4: given time. It makes sense that prevalence is increasing because
Speaker 4: we're living longer. We're an aging global population, and Parkinson's
Speaker 4: disease is predominantly a disease of age. But the incidents,
Speaker 4: or the number of new cases that are diagnosed year
Speaker 4: after year, is also on the rise.
Speaker 3: And this may.
Speaker 4: Be partially but certainly not entirely explained by better diagnostic accuracy,
Speaker 4: especially because Parkinson's seems to be growing faster than other
Speaker 4: neurologic disorders for which we in some cases might have
Speaker 4: better or at least newer diagnostic accuracy, like MS for example. Overall,
Speaker 4: the global burden has more than doubled in the last
Speaker 4: couple of decades, and Parkinson's disease today is often recognized
Speaker 4: as the second most common neurodegenerative disorder after Alzheimer's disease. Okay,
Speaker 4: so it's like Alzheimer's disease and Parkinson's as like the
Speaker 4: two most common neurodegenerative dementia causing diseases. Parkinson's is, of
Speaker 4: course found across the globe. Prevalence is perhaps higher in Europe,
Speaker 4: North America, South America when compared to Africa, Asia, and
Speaker 4: countries in the Middle East. It's really difficult, I think,
Speaker 4: in cases like this to really get a sense of like,
Speaker 4: how true is this versus are places that tend to
Speaker 4: be higher income better at diagnosing this disease unlear But overall,
Speaker 4: this is a disease that is affecting millions and millions
Speaker 4: of people. And like we mentioned in the biology section,
Speaker 4: while Parkinson's disease is not causing death outright, it does
Speaker 4: significantly reduce the length of a person's life, and the
Speaker 4: degree to which that is true varies a lot by
Speaker 4: the time course of the illness. So if we think
Speaker 4: back to dividing Parkinson's into maybe three different subtypes, the
Speaker 4: kind of worse or diffuse malignant group, the intermediate group,
Speaker 4: and the kind of mild motor predominant group, the median
Speaker 4: survival after diagnosis in the diffuse malignant group in some
Speaker 4: studies is only eight years, which is really short, compared
Speaker 4: to thirteen years for the intermediate subtype and twenty for
Speaker 4: a mild motor predominant subtype. Often, when we look at
Speaker 4: just all Parkinson's altogether, the median survival after diagnosis is
Speaker 4: between like six and fourteen years. The good news is
Speaker 4: that there is a lot being done about this disease,
Speaker 4: so much so one of the big hurdles right now
Speaker 4: in Parkinson's disease that we've mentioned a lot is that,
Speaker 4: because this is a clinical diagnosis, you have to have
Speaker 4: these signs and symptoms present, at least some of them
Speaker 4: before somebody can be diagnosed. And these predominantly motor signs
Speaker 4: that are used are not the first signs of neurodegeneration.
Speaker 3: There is this.
Speaker 4: Prolonged, in some cases, very prolonged prodromal period before the
Speaker 4: onset of these symptoms, and that window, first of all,
Speaker 4: neurodegeneration is happening already. So if we can diagnose something earlier,
Speaker 4: we can potentially treat much better because we could potentially
Speaker 4: prevent the progression of disease. Right, So, could we diagnose
Speaker 4: Parkinson's earlier? And can we develop disease modifying treatments that
Speaker 4: actually work?
Speaker 3: So those I.
Speaker 4: Think, in like looking at all of the literature are
Speaker 4: the two biggest areas of research. Can we identify biomarkers
Speaker 4: to diagnose Parkinson's earlier and can we develop disease modifying treatments.
Speaker 4: We've made really big strides and we have so far
Speaker 4: to go. So just this year, a few months ago
Speaker 4: actually maybe a little over a month ago as of
Speaker 4: the time of recording, so by the time this is
Speaker 4: released a few months ago. In the year twenty twenty three,
Speaker 4: a paper came out in Lancet Neurology that was the
Speaker 4: result of this really massive longitudinal study funded in large
Speaker 4: part by the Michael J. Fox Foundation for Parkinson's Research,
Speaker 4: does a huge amount of funding for Parkinson's research, that
Speaker 4: in fact identified a potential biomarker of Parkinson's.
Speaker 3: Ooh.
Speaker 4: What they did was found a way to actually amplify
Speaker 4: and then identify abnormal alpha sin nucleon, that protein that
Speaker 4: makes up the large part of Louis bodies in the
Speaker 4: spinal fluid of people with Parkinson's, including people with only
Speaker 4: prodromal symptoms.
Speaker 3: Wow.
Speaker 4: So they were able to with a lumbar puncture detect
Speaker 4: this abnormal alpha sinnucleon in a way that could predict
Speaker 4: Parkinson's disease that was highly sensitive and specific.
Speaker 3: This is huge. That is huge.
Speaker 4: Yeah, so there is a biomarker.
Speaker 3: Wow.
Speaker 4: This is the first step to having a diagnostic test.
Speaker 4: It is not a diagnostic test. That is the caveat
Speaker 4: This is very very early days. We're not going to
Speaker 4: go around doing lumbar punctures on everyone with constipation, or
Speaker 4: everyone even with a rem sleep disorder or that has
Speaker 4: these prodromal signs or symptoms, and certainly not at the
Speaker 4: point of being able to test, for example, the general
Speaker 4: population or people with a family history or anything like that.
Speaker 4: But this is the kind of breakthroughs in research that
Speaker 4: leads to the potential for these early diagnoses that can
Speaker 4: someday maybe even lead to screening tools that could be available,
Speaker 4: which is incredible. But then with this knowledge, this knowledge
Speaker 4: without a disease modifying therapy doesn't really do anything right.
Speaker 4: So the next step has to be disease modifying therapy
Speaker 4: because otherwise you're diagnosing something very early with nothing that
Speaker 4: you can do to treat it.
Speaker 3: But there's a lot of research.
Speaker 4: Being done on actually finding therapies that could change the
Speaker 4: course of disease.
Speaker 3: It feels maybe this is my bias, but I feel
Speaker 3: like we've been on the precipice of discovering something that
Speaker 3: will halt Parkinson's disease progression for decades. Like it just
Speaker 3: feels like it's just around the corner and just out
Speaker 3: of reach, and like one more study, one more, we
Speaker 3: just need one more transformative breakthrough like we've had so
Speaker 3: often in the history of this disease.
Speaker 4: I think that I agree. I think it's it's so
Speaker 4: disappointing that we're not there yet. I think because there
Speaker 4: have been a lot of studies that have tried a
Speaker 4: lot of different targets, and so far in terms of
Speaker 4: actually halting the progression, there really hasn't been any thing
Speaker 4: that has shown very much promise. There are a lot
Speaker 4: of studies underway. There are drugs that are targeting alphas
Speaker 4: and nucleon There are drugs that are targeting dopamine receptors.
Speaker 4: There are even studies looking into using GLP one agonists,
Speaker 4: which are the drugs that are all the rage right now.
Speaker 4: They were developed as treatment for diabetes. They're also being
Speaker 4: used for weight loss. They're like the drugs that everyone's
Speaker 4: heard of.
Speaker 3: We should do an episode on that.
Speaker 4: Oh, definitely, there's we streched into whether these drugs could
Speaker 4: be beneficial in terms of Parkinson's disease modification.
Speaker 3: There's a lot.
Speaker 4: When I looked at clinicaltrials dot Gov, there are over
Speaker 4: two thousand, six hundred registered clinical trials if you search
Speaker 4: for Parkinson's. Not all of these are drug trials, but
Speaker 4: over twenty three hundred of them are interventional trials of
Speaker 4: some kind, so it's a lot and the third avenue
Speaker 4: of research, in addition to biomarkers identifying disease early and
Speaker 4: disease treatment like changing the course of disease or slowing
Speaker 4: progression of disease, the third very interesting avenue of research
Speaker 4: that is separate but very closely related, is better following
Speaker 4: this disease in terms of clinical progression. So Aarin, you
Speaker 4: sent me an article that was about wearable devices that
Speaker 4: can be used to track the movement of people with
Speaker 4: Parkinson's disease. So these devices in combination with machine learning
Speaker 4: give us better resolution on progression of disease. There's other
Speaker 4: ones that look at speech pattern recognition and deep learning
Speaker 4: and AI machine learning things to be able to track
Speaker 4: the progression of Parkinson's disease in a very nuanced way,
Speaker 4: which is going to be a very important tool when
Speaker 4: we're trying to find disease modifying therapy because if we
Speaker 4: can better parse out what's working and what's not by
Speaker 4: better tracking the progression of this disease, then we're going
Speaker 4: to be able to get a lot better data on
Speaker 4: what's working and what isn't and.
Speaker 3: How yes, I didn't even think about that that aspect
Speaker 3: of it. That's huge for application. Yeah, exactly, exactly. Wow.
Speaker 4: Cool, So there is a lot of hope on the horizon.
Speaker 3: It does, it does feel very hopeful.
Speaker 1: Yeah.
Speaker 3: With that, if you'd like to read more, and there
Speaker 3: is a whole lot more sources, Yeah, I have a bunch,
Speaker 3: but I want to shout out one in particular, and
Speaker 3: it is a book titled Brainstorms, The Race to Unlock
Speaker 3: the Mysteries of Parkinson's Disease by John Paul Ferman. And
Speaker 3: I really really enjoyed this book. The author start to
Speaker 3: write this book because he had gotten to Parkinson's diagnosis
Speaker 3: and it was a really just excellent It was an
Speaker 3: excellent and informative read. Yeah, I recommend. Yeah.
Speaker 4: I have a number of sources as well, but got
Speaker 4: to always shout out whenever the Lancet has a disease
Speaker 4: primer series is just golden.
Speaker 3: Just makes my life so easy. So there was a few.
Speaker 4: There was one from twenty fifteen and then there was
Speaker 4: an update in twenty twenty one. Both are just called
Speaker 4: Parkinson's Disease. They're great, like overall comprehensive reads. There was
Speaker 4: a really interesting paper from twenty twenty two called the
Speaker 4: Neuropsychiatry of Parkinson's Disease, Advances and Challenges from the Lancet Neurology,
Speaker 4: as well as papers on these biomarkers and other research
Speaker 4: being done in terms of treatment. We will post the
Speaker 4: list of sources from this episode in all of our
Speaker 4: episodes on our website This podcast will Kill You dot
Speaker 4: Com under the episode's tab.
Speaker 3: Thank you so much, Stacy for sharing your story with us,
Speaker 3: just truly from the bottom of our hearts.
Speaker 4: Thank you, yeah, so so so much for sharing your
Speaker 4: story with us. Thank you to Bloodmobile for providing music
Speaker 4: for this episode and all of our episodes.
Speaker 3: Thank you to Tom bry Fogel for the audio mixing.
Speaker 3: Thank you, thank you, Thank you to the Exactly Right Network,
Speaker 3: and thank you to you listeners. We hope that you
Speaker 3: learned something.
Speaker 4: Yeah, I'm sure that you did something.
Speaker 3: Yeah.
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Speaker 3: Much, so so much. Well, until next time, wash your
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