Episode 32: The Neuroscience of Parkinson's Disease

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spk_0 Hello, my name is Barbara and this is neuroscience amateur hour.

spk_0 So for today's episode I want to talk about Parkinson's disease, a neurological disorder

spk_0 that is characterized by unintended or uncontrollable movements as well as problems with cognition

spk_0 and coordination. So for the overall structure of this episode we're going to first talk about

spk_0 the symptoms of the disease, then the specific brain regions and neuronal subtypes involved,

spk_0 as well as why those specific neurons might be vulnerable. Finally we'll talk about treatment

spk_0 options and what could go wrong with those treatments. So let's get right into it. There are a couple

spk_0 main motor symptoms, trimmers in the hands, arms, legs, jaw or head, muscle stiffness, difficulty

spk_0 initiating and executing voluntary movements, slowness of movement, otherwise known as bradykinesia,

spk_0 and impaired coordination which can sometimes lead to falls. Other lesser known symptoms that

spk_0 may or may not be movement related are depression and other emotional changes, difficulty speaking

spk_0 or chewing urinary problems or skin problems. I've also read that individuals with Parkinson's can

spk_0 have issues with low blood pressure, constipation, loss of sense of smell and sleep problems.

spk_0 I know that that sounds kind of like a grab bag of symptoms, but maybe once we get into the brain

spk_0 regions that are affected by this disorder and the relevant cell types we can start to dissect

spk_0 out why so many different body systems are affected. Parkinson's is fundamentally a neurodegenerative

spk_0 disease which means that it gets worse over time, usually several decades. Symptoms most commonly

spk_0 start at the age of 60 and progressively increase in severity. The rate of deterioration is very

spk_0 individual dependent, although certain events can increase the rate, including stroke, stress,

spk_0 emotional trauma and infections, including urinary tract infections. I actually ended up googling

spk_0 why? Because I found that finding a little surprising and it turns out that untreated infections

spk_0 may result in inflammatory upregulation, which in turn can affect brain function and lead to a

spk_0 sharp exacerbation of the disease. So in terms of the progression timeline, there are five stages of

spk_0 the disease, as defined in 1967 by Hohen and Yar. Stage 1 means that the individual has mild

spk_0 symptoms that generally don't interfere with daily life. There might be some tremors or movement

spk_0 issues that occur on one side of the body, but people are generally doing okay. Stage 2 involves

spk_0 tremors, rigidity and other movement symptoms starting to affect both sides of the body,

spk_0 as well as coordinated tasks like walking. Stage 3 or mid-stage involve the individual starting

spk_0 to have balance issues and false are pretty common here. Functionally, this person is still capable

spk_0 of day-to-day tasks, but they are becoming difficult. At stage 4, the person needs significant

spk_0 help with daily living, and stage 5 means that stiffness in the legs may make it impossible to

spk_0 stand or walk. The person likely needs around the clock care. The average age of diagnosis for

spk_0 someone Parkinson's is around 60 years old, and the life expectancy is around 80 or 81. The disease

spk_0 is named after the man who, quote unquote, first documented it, James Parkinson, who penned an essay

spk_0 on the shaking palsy in 1817. However, fascinatingly, medical accounts have been traced back to Indian

spk_0 texts from 1000 BC, and ancient Chinese texts from 425 BC, more than 2,400 years ago.

spk_0 You can read the paper that I got that little negative information from if you want to, it is

spk_0 cited in the show notes. It's source number 4. Also, if for some reason you really want a paper

spk_0 that I have cited, and it's not easily accessible to you, please feel free to email me, and I will do

spk_0 my best to acquire it. Parkinson's is most frequently diagnosed by a doctor assessing the

spk_0 symptoms conducting a neurological and physical exam, and then seeing how the patient responds to

spk_0 treatment. However, my friend recently sent me this amazing New York Times article that I wanted

spk_0 to stick in this episode about a woman who can smell Parkinson's, even months before an individual

spk_0 shows any neurological symptoms. The article is from the New York Times, which I thoroughly encourage you to

spk_0 read, and it dives into the story of Joy Milness, who has an incredible sense of smell, and one day

spk_0 realizes that her husband is starting to smell different, or a little mustier than normal.

spk_0 Over the next decade, her husband begins to undergo a series of personality changes,

spk_0 becoming cooler, resentful, and then even having some trouble with everyday physical tasks.

spk_0 Eventually, he's diagnosed with Parkinson's, and when joy in her husband go to a support

spk_0 group for people with Parkinson's, Joy recognizes that everyone there has the same kind of awful

spk_0 musty smell. Now, while diagnosis by smell is not a terribly exotic idea, we know there've been a

spk_0 multitude of stories of dogs being able to sent leukemia or even COVID-19, but a human doing so

spk_0 sounds a little bit more Atlantis. So, Joy underwent a pilot study where 12 participants

spk_0 six with Parkinson's and six without were asked to wear clean t-shirts for 24 hours, and Joy was

spk_0 asked to determine whether the wearer of the t-shirt had Parkinson's or not based on the smell of

spk_0 the t-shirt alone. She correctly identified all six Parkinson's participants, but she wasn't perfect.

spk_0 She misdiagnosed one of the control group members as having Parkinson's, but in an insane turn of

spk_0 events, the man was actually diagnosed with Parkinson's just a year later. And later, with Joy's

spk_0 help, scientists were actually able to identify the specific compounds that contributed to the

spk_0 Parkinsonian smell. And this is incredibly exciting because this kind of early diagnosis would be a

spk_0 boon for patients. The ability to identify a neurodegenerative disease years, decades before

spk_0 symptoms are felt, could possibly save time, money, a world of hurt and resentment from people

spk_0 undergoing personality changes, and potentially give patients the time for meaningful intervention.

spk_0 Okay, so now that we have an understanding of the wide variety of body systems that are

spk_0 impacted by Parkinson's, let's dive into the brain regions and the cell types that are affected.

spk_0 Parkinson's is most commonly understood to be a movement disorder. So we have to take a look at

spk_0 the brain regions that govern voluntary movement, specifically one called the basal ganglia.

spk_0 The basal ganglia is made up of a bunch of subcortical nuclei, including the stradum, which is in

spk_0 turn made up of the caughtate and the putamen, the global pallitis, which is composed of the internal

spk_0 and external segments, the subthalamic nuclei, and the substantiant substantiant nigra, which is

spk_0 so there's going to be a lot of brain regions discussed in this part and I encourage you to either

spk_0 look at the Instagram post for this episode or just Google a picture of basal ganglia circuitry.

spk_0 Otherwise, it can get a little confusing, but we're new or best anyway. So once again, the basal

spk_0 ganglia is made up of the stradum, the global pallitis, the subthalamic nuclei, and the substantiant

spk_0 nigra. These brain regions contain a couple different kinds of cells. They could contain

spk_0 excitatory neurons, which can turn up their downstream targets. They could contain inhibitory

spk_0 neurons, which turn down their downstream targets, or they could contain neurons that release neuro

spk_0 modulators like dopamine or serotonin, which guessed it, modulate the activity.

spk_0 Now there are two broadly defined pathways or loops for information to flow through this brain

spk_0 region. There is first the direct pathway known for its role in facilitating movement. Here, excitatory

spk_0 neurons, aka those that will cause downstream neurons to turn on from the thalamus project to

spk_0 the motor cortex. These projections are thought to stimulate movement. A little background on the

spk_0 motor cortex, slightly simplified. This is supposed to be the site where motor commands originate

spk_0 from, where your brain says, okay, let's move our leg. Motor cortex is situated kind of like a

spk_0 stripe going from ear to ear across the top of your brain, anterior to the central sulcus or the

spk_0 major fold in the brain. The motor cortex is arranged topographically, which means that different

spk_0 parts of motor cortex in space, specifically along the rostral caudal axis, represent different

spk_0 parts of the body. One site might represent your arm, and then somewhere else might represent

spk_0 your hand, and then further down the axis, might represent your leg, and then your calf, and then

spk_0 your ankle. If you want to see something deeply cursed, I recommend looking up a picture of the

spk_0 motor cortex homunculus. It is very creepy to look at. But informative, don't get me wrong.

spk_0 So back to the direct pathway. Simultaneously, the thalamus is receiving projections from the

spk_0 our inhibitory, aka, they turn down the subsequent neurons. So these projections are constantly

spk_0 trying to inhibit the laminate neurons and suppress movement. This helps your body regulate which

spk_0 movements occur, including blocking unwanted ones. When we want to make a movement, information from

spk_0 the motor cortex that commands signal is sent via the excitatory corticosteratol pathway to the

spk_0 stradum. In response, turned up stradal neurons, which are inhibitory, released GABA, an inhibitory

spk_0 neurotransmitter, onto the global pallidus, the internal part, and the substantiant nigra parts

spk_0 reticulata. So what you get is a loop. When you want to make a movement, motor command comes from

spk_0 the motor cortex, which turns on stradal neurons, which turns down neurons in the global pallidus

spk_0 internal, and the substantiant nigra parts reticulata, which stops turning down thalamus. We call this

spk_0 disinhibition, which is where you inhibit an inhibitory population of neurons, and this results

spk_0 in an overall increase of activity. It's actually a really common network motif or a way that your

spk_0 brain functions, and you see it in a bunch of systems. Now, the substantiant nigra parts

spk_0 compacta also has projections into the stradum. Here, the neurons are dopamine releasing, aka,

spk_0 they modulate the activity of the direct pathway by acting on neurons in stradum. Specifically,

spk_0 GABA urges spiny projection neurons, although they're not really part of this loop-mediating movement.

spk_0 So when dopamine is released, it facilitates movement. So far so good.

spk_0 Now, the second pathway for the flow of information is the indirect pathway, which is known for

spk_0 its role in inhibiting movement. So how do we do that? We start with some new but adjacent brain

spk_0 regions as the direct pathway. First, let's look at the neurons in the global pallidus external.

spk_0 These are inhibitory neurons, which inhibit excitatory cells in the subterlamic nucleus.

spk_0 When you want to inhibit a movement, the motor cortex sends a signal,

spk_0 activating inhibitory neurons in stradum, which in turn inhibit inhibitory neurons in the

spk_0 global pallidus external, which stops them from inhibiting neurons in the subterlamic nuclei.

spk_0 Because they are no longer inhibited, neurons in the subterlamic nuclei, which are also

spk_0 simultaneously receiving information from the motor cortex, can activate neurons in the global

spk_0 pallidus internal and subternein-chinaigra parts reticulata, which inhibit the thalamus and prevent

spk_0 a movement from being executed. Again, kind of a giant loop, except this one has a few extra

spk_0 steps and acts kind of directly opposite to the direct pathway. And you can bet this was really

spk_0 fun to memorize when I added ignore finals. So dopamine neurons from the subternein-chinaigra parts

spk_0 compacta, have to stop neurons in stradum from firing, which prevents them from inhibiting global

spk_0 pallidus external neurons, etc., etc., which facilitates movement. Okay, I'm tired, we did it. We

spk_0 got through the direct and the indirect pathways that was going to be the hard part. But ultimately,

spk_0 the point of this is that the direct and the indirect pathways make sure that the only the correct

spk_0 motor program is executed and all other competing ones are canceled. So what does this have to do with

spk_0 Parkinson's? Well, Parkinson's is a disorder that is known to be caused by the degeneration of

spk_0 dopamine neurons in the subternein-chinaigra parts compacta. Less dopamine, more trouble facilitating

spk_0 movement, which explains why individuals with Parkinson's suffer from slowness of movement and

spk_0 impaired coordination. Their brains are literally having trouble executing voluntary movement commands.

spk_0 That's kind of cool, right? Also, I highly recommend two-minute neuroscience on YouTube for an

spk_0 excellent and short explanation of these pathways with visuals. Now, you might ask, how do the same

spk_0 dopamine neurons coming from the same brain region have different effects on these two pathways?

spk_0 It turns out that another distinguishing factor between the direct and the indirect pathway

spk_0 is the dopamine receptors on the spiny projection neurons in the stradum that are involved in each.

spk_0 The neurons that are part of the direct pathway express D1 receptors, whereas those that are

spk_0 part of the indirect pathway express D2 receptors. Thus, dopamine has different effects on downstream

spk_0 neurons depending on whether it binds the direct pathway associated D1 receptors or the indirect pathway

spk_0 associated D2 receptors. They do so because both D1 and D2 receptors, G-protein coupled receptors,

spk_0 have distinctive linkages to intracellular signaling cascades and targets, leading to fundamentally

spk_0 different cellular responses to dopamine and fundamentally different downstream effects.

spk_0 Now, looking solely at the basal ganglia is a fairly limited, if quite clean, view of what goes wrong

spk_0 during Parkinson's disease. But we know that when it comes to neurodegenerative disorders,

spk_0 rarely is only one brain region involved. Indeed, other work has shown that the basal ganglia

spk_0 works closely with the cortex and the cerebellum and likely a bunch of other brain regions to form

spk_0 the circuitry that underlies motor and cognitive tasks of varying complexity. But this is unfortunately

spk_0 a little outside the scope of this episode. I recommend reading the 2016 review from Caliguary at all,

spk_0 if you want to learn more about Parkinson's as a system level disorder. Again, cited in the show notes.

spk_0 Is there something specific about dopamine neurons that might result in their degeneration?

spk_0 Why these cells in particular? What makes them vulnerable? It might have something to do with their

spk_0 structure, their function, or their makeup. Dopamine neurons have very long and extensively

spk_0 arborized or branched out axons, as well as a large number of neurotransmitter release sites.

spk_0 Estimates say that human substantioneigric compacted dopamine neurons may have over 1.5 million

spk_0 axon terminals each. 1.5 million axon terminals per cell. They are also tonically active,

spk_0 which is just a fancy way to say that they are constantly firing. These kinds of cells can also be

spk_0 called autonomous pacemakers. So this means that they have very high energy demands, and a small

spk_0 margin for error if those energy demands are not met, which can give rise to degeneration.

spk_0 Another explanation for the vulnerability of this specific neuronal subtype is the presence of dopamine

spk_0 itself. Dopamine can get oxidized, which produces reactive oxygen species that contribute to neuronal

spk_0 toxicity. Another hallmark of Parkinson's disease is the presence of misfolded protein or alpha

spk_0 stanucleon aggregates called Louis bodies in the substantioneigra. I think there's still debate

spk_0 about whether the accumulation of Louis bodies is a symptom of the disease or the cause. A little

spk_0 bit of a chicken or the egg situation. However, we do know that some parts of the brain are particularly

spk_0 vulnerable to the formation of Louis bodies. What we don't really know is why. It could once again be

spk_0 linked to issues with meeting the energy needs of the cells there. One of the reasons that protein

spk_0 aggregates can occur is because the cell is failing at clearing them out, which is in itself a very

spk_0 energy intensive process. Now, there are currently no treatments available for Parkinson's disease that

spk_0 will slow or cure the disorder. However, there are treatments that help to alleviate the symptoms.

spk_0 Perhaps the most famous one is Libidopa, an aromatic amino acid L34 dihydroxy phenylalanine.

spk_0 Libidopa is a precursor to dopamine itself. It is administered to Parkinsonian patients,

spk_0 enters the bloodstream, and is then converted to dopamine via the enzyme Dopa carboxylase.

spk_0 It's important to note that Libidopa itself cannot cross the blood brain barrier and enter the

spk_0 300 BC used to prescribe the seeds of a plant called mucuna purions to treat symptoms of Parkinson's,

spk_0 which was later found to contain about 4 to 6% Libidopa. Ultimately, this treatment takes a very

spk_0 brute force approach to alleviating Parkinson's symptoms. It raises the levels of dopamine in the

spk_0 brain, which can compensate for the decreased levels of dopamine that occur when dopamine neurons in

spk_0 the substantionegroid degenerate. It is known to be particularly useful for motor symptoms,

spk_0 but it's thought to be less useful for non-motor symptoms, such as cognitive decline,

spk_0 sleep disorders, or depression. I think it's also really important to note that Libidopa is kind of

spk_0 taken as a pill throughout the day, which can result in waves of dopamine in the brain, increasing

spk_0 after treatment, and then declining over time until the next treatment. Pharmacological companies

spk_0 are striving to improve the means of administering this medication to create a more stable effect.

spk_0 For example, a novel long-acting preparation involves a microsphere that is coded and governs

spk_0 the rate of the drug released, resulting in a longer-acting effect. Companies are also experimenting

spk_0 with the form of Libidopa that you can inhale, and one that you can inject under the skin,

spk_0 in addition to the most common, like, ingested Libidopa form.

spk_0 Another, perhaps, unconventional and unexpected treatment for Parkinson's is the use of gamma

spk_0 hydroxybutyutaurate, or GHB. GHB is commonly used in a medical setting as a treatment for certain

spk_0 disorders, like alcoholism, but it's probably better known to the general public as a date rape

spk_0 or recreational drug. This approach works as a treatment because it tackles the problem that I

spk_0 mentioned with neuronal vulnerability. GHB is a GABA metabolite that can suppress the

spk_0 pacemaking activity of dopamine neurons in the substantial nigra,

spk_0 comapars compacta, in some anesthetic doses. GHB can also apparently serve as a source of energy

spk_0 for the brain, and it's an effective antioxidant. Some clinical trials have been conducted and

spk_0 found that the drug is well tolerated and significantly reduces drowsiness and improves the

spk_0 quality of sleep. There's also some evidence, though, not conclusive, that taking GHB over a longer

spk_0 time period may have neuroprotective effects and could delay or slow the progression of Parkinson's

spk_0 disease. Another therapeutic approach is to target alpha-synucleon aggregates. Some clinical trials

spk_0 involve the intravenous infusion of alpha-synucleon antibodies to stimulate an immune response

spk_0 against them. Other approaches in a similar mindset involve treating with compounds that may block

spk_0 the aggregation of alpha-synucleon in the first place. Now, I wanted to finish this episode by

spk_0 talking about what could go wrong with Parkinson's treatments, particularly focusing on lebedopa,

spk_0 which as I mentioned before, acts to increase dopamine levels in the brain as a whole.

spk_0 But dopamine doesn't just function to govern voluntary movements, it's involved in mood,

spk_0 addiction, motivation, etc. One of my professors who was lecturing on reward pathways in the brain

spk_0 was discussing how Parkinson's could be as much a disease of motivation as it could be a disease

spk_0 of movement. He talked about how if you shout, fire, a Parkinsonian patient would be capable of

spk_0 getting out of their chair and running out of the building. But if you just asked a Parkinsonian

spk_0 patient to simply get up and leave, they would have trouble. So two of the major side effects of

spk_0 long-term lebedopa treatment are lebedopa induced dyskinesia and impulse control disorder.

spk_0 It turns out that when patients start taking lebedopa, they experience a honeymoon period,

spk_0 where I believe there's some upregulation of dopamine receptors on stradal neurons,

spk_0 so the treatment has maximum effectiveness and minimal side effects. This also leaves the

spk_0 system poised to be hypersensitive to incoming dopamine. However, after four to six years,

spk_0 many patients start developing involuntary movements or dyskinesia. This may be because when

spk_0 lebedopa is administered in structured doses, like a patient taking a pill every few hours,

spk_0 as opposed to the natural kind of continuous way that it would happen in the brain. It may cause

spk_0 some changes in the proteins and the genes of the neurons in the direct and indirect pathways,

spk_0 which results in abnormal neuronal transmission and leads to dyskinesia.

spk_0 The other major side effect of long-term lebedopa treatment is impulse control disorder.

spk_0 Treating Parkinson's involves giving the brain dopamine to combat decreased levels due to the

spk_0 generation of dopamine neurons, but dopamine affects regions other than the basal ganglia,

spk_0 such as the reward and motivation circuitry. In impulse control behaviors, could be pathological

spk_0 gambling, hypersexuality, compulsive shopping, binge eating, hobbyism, etc., all repetitive reward

spk_0 based actions. Incidents of this disorder varies, likely between 15 and 40% of patients taking

spk_0 lebedopa, and that ranges so broad because of differences in diagnostic criteria,

spk_0 potentially cultural differences, or assessment tools. But that is a brief look into the neuroscience

spk_0 of Parkinson's disease. I hope that you enjoyed the episode, and thank you for listening. As per

spk_0 usual, I've cited all my relevant sources and papers in the show notes, and you should keep an

spk_0 eye out on Instagram for any cool figures. Please rate, review, and subscribe, and if you have

spk_0 any questions, comments, concerns, queries, or complaints, please email me at neuroscienceameterhour

spk_0 at gmail.com or DM me at neuroscienceameterhour on Instagram. This podcast is available most everywhere,

spk_0 so please recommend it to your friends and loved ones. And if you're feeling so inclined to

spk_0 financially support my work, please buy me a cup of coffee at buymeacoffee.com,

spk_0 slash neuroscience. Also, if you have something you really want to learn about, contact me,

spk_0 and you might see an episode about it soon. Happy researching, and I'll see you again.

Episode 32: The Neuroscience of Parkinson's Disease

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