Kendal Williams, MD (Host): Welcome to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams. So, Parkinson's disease is a topic I have wanted to do for some time, partly because I really wanted to refresh my own knowledge, which is now a couple of decades old, but also because I'm seeing it more commonly in my practice. I think it's been about three, maybe four patients in my practice have been diagnosed in the last two years. It's very relevant to primary care, and I think this is true of other practices around the area. And my knowledge was really based on things I learned in residency, so I wanted to bring in experts to talk about Parkinson's disease because we're frequently encountering it in primary care.

And the two experts I brought on are both from the Penn Movement Disorders Clinic. I'm going to start with an old colleague who I overlapped with back in my Presby days, Dr. Meredith Spindler. Dr. Spindler is a Professor of Clinical Neurology at Penn. She is the Director of Clinical Operations for the Parkinson's Movement Disorders Clinic and the Medical Director of the Deep Brain Stimulation Program. Meredith, thanks for coming on.

Meredith Spindler, MD: Thanks for having me.

Host: Meredith, when she was transitioning out of her fellowship program before becoming full faculty, did a year of general neurology at Penn Presbyterian, and we talked about a lot of cases, a lot of interesting challenges during that time before she went on to focus on movement disorders.

With her today is Dr. Nabila Dahodwala. Dr. Dahodwala is also a Professor of Neurology. She is the Director of the Parkinson's Foundation Center for Excellence at Penn. Nabila, thanks for coming.

Nabila Dahodwala, MD: Oh, it's a pleasure to be here. Thank you.

Host: So, I want to start off with just some questions about the epidemiology here, because I feel like I'm seeing this more often. And I understand there is an increase in incidence in Parkinson's disease. Nabila, can you speak to that?

Nabila Dahodwala, MD: Yeah, for sure. There have been several recent epidemiological studies looking at this, the trends, and the number of cases are definitely increasing in part because people are living older. So, there's just a larger prevalence. But there's also an increasing incidence that we think is related to environmental exposures. And perhaps it's just longer lifespan means more lifetime exposure to the toxins like air pollution and different pesticides and herbicides that can get into our water or that we can ingest in some way.

Host: I saw a recent study or some report of people who lived within proximity to golf courses had a higher incidence of Parkinson's, and I assume we believe that's because of what's sprayed on the golf courses.

Nabila Dahodwala, MD: That's the assumption. Also, people who live near military sites that do high volume dry cleaning have higher rates. There was a report about Camp Lejeune, I don't know if you were familiar with this, in North Carolina, that exposure to tri—

Meredith Spindler, MD: Trichloroethylene.

Nabila Dahodwala, MD: Trichloroethylene also increases risk of renal cell carcinoma and Parkinson's disease.

Host: Obviously, there's been no change in genetics. I understand that there is a genetic component to Parkinson's disease. My reading is about 10% or 15% of cases can be genetically associated. Is that about right?

Nabila Dahodwala, MD: It might be even a little bit higher. We are learning more and more about different genetic risk factors. So, alleles that increase your risk but don't guarantee that you'll develop Parkinson's disease. So, it may be closer to 20%. And there's additional literature suggesting that there's a two-hit hypothesis, that you have the genetic mutation plus something in the environment that then brings it out in you versus someone else with that allele who doesn't develop Parkinson's.

Host: So, you mentioned that folks are living older, and that may be one of the reasons we're seeing a greater increase in the incidence. Are we seeing a shift into younger cohorts at all, where younger people are getting it earlier? We're seeing that with some cancers. We've talked about colon cancer recently, but...

Meredith Spindler, MD: I don't believe I've seen any literature that we're actually seeing it younger. There is young-onset Parkinson's. There are people who get it even as teenagers. It can be as young as that. But the incidence kind of starts to increase significantly after age 50, and that's where we're seeing most of the growth in the incidence.

Host: Yeah, I think, you know, we should all honor the actor Michael J. Fox, who came out openly about his Parkinson's disease diagnosis, you know, early. And he was still a young man when he was diagnosed. And then, really—was he that young?

Nabila Dahodwala, MD: Twenty-nine. Yeah. It's remarkable. He's lived over 30 years with it, but it means he's only in his, you know, early 60s at the moment.

Host: And that's the part I want to ask you about as well, is just sort of the—we'll get to that a little bit later when we start talking about treatment but just about how long are people living with Parkinson's, and how well can you live with it. We talked about genetics, we talked about environmental exposure, but what's happening in the brain of an individual who's developing Parkinson's? What's pathophysiologically happening?

Meredith Spindler, MD: Right. So, the key thing that's happening that causes the initial symptoms that everyone recognizes being Parkinson's disease is degeneration of your dopaminergic neurons. So, the brain cells in the midbrain that are producing dopamine, also storing dopamine and regulating its release. And literature suggests that probably by the time you start having the motor symptoms of Parkinson's, the stiffness or rigidity, the slowness or bradykinesia, and also tremors in 70% of cases, by the time that all happens, you've probably lost about 50% of those cells. And you're getting those symptoms because of the lack of dopamine.

And that's kind of the key change that's happening early in the brain. There are other things going on. We think that the same pathology is affecting other parts of the brain even at that time, and that's why we might see some prodromal signs like acting out dreams, REM sleep behavior disorder. And then, as the disease progresses, some of the problems that patients develop in terms of how the treatments are working are related to the fact that more of those dopaminergic neurons are degenerating. And so, they're not able to hold onto the dopamine medication they're taking for very long. And so, the benefit from the pills doesn't last very long.

And in addition, there are fewer of those cells around to buffer the high levels of dopamine that happen when they take their meds. And that's why they have kind of these complications of the medications they're taking with early wearing off and dyskinesias. So, this degeneration and loss of the dopaminergic neurons is like a key feature of the pathology of the disease, but it does then spread to other parts of the brain and cause other problems as well, non-motor symptoms, dementia, balance problems, et cetera.

Nabila Dahodwala, MD: And I'll just add that the key pathological feature is that you have an accumulation of alpha-synuclein, you may remember this from medical school, into clumps called Lewy bodies, and that biomarker has become something that we can test through skin biopsies and through spinal fluid. So, we can test for the presence of phosphorylated alpha-synuclein, these are new diagnostic tests that we didn't have even, like, three years ago

Host: So, alpha-synuclein is sort of equivalent to amyloid that you might see in an Alzheimer's situation, right? So, you have the accumulation of a misfolded protein, I guess you'd say, right? Why that leads to loss of dopaminergic neurons, I'm not sure. Maybe you can educate me on that.

Nabila Dahodwala, MD: We're still learning about it. I believe that alpha-synuclein, the normal protein, is involved in microtubule transport, so that the accumulation leads to dysregulation within the cell that could then lead to cell death. But the other question, I think, that's part of that is why the substantia nigra and not other parts of the brain. Penn is a leader in this area of trying to understand the pathways for progression, and their Virginia Lee and John Trojanowski in the Center for Neurodegenerative Disease Research have shown that there's cell-to-cell transmission so that alpha-synuclein spreads through its connections, so through the neurons that it's connected to, and that's how we get the progression.

How it starts, there's theories that it comes from our gut. It might go up through the vagus nerve to the lower brain stem, and then spread up through to the midbrain. There's also, like, a brain-first hypothesis that maybe we're inhaling toxins that go in through the olfactory bulbs, and that's why we have loss of sense of smell early on. But these are still theories that are being tested.

Host: When I was young physician, we would talk about Parkinson plus syndromes, and we can kind of go over those a little bit. They may be named something else now. I actually didn't look it up before the podcast. But one of those things was just a lot of autonomic changes, right? That were sometimes, in some cases, the prominent feature of the disease as opposed to really a lot of the typical Parkinson syndromes. Can we just talk about that a little bit and if that relates to anything in the pathophysiology we're talking about here?

Meredith Spindler, MD: Yeah, absolutely. So, there are several atypical parkinsonisms, and the one that you are touching on is multiple system atrophy, which can have earlier and more prominent dysautonomia than Parkinson's disease. Although it should be noted that Parkinson's disease also causes dysautonomia. So, you can have plenty of orthostatic hypotension and urinary problems, bowel problems in just regular Parkinson's disease. And multiple system atrophy actually has a few subtypes, including a subtype that's predominantly cerebellar. So, those people can look like they have ataxia rather than a parkinsonian syndrome.

But there's a parkinsonian subtype and an autonomic subtype of multiple system atrophy. And the parkinsonian subtype is the diagnosis that's most commonly misdiagnosed as Parkinson's first, and then you figure out that it's actually MSA-P or MSA Parkinsonian subtype.

So, all of those do involve the deposition of alpha-synuclein, but it's in the oligodendrocytes instead of in the neurons. So, it is slightly different. And then, you have other atypical parkinsonisms as well. You've got another synucleinopathy, which is dementia with Lewy bodies, which causes cognitive changes and especially visual hallucinations.

And the cognitive changes happen about the same time as the motor changes or maybe even before the motor changes. Otherwise though, the same Lewy bodies, theaccumulation of alpha-synuclein that you see in Parkinson's disease, you also see in dementia with Lewy bodies. It's just distributed among the cortex much at the start of the disease instead of later in the disease, as in Parkinson's.

And then, two other atypical parkinsonisms, corticobasal syndrome and progressive supranuclear palsy, those do not involve deposition of alpha-synuclein. Those involve deposition of a protein called tau. So, this is how you can see how alpha-synuclein testing can be helpful in differentiating these sometimes.

Host: Do you regard those that have some different pathophysiological mechanisms, you know, sort of now a little separate from Parkinson's? I think about, you know, sort of this Venn diagram. You know, have Parkinson's in the middle, and then there's Lewy body and multisystem atrophy, and they're separate, but there's some overlap there, right, and certainly in symptomatology. But the other two, I'm not sure.

Meredith Spindler, MD: Right. I mean, they do all cause Parkinsonism. That's their unifying feature. So clinically, they cause Parkinsonism, and they affect the basal ganglia in the brain. So, these are the things that unify them. But you're right. I think of Parkinson's disease and dementia with Lewy bodies as kind of on a spectrum. And then, multiple system atrophy, despite being a synucleinopathy, is separate. And then, the tauopathies are also separate. I don't know if you see them.

Nabila Dahodwala, MD: Yeah. I agree. And I think what complicates the picture is there can be co-pathology. So, it's not always you just have one syndrome, and you, like, read the textbook, and you have all of those symptoms. There's a lot of overlap, and I think sometimes there's people in the field that are lumpers, and they'll just put everything into synucleinopathy and especially around the PD DLB spectrum. Because even in early PD, you have some cognitive impairment. So, like, where do you draw the line versus the splitters who really want to say, like, there are all these distinct entities.

But I think what we're moving towards is more of this personalized medicine where we're learning as we develop these biomarkers and can detect either tau or synuclein through imaging, which we're not there yet, but we can find amyloid through imaging. We can detect some of these markers in the spinal fluid. We can test for tau, amyloid, alpha-synuclein in the spinal fluid, alpha-synuclein in the skin. We're just getting a better sense of what we see in the office correlates with their biology.

Host: And I imagine it, there is a practical reason to distinguish between these because I imagine the responsiveness to some of the treatments we're going to talk about further on down the line of the podcast, you know, do come into play, right? They all don't respond exactly the same way to the same drugs, right?

Nabila Dahodwala, MD: Exactly. And then, I think the other big thing just clinically is what prognosis, what to expect. Like people, it very much helps them to have a diagnosis to know how to plan for the future, what to expect with symptoms and how to address them as they come up.

Host: Maybe we should talk about that now. I have the impression of multisystem atrophy being a little bit more of a graver prognosis than Parkinson's itself, right?

Meredith Spindler, MD: Yeah, I would say all of the atypical parkinsonisms have a graver prognosis than Parkinson's. And it is interesting how a key differentiating feature is actually how they respond to therapy. We use that more than any diagnostic test actually, is just seeing if they have—a levodopa response is a key diagnostic feature of Parkinson's disease.

Host: Well, in the patients that have been diagnosed with Parkinson's in my practice, I have one in particular probably mentioned at an annual visit a year or two ago, a loss of smell. And, you know, we were thinking, is this COVID? And then, as things evolved, you know, gradually, now we recently have a diagnosis of Parkinson's disease.

And I think that, you know, I wonder now if that was an early sign. So maybe we should talk about some of these early signs. I listened to a podcast about a year ago where they were making the point about constipation sort of out of the blue, you know, being an early sign as well. What are some of the other ones that we should be looking out for?

Nabila Dahodwala, MD: So definitely, a loss of sense of smell, which leaves hyposmia or anosmia, which is complete loss of sense of smell versus reduced sense of smell. Dr. Spindler, Meredith, mentioned earlier this REM sleep behavior disorder, which you may be familiar with, but it's a sleep disorder when during REM sleep you have dream enactment because you've lost the normal atonia that you have during REM sleep. And that can precede the onset of the motor symptoms, both of those two, which are more specific for early or at-risk Parkinson's than constipation, which is not very specific.

But once you start putting them together, hyposmia, the REM sleep behavior disorder, constipation, you can have mood changes that precede the motor symptoms, depression, apathy, loss of interest, withdrawal from normal activities, anxiety, you can have some of these subtle executive dysfunction, like the very mild cognitive changes and maybe even some early autonomic features. Once they start, like, adding up, then you start to get this picture. And those are specific for synucleinopathy. So, the hyposmia RBD can be with MSA, which is multiple system atrophy or dementia with Lewy body as well.

Host: The autonomic piece, I always think of it as sort of a more advanced symptom in Parkinson's, but that's not necessarily the case from what you're saying.

Meredith Spindler, MD: It can be really at any point and precede the motor symptoms.

Host: And I want to go back to the sleep things because patients do come with sleep issues all the time, and I know what's going to happen. They're going to listen to this podcast and they're going to come in with questions about, "My gosh, my wife tells me I move a lot in my sleep. Do I have this REM behavioral disorder?"

We also send patients to you for restless legs, right, which I think falls under your area. That's different, right? That's this sort of tremendous desire to move your legs. You're conscious generally, right? This is something different. You're asleep, and yet you start to act out in some way.

Meredith Spindler, MD: Yeah. Most often, it's actually like a pretty violent nightmare, and you're kicking, you're punching, and if there's a bed partner, they can get hit. You can throw yourself out of bed. It's generally not subtle. So, it's like a pearl, honestly, to know to ask about if you're contemplating the possibility of Parkinson's or even the atypical Parkinsonism, just asking if they have a bed partner, "Have you ever been told that you act out your dreams?"

Nabila Dahodwala, MD: Yeah, the pearl is that REM sleep behavior disorder is quite specific for the later development of synucleinopathies to the degree of almost 90% of people will develop a synucleinopathy if you follow them long enough, you know, up to 20 years. And it does not have to happen every night. It could happen like once a month, once every six months, once a year. Usually, when it's happening more often, people have seen a sleep specialist.

And restless leg is, I think you mentioned this earlier, this uncomfortable sensation in your legs that leads to an urge to move that happens towards the early evening. It can be associated with periodic limb movements during the night. So while people are asleep, their legs are actively moving, but that's different from the dream enactment. This is actually while they're in REM dream sleep. They're doing what they're dreaming. So, they're like having conversations and punching and kicking. They tend to be violent dreams. And usually, I try and distinguish it from the periodic limb movements by the arm movements and the vocalizations as well.

Host: And this is a symptomatology that develops sort of anew, right? Like if somebody says, "You know, I've been acting out my dreams since I was a kid," you know, that's probably something else, right?

Meredith Spindler, MD: Yeah. I think though saying new, be a little careful there because it can precede the motor symptoms of the disease by a decade or more. But you're right. If they've had it since childhood or early adulthood, that does call it into question a little bit. And one mimic of REM sleep behavior disorder to maybe keep in the back of your mind is PTSD. PTSD can cause dream enactment, but the difference is that it's not during REM sleep. It's during slow-wave sleep. But if someone's been acting out their dreams since early adulthood ever since like a particular trauma, that might be something different. But if in some point in middle adulthood they develop dream enactment, that's a clue that what you're looking at might be a synucleinopathy

Host: That's very interesting. I didn't know much about that. By the way, what is—I.. should know more about sleep—but, you know, REM is in the middle phase, right? But the slow piece is either when you're waking up or—

Nabila Dahodwala, MD: REM is the dream sleep. That's when you're dreaming.

Host: Right. Right.

Nabila Dahodwala, MD: Yeah. And it can be towards the middle to the end. It's not just in the middle. And it changes as you get older, like how long the deep sleep is and the shorter phase sleep is. But usually, it's through to when you're waking up.

Host: I guess my question is how would I know somebody's having it during REM sleep versus not in REM sleep?

Nabila Dahodwala, MD: A sleep study. You need a polysomnogram.

Host: Okay. Not expected to know that in clinical medicine without another tool. Okay. So, most of the time, folks come into us though and they say, "Doc, I have a tremor. I noticed it." You know, sometimes they say like a patient did today, "My dad's had a tremor," and which gives me a little bit of a clue because I know essential tremor is highly heritable. But nevertheless they have a tremor.

Now, when I was reading about this years ago as a resident and a student, they would talk about different hertz of tremor. "Oh, it's a this hertz tremor." Meant nothing to me and still doesn't. So, maybe we can kind of go into a little bit. When someone says they're having a tremor to you all as experts, what are the things that you're looking for to sort of distinguish what's going on here?

Meredith Spindler, MD: Yeah. There are so many things. It's hard to know where to start. So first, I'll talk about features of the tremor, like when it happens. And I think actually this is probably something your audience is well aware of, which is that resting tremor is more typical of Parkinson's, whereas essential tremor is more likely to be a postural and an action tremor. And yes, the tremor can be faster in essential tremor than Parkinson's. Parkinson's is maybe a little slower, but the truth is I don't really hang my hat on that anyway. I wouldn't really worry too much about that.

A couple of other points on history for essential tremor, I'll be interested to know if there's a head tremor or a vocal tremor, especially the vocal tremor is pretty specific to essential tremor. A head tremor as well is pretty specific in comparison to Parkinson's. Whereas on the Parkinson's side of things, I'll want to know, are they noticing stiffness, slowness, walking changes, balance changes, all of those non-motor symptoms that Dr. Dahodwala mentioned earlier that are supportive features of Parkinson's.

So on the history, those are the things I'll be asking about. Whether alcohol improves the tremor is like a fun one we all learn in med school. I also don't hang my hat on that because I think there are Parkinson's patients who think that alcohol can improve their tremor. On exam, I'm obviously definitely looking for bradykinesia and rigidity as a distinguishing characteristic. If you see that and it's convincing, that's very concerning for it being Parkinson's disease. Whereas essential tremor should not really have bradykinesia or rigidity and should be a predominantly action tremor. And again, dream enactment is a pearl here. That should really put up your antenna for it being Parkinson's.

Nabila Dahodwala, MD: I would add the asymmetry. So usually, in Parkinson's disease, it's one side, or at least one side is much worse than the other. So, something highly asymmetric, whereas essential tremor is generally bilateral. People may complain of their dominant hand, like, "Oh, my right hand is shaking." But when you examine them, it's actually in both hands, and they're like, "Oh yeah, that hand shakes, but it's not a big deal because I don't use it." But the asymmetry is a hallmark feature for Parkinson's.

Meredith Spindler, MD: Also, leg tremor at rest. Leg tremor at rest, especially if it's asymmetric, should not happen in essential tremor. Occasionally, people with essential tremor get a little, like, shiver of their knees while they're sitting, but that toe-tapping tremor that you see in Parkinson's, that should not happen in essential tremor

Host: So, you should not see leg tremor with essential tremor. That's a Parkinson's—

Meredith Spindler, MD: Not at rest.

Host: Right, not at rest. So take me through an exam. You have a patient that comes in with a tremor. Can you just take me through an exam that you would do, things that you might focus on when you're doing your exam?

Nabila Dahodwala, MD: Sure. So, I look at their face. Someone with Parkinson's will be less expressive. They might be blinking less. It'll look like they're staring at you. It might look like they're depressed or tired. But just look at their blink frequency, if their mouth's a little bit open. I'll listen to their voice. Sometimes their voice gets softer or they might start, like, slurring their ,words at the end. Whereas with essential tremor, their voice is shaky, like, kind of like Katharine Hepburn. I might be dating myself. But, you know, there's that very, up and down voice. If you want to try and hear that, you can have them say, like, a vowel for, like, one breath. Just say like "Eeee" for a long time, and you can hear the waver in the voice.

I want to look at them at rest, and sometimes it's hard to get people to rest and relax when you're staring at them and relaxing them. So, some maneuvers to try and get them rest, let their hands sit on their laps and have them close their eyes and do like a distraction technique, like give you the days of the week backward or the months of the year backwards, and then see if that brings out a rest tremor. I'll have them hold their arms out in front of them and look at the tremor in that position. So, that's with posture. And in essential tremor, you'll immediately see a high frequency, low amplitude oscillation of the hands.

In Parkinson's disease, you might see the emergence of the tremor that you saw at rest, like the same frequency, same amplitude, but not immediately. It takes a little bit of time, and then it comes out, and it should be asymmetric. And then, I have them use their hands. So, I'll do like a finger-nose-finger and look at the tremor with that. So with essential tremor, you usually see the action tremor component as well, and it might be about the same as with posture or a little bit worse with action.

I also like to see them write, like do some handwriting. You can do the Archimedes spiral, if you remember that from medical school, or have them write a sentence. And that distinguishes Parkinson's from essential tremor, I think, really nicely because the spiral in essential tremor stays really big with an oscillating line as you go around. Whereas in Parkinson's disease, it gets smaller and smaller, and the handwriting gets smaller in Parkinson's. Whereas in essential tremor, it's really big and shaky.

I also look at the speed of their movements with like finger tapping, toe tapping. I move their limbs around to feel their tone, and I always watch them walk. Again, like their Parkinson's walk, stooped posture, decreased arm swing, usually on one side. They're not lifting their feet up as they walk. They might be shuffling, taking slow steps. It takes them several steps to turn. That's what we call the en bloc turning, and they might lose their balance easily, whereas essential tremor should be a normal gait.

Meredith Spindler, MD: Sometimes people with essential tremor have a little bit of imbalance, and they might have like a slightly wide-based gait, but they shouldn't have reduced arm swing or stooped posture or shuffling. I'll just add a couple of other little tidbits here. I do think looking for bradykinesia both globally and in their limbs is super important. So in addition to their face being masked, sometimes they're just very still. Like, you just notice a loss of spontaneous movement.

And then, when they go in their bag to reach for their binder of documents, it's like a very slow movement. And in their hands, when we have them do these finger taps and these fist open-close, if you remember this, we're not just looking for slowness, we're looking for something called decrement, where the amplitude of the movements gets smaller and smaller as they go. And that's a pretty key feature, and it should be asymmetric. And if you see that, that's really concerning for Parkinson's.

I'll just make one other point too that I thought of as Dr. Dahodwala was talking, I thought about when I said you ask them if their tremor's at rest versus with action, many people, when you ask them if it's at rest, they think you mean with posture. So, they think if they hold out their hands, that's at rest. So when you ask that question, make sure they understand that at rest is fully supported, like resting on their lap while they're watching TV, because otherwise they might tell you, "Yes, it shakes when I'm holding papers," for example, and they think that's at rest.

Host: So just for our audience to distinguish between the movement and the postural and the resting, can you just clarify the difference between the essential tremors and Parkinson's tremors in relation to movement? Can you go through that again?

Meredith Spindler, MD: Yeah. Parkinson's usually causes a resting tremor. So, the hand shakes while their arm is fully supported. They're watching TV, they're not really doing anything with their hand and it's shaking. Or while they're walking, their hand's at their side, it's shaking. An essential tremor, it shakes when they're trying to use their hand to do something, like write or eat or shave or type.

Host: And Meredith, I want to go back to this decrement issue. You said that as you ask them to squeeze their hand, maybe from an open fist, go like this. So, you're starting with a fully open fist, and then you're squeezing down.

Meredith Spindler, MD: Open, close, open, close.

Host: And what's happening there?

Meredith Spindler, MD: It just kind of gets smaller with time.

Host: Smaller and smaller. Smaller. They're not fully extending their fingers.

Meredith Spindler, MD: The excursion is getting smaller and smaller in the movement. Yep.

Host: Yeah. I mean, I think the trickiest cases even for us, because folks come into primary care with tremors all the time and ask us about stuff, is the signs that we might see that might symbolize symbolize Parkinson's would be very subtle often at that point, and that's where it gets tricky for us. So, these little clues are really helpful.

I think we can all recognize—I had a patient of mine who was ultimately diagnosed with Parkinson's, and she came out of the bathroom. I just, you know, noticed her coming down the hallway out of the bathroom and I said, "Oh, she looks parkinsonian." And it was just a glimpse out of the blue, you know? She wasn't there for anything specific. It was just an annual visit. It just struck me. But, you know, within a year or two, she was formally diagnosed. But in any case, I think a lot of folks have very early symptomatology, and it can be tricky. So, I send them to you, you do these exams. Oh, by the way, cogwheel rigidity, something I was taught in medical school, early sign or late sign?

Meredith Spindler, MD: Early.

Nabila Dahodwala, MD: Early, yeah. For us, when we make the clinical diagnosis, they have to have at least two of the four cardinal features, which I remember the mnemonic from it. It's TRAP is my mnemonic. So, tremor, rigidity, akinesia for the A, but bradykinesia, and then postural changes and gait changes.

The bradykinesia is required, but rigidity almost always goes along with the bradykinesia. And it can be subtle. Again, you have to, like, get them to relax. And usually, I distract them because if you say relax, that's like you're going to do the opposite. But you're moving their limbs across two joints and feeling for the resistance.

Host: And bradykinesia manifests on exam as that increased tone, right?

Nabila Dahodwala, MD: That's rigidity.

Host: That's rigidity. Okay

Nabila Dahodwala, MD: And bradykinesia is the slowness.

Host: Bradykinesia is just they're moving slowly. I don't know if I ever got that teaching But if I did, I'd forgotten a lot of it. And so, that's just really helpful.

Nabila Dahodwala, MD: I mean, it's a lot. Like, I think as primary care doctors, you're doing—it's, like, impossible to know everything, to know the breadth and the depth for, like, every disease under the sun. ,So I think, you have to rely a little bit on what people tell you, like, if they notice changes or slowness. I think the hardest is if they don't have tremor, because at least tremor is obvious and you can pick up on it.

But like Meredith mentioned, 70% of people have tremor with their Parkinson's, but 30% don't. And those are the people who you notice, like, when they come out of the bathroom or when they walk down to your office, there's just a change in the dynamic of, like, one side isn't moving the same way. Sometimes it's their spouse or child that notices that they think they had a stroke because they're holding their arm to their side. So, it's not easy, and it happens slowly. And you're seeing, you know, takes something to bring it out for them to talk about it. that's why we need better, I think, either diagnostic tests or screening tests, because I don't think it's, like, an easy thing to detect when it's so early.

Host: So in our remaining minutes of our part one of Parkinson's disease, because I really actually want to make sure we do a part two to go into this in more detail. You know, sometimes I've sent patients to you guys and you basically send me back a note saying they have Parkinson's disease, it's clinical, it's clear, and so forth. But then, other times, I think you're not sure either, and so you're going to another set of tests. What are those next tests?

Nabila Dahodwala, MD: If they have atypical signs let's say they are falling very early on or they have some cognitive changes, I'll usually get a brain MRI scan, because the brain MRI scan can show us some subtle signs of atypical Parkinson's through the structural changes. It can also show secondary causes of Parkinson's, like vascular disease that causes usually like a more gait-predominant parkinsonism. If I'm not sure about other overlapping features, like if they've had exposure to neuroleptics, so it could be a drug-induced parkinsonism, but they also have some prodromal features. I might get a dopamine SPECT scan, which shows us the integrity of the dopamine receptors in the striatum, which will be reduced in Parkinson's disease, but not in a drug-induced parkinsonism. It won't be reduced in essential tremor or like a functional tremor, but typically are reduced in the atypical Parkinson's. So, it wouldn't necessarily distinguish all of them.

So imaging, sometimes I will go to a skin biopsy now that we've had that available. I find that helpful when there might be a contraindication for DaTscan. So, some medications that they're taking also block the binding of the tracer. So, it might be artificially reduced, because of the medicine they're on. And if they can't come off the medicine, and some of them they have to be off for like weeks at a time. I'll try the skin biopsy first. I very rarely get the spinal fluid test, because it's just more invasive. But if I have a more complex case of dementia where I want to get spinal fluid for something else, like say I'm thinking about normal pressure hydrocephalus, I'll send the test then, because we're already sampling the fluid. What about you?

Meredith Spindler, MD: Yeah, I want to make a couple of points. You'll note that Dr. Dahodwala said she gets an MRI if there are concerning signs of an atypical syndrome. But if there aren't, and if it's a classic case, we really don't get MRIs of the brain at all. And probably before we even go to that testing, we've tried levodopa. Because if there's a good levodopa response, we probably don't need any further testing.

So before we've even done these things, we've tried levodopa. In those subtle cases that we were talking about, like maybe someone is really early and you're just not sure. That does happen sometimes. The test I prefer is a DaTscan because it's going to show me that the problem is actually in the brain. There is this theoretical chance that the alpha-synuclein in the skin hasn't actually led to degeneration in the brain yet, so that's going to be my test of choice if I'm really trying to determine that they have a degenerative parkinsonism.

Host: Can we go over the DaTscan in terms of what is it? Is it nuclear medicine, right? Yeah.

Meredith Spindler, MD: So, it's nuclear medicine.

Host: Nuclear medicine, not widely available, I would imagine.

Meredith Spindler, MD: It's not too bad, but I will say that I try to have them get it done at Penn because it can be very tricky to interpret and read. So if there isn't a lot of experience with a high volume of scans, there can be false positives or negatives in the read. And so, I do try to have them done here. But yeah, so it's a nuclear medicine scan and the ligand binds dopamine transporters. And so if you've got degeneration of your projections from the substantia nigra, there's fewer dopamine transporters. So, you're directly measuring the degeneration. But it's positive in the atypical parkinsonisms as well. So, it's not going to differentiate those.

Host: Sensitivity and specificity, what do you think the numbers are? Over 90% on each?

Meredith Spindler, MD: No, I think it's going to be in the 80s.

Nabila Dahodwala, MD: It's lower. So, there was one study that was published in Neurology that compared our clinical diagnosis to the DaTscan, and it wasn't better. So, we're about 80% to 90% accurate, especially with like a one-time visit. And the DaTscan is about there. A lot of it depends on the pretest probability, like who are you doing it on? And we tend to do it on people that we're unsure about, like they're early. And so, it's definitely not perfect.

Meredith Spindler, MD: There can even be like inconclusive ones where the reader says equivocal.

Host: I imagine you get second opinion questions about patients who have had DaTscan in the community and are coming in to see you, and you're sorting out the clinical picture in that context, right?

Nabila Dahodwala, MD: Yeah. I mean, maybe we've had different experiences, but my experience on average is that the DaTscan are quite useful, and my second opinion is confirming what the community doctor had thought. But rarely, it's a normal DaTscan and I'm still concerned about parkinsonism, we'll say maybe we should repeat it here or look more closely at the scan and do a dopamine trial.

Meredith Spindler, MD: I usually want to get the images myself and reread them and potentially have someone here read them because I often find an overread is not the same as the original read.

Host: And so, we've talked about skin testing. Here we're detecting alpha-synuclein directly, right? And you can do that in the spinal fluid. But, you know, nobody can do an LP anymore. You know, back in the day when I trained as a resident, we had to sign off on certain numbers of them. And now, I'm not even sure our internal medicine residents will get more than one or two.

Meredith Spindler, MD: Yeah, they're not getting signed off.

Host: Yeah. So, LPs are harder to do nowadays. But nevertheless, you have a skin biopsy. Do you guys do the skin biopsy?

Nabila Dahodwala, MD: That's correct. We do them in our clinic.

Host: Yeah. And is it a punch biopsy? Is it—

Nabila Dahodwala, MD: It's not too bad. It doesn't even require a stitch. There's three punch biopsies that happen in the cervical area of the neck, on the upper leg and the lower leg. It takes probably about 30 minutes, and we just pack it with foam gel that has clotting material and put a bandage over it. And then, it takes maybe about two to three weeks for the results to come back. But yeah, it's been really nice to have just more tools in our toolbox. Again, we don't do this in most people. But when we're trying to distinguish it from atypicals or we're not able to get a DAAT scan, it does give us extra helpful information

Host: And that's the newer test, right? The skin biopsy is newer than DAT, right? You had DAT for a while. So, you're starting to use that. And the sensitivity and specificity, I did look this up. It does appear to be above 90%, I think, in both or something like that. But maybe I don't remember what I looked

Meredith Spindler, MD: Yeah. No, you're right. In the largest study, it was over 90%. Although that was in patients who had sort of a more clear diagnosis clinically. Then, there was another study published that was a little smaller in people who were brand new. And actually, the sensitivity was a little bit lower in that study, but the specificity was still very high. The sensitivity was 80%.

Host: Because you shouldn't really have alpha synuclein in your skin, right? It's not a normal resident of your skin. So if it's there, the specificity for something abnormal is higher.

Meredith Spindler, MD: Yeah. Not the kind that's detected in the seeding assay, yes. And I will just say, I think some of the sensitivity aspect might be driven simply by sampling. You know, they designed it to have three samples because that increases your sensitivity, but it's still not perfect with just three samples.

Host: So much of our work in primary care centers on the diagnosis piece, which is why I really wanted to spend time and hover over that and go into detail on your exams. This was as much for my benefit as for the audience I assure you. But I do want to bring you back for a part two and really start to go into the treatments and distinguishing—I mean, there's a long list of possible options, and Sinemet itself, carbidopa/levodopa, comes in several different formulations, generic and trade name, and we're going to need some time just to work through that.

Nabila Dahodwala, MD: Definitely. I love that you're interested as a primary care audience in this, because it i is so important to help identify people that should get treated for the Parkinson's disease. We have really amazing treatment. And so, I think recognizing that helps people really improve their quality of life.

Host: And avoid the complications before they become complications, right? Falls and the other issues.

Nabila Dahodwala, MD: Exactly.

Meredith Spindler, MD: Yes. Yeah.

Host: Yeah. Well, thank you so much, Nabila and Meredith. I look forward to the second part of our discussion, and I hope the audience of the Penn Primary Care Podcast will join us again next time.