Stephen Wilson 0:06 Welcome to Episode 19 of the Language Neuroscience Podcast, the first episode for the year of 2022. I'm sorry that we're already well into February. I've been busy submitting papers, and I'm pleased to report that I've now completed my to do list... from 2019. My guest for the first episode of the new year is a very special one, Keith Josephs, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. Keith is one of the world's leading experts on the neuropathological underpinnings of speech and language disorders that are caused by neurodegeneration. He's also made a compelling case that primary progressive apraxia of speech is a distinct neurological entity. And he's identified two different forms of apraxia of speech with contrasting clinical linguistic features, that have different etiologies. I've been reading his work for a long time, and I hope you'll enjoy learning about it. I'd like to thank the journal Neurobiology of Language for supporting transcription of today's episode and I'd like to thank Marcia Petyt for her work on the transcription. Okay, let's get to it. Hey, Keith, how are you today? Keith Josephs 1:07 I'm good, thanks. It's snowing here but otherwise, I'm doing fine. How about you? Stephen Wilson 1:10 It's snowing? Keith Josephs 1:12 Ah, it's snowing a little bit. Yeah, it was snowing a bit more this morning. Stephen Wilson 1:15 Yeah, I guess you're way up there in Minnesota. Right? Keith Josephs 1:18 Correct. Correct. I've been looking outside right now and everything is just white. It's pretty but it's cold. Stephen Wilson 1:25 Right. Yeah. In Nashville, it's almost going to be spring, I think and it's just windy and sunny. Keith Josephs 1:31 Rub it in Stephen, rub it in. Stephen Wilson 1:32 Weirdly, weirdly windy. Yeah. I don't know what it's like to live in a really cold place. Keith Josephs 1:37 Yeah, it's different. It's very, I used to live in Florida and I can tell you, it's very different. Stephen Wilson 1:44 Yeah, but you've been up at Mayo for quite a while now, certainly all the time since I first met you. Keith Josephs 1:50 Yeah, I've been here for 25 years, I think. Stephen Wilson 1:53 Wow. Keith Josephs 1:53 Since I graduated med school. A long time. Stephen Wilson 1:57 Okay, so you have plenty of chance to get used to it? Keith Josephs 2:00 Yeah. I don't think you ever get used to it unless you're born here. You know, the shoveling, the cold and the ice. But, I think it's you tolerate it much better than probably you, you would the first couple of years that you're here. Stephen Wilson 2:17 All right. Well, thanks so much for taking the time to talk with me today. Keith Josephs 2:22 Sure. Stephen Wilson 2:22 I've always been really interested in your work and I think a lot of people will be too. I always like to start by asking people about, essentially their childhood and the path that led them to become the kind of scientists that they are. So, can we start by talking about that? Like, how did you grow up and grow up to be a scientist? Keith Josephs 2:40 Yeah, so I actually I grew up in the, in the Caribbean, actually. And when you grew up in the Caribbean, you're in, there's a lot of British influence, you know, and your examinations are sort of set by Cambridge and Oxford and so your focus is really on, you know, the sciences, chemistry, physics, biology, and then of course, mathematics. And so my, you know, I was always very interested in mathematics, I was very good at it. And actually, when I migrated to this country, I don't know, you know, 30, 40 something years ago, I decided that I was going to be a mathematician. And there were, you know, these theorems that needed to be solved, and I wanted to solve them. And then, you know, for some reason, during college, I maybe, I started grad school, I got a little bit bored and decided I was going to go to med school. And then, you know, the funny thing is, I knew nothing about research. I actually sort of stopped my PhD in math early, got the masters and then just jumped into med school, it was all clinical. I didn't really get involved in research until you know, I was really a resident. And it's funny, because at that time, I think I woke up one morning, and just thought, you know, read about a disease called Von Economo disease or post-encephalitis parkinsonism, about these people that had an infection and then developed a Parkinsonian condition, and I wanted to study the pathology. But how do you find brains of patients that died in the 1930s and 1940s? And so unless you're at, you know, Bellevue Hospital in New York, it was very difficult and so I actually went to the bowels of the Mayo Clinic and we found paraffin blocks of three cases. Three patients brains. And that's kind of where it all began, you know. I was very interested. Nobody else could do this. I remember my chairman saying, you know, you don't want to study that. Nobody cares, you know, study normal pressure hydrocephalus (NPH). And I was like, absolutely not. Stephen Wilson 4:29 (Laughter) Keith Josephs 4:30 And so I did my own thing, you know. And I, it because I, it was fun for me. And, you know, as a resident I actually got invited to the American Academy of Neurology to present these three cases they thought it was, I didn't know it was that important but they clearly did. And then that's kind of how it all started for me. Stephen Wilson 4:48 So pathology came first for you. Keith Josephs 4:51 Absolutely. Yeah, that that is you know, it that that was and still is my my first love. I think. I enjoy it. I could spend eight hours a day looking under the microscope and just never get tired. Stephen Wilson 5:04 Yeah. So as we talked about on email, we're going to talk today about the neuropathology underlying neurodegenerative aphasias. But I think it'd be really interesting to hear about, like those first three brains and like, what was it that you saw, and then that that made a splash in that scientific community? Keith Josephs 5:20 I think, you know, the issue is or was back then, whether or not post-encephalitic parkinsonism, was a, was similar to Parkinson's disease in terms of the pathology. And so, you know, most of us will, will tell you that in Parkinson's disease brains, you have these Lewy bodies, and these Lewy bodies are characterized by the deposition of this abnormal protein called Alpha-synuclein. And so, the question I had was, well, do you see Lewy bodies? And if you do, are they Alpha-synuclein immunoreactive? Are they positive for this protein, alpha-synuclein. And so we got these brains, dissected them got blanks, stain them with alpha-synuclein, and some other stains, and it was negative. Stephen Wilson 6:03 Ahhh! Keith Josephs 6:04 So it was the first study to really show that even though patients had this infection, and I think it's kind of an interesting conversation, because we're sort of back here with COVID-19 in the sort of back at the same point, those folks were in 1914, where they had this infection, then 10 years later they had a Parkinsonian condition. But instead, what I found, which I, this was known before, though, that it was, there was a lot of tau in the brain. And the tau was quite similar to the tau that you actually see in Alzheimer's disease. That was known. I wasn't the first to show that. But what was novel, was that I did not see Alpha-synuclein immunoreactive Lewy bodies. Stephen Wilson 6:40 Uh huh. And so did you sort of have an idea about where the Parkinsonism came from, given that the underlying etiology was so different? Keith Josephs 6:49 So after we started studying the brain, that the thinking was that yes, it was coming from the abnormal deposition of tau. And in fact, we do see patients now, they're not common, that will present with Parkinsonian conditions and when you look under the microscope, you don't see these Lewy bodies instead, instead, you'll see Alzheimer's pathology. Now, of course, you have to have the pathology in the correct areas of the brain, you know, the brainstem, the basal ganglia. But, but the thinking is that it's actually post-encephalitic parkinsonism is now considered a, a tauopathy, similar to to the Alzheimer's disease and progressive supranuclear palsy and some of these other conditions we'll be talking about today in the speech and language disorders. Stephen Wilson 7:37 Yeah. Well, that's such a fascinating path towards what you now are working on. So I think most language researchers, which is kind of who listens to this podcast, when we think of aphasia, we mostly think of stroke and we sort of think about focal damage to nodes of the language network. And then, most people, I think, don't think too much about neurodegenerative disease and when we do we think about, you know, Alzheimer's memory things other than language. And I think there's also this general sense out there that neurodegeneration is kind of non focal and messy. But that's just not the reality of the world revealed by your work and the work of others in this field is it? Keith Josephs 8:15 No, that's that that's very far from the truth. In fact, you know, there's data going back to Arnold Pick's work in the 1800s, 1840 something or 1860 something where, you know, there was evidence that, that there can be very focal degeneration within the brain. And it can be super focal, when if you have very, very sensitive imaging, sometimes, you know, I recall a patient I one of the first patients that I saw, a woman with two PhDs that had a language presentation known as a logopenic progressive aphasia, and we did a PET scan in her and she had essentially a single dot, one little spot that was in the sort of the posterior part of the temporal lobe on the left side, that was it, everything was clean. Saw her years later, maybe 10 years later, or eight years later, and at that time, the it was still focal, but it wasn't as focal. It wasn't, it had now extended to involve more of the temporal lobe and even some of the parietal lobe. So, so you know, these degenerative conditions that we see presenting with aphasia, or at least in my world, with mixture of a phaser, and motor speech disorder known as apraxia of speech, we tend to see very, very, very focal abnormalities, anatomically and functionally, Stephen Wilson 9:34 Right. So I don't know, do you do you ever work much with stroke patients or do you I mean, are you familiar with their... Keith Josephs 9:39 Well, you know, when you train as a neurologist, in fact, you know, before I started doing, you know, this kind of research, everything I knew about speech was based on the stroke literature, which of course, now I've completely forgotten, but you know, you learn about the conduction aphasia, and you're affecting the, you know, the arcuate fasciculus and Broca's aphasia and you know, wernickes aphasia due to a stroke here. So that's kind of how I think most of us are taught. You see these patients in the clinic, and that's what you, that's all you know. But my world is very, very, very different. Stephen Wilson 10:11 And do you think that progressive aphasia is a more or less focal than stroke aphasia is? Or do you think it's a silly question? Keith Josephs 10:19 Um, no, I, you know, I don't think it's a silly question. I think it's, they're both very focal, I don't know if I can say that one is more focal or the other because, you know, it probably, it all depends you know. You can have a pretty big stroke, a non focal stroke or a multi, multi infarct disorder that can cause aphasia, and, you know, you can have a big neurodegeneration or, or focal neurogeneration that can cause aphasia, I think the key is the anatomy, right? Whether the area that's that's that's involved in the, in the aphasia, or the apraxia of speech is affected, or is covered by where the stroke is, and where the neurodegeneration is, is occurring. Stephen Wilson 11:00 That makes sense, Keith Josephs 11:01 You know, they're very similar. I mean, there are differences, for example, one type of motor speech disorder that that I see and was instrumental in describing, we don't see it in the, for whatever reason, we do not see it in the stroke, in stroke patients. Stephen Wilson 11:15 You mean pure apraxia of speech? Keith Josephs 11:17 Well, we're talking about the the prosodic type, okay. Stephen Wilson 11:21 Yeah. Okay, we're gonna get a plan to get into all those details. Yeah. Cool. So can you tell us about the spectrum of speech language syndromes that result from the neurodegeneration? Maybe sort of, and also just contrasting your view to other views that are out there? Like, how do you see this sort of, breakdown of clinical syndromes? Keith Josephs 11:45 Yeah, good question. So I, you know, I see, you know, the speech and language disorders presenting in isolation. And I also see them present in the context of more widespread neurological findings, symptoms, signs. If we, you know, we can talk about either or, because I think there could be a conversation or conversation and either but if we just go to the relatively focal presentation, so you're not getting involved into the limbs or the eyes or the balance, you know, this is just a speech or language disorder, the way I look at it or we look at it here, is that you can have a, a pure aphasic disorder, you can have a pure motor speech disorder, which I'll get into a little bit more, and you can have a mixed aphasia motor speech disorder. So they can occur in separate or they can occur together and when I'm talking about motor speech disorder, I have to be very clear because I think most people think about dysarthrias and that's not what I'm talking about. Dysarthria can occur with aphasia, it can occur with apraxia of speech, so sort of, you know, this goes back to Fred Darley's work, where he champion you know, the entity you know, apraxia of speech and the way we think about it here is that you know, motor speech can be divided into dysarthria and apraxia of speech. And in apraxia of speech, you know, we have two subtypes, and then dysarthria have multiple subtypes. So, you can have, you know, at least in the way we diagnose patients, you can have any aphasia then you can have different types of aphasia. You can have apraxia of speech type of motor speech disorder, and you can have you know, you mentioned type one or type two, which you know, is also referred to as the phonetic or the prosodic type. And then you can have a dysarthria. And with dysarthria you can have a hypokinetic, ataxic, spastic and flaccid, a mix spastic flaccid, a mix apraxic, I'm sorry, a mix ataxic flaccid and then those mix dysarthrias can also combined with apraxia of speech and or aphasia. So you could typically, you could, you could tentatively have a patient that have an agrammatic aphasia with an apraxia of speech, maybe say the prosoduc, the phonetic type and a mix dysarthria with both a spastic and flaccid component, you know, so we really break it down to the individual aphasic and motor speech disorder diagnosis and then build it back up when we see the patients here. Stephen Wilson 14:20 Okay. So, your first impulse is not to answer this question in terms of clinical syndromes, but to focus on actual specific deficits, which then may or may not co-occur in any given syndrome. Keith Josephs 14:35 Correct. I mean, we do both, but but we do them separately, you know. So, we, we focus on the speech and language problems and we also focus on the non speech and language problems. So, we try to put it together, you know. So and which is why I said in the beginning that you can have these, you know, these aphasic, apraxic dysarthric conditions occurring in isolation where the neurological examination is completely normal. But for example, have you heard of a syndrome, corticobasal syndrome, the corticobasal syndrome, or CBS. So the corticobasal syndrome, for example, many patients with the corticobasal syndrome will present with an aphasia and or apraxia of speech, and maybe even a spastic dysarthria. But those patients will also have, for example, apraxia of the limb, and Parkinsonian features. And so, you know, we break down the speech component, they'll get a speech language, diagnosis, but but we know that that is in the context of this condition, or this, this this bigger syndrome, that we would diagnose as, so the patient get a diagnosis of corticobasal syndrome, characterized by ideomotor apraxia, as well as a mixed aphasic motor speech disorder. And then, you know, with that, you know, what I am pretty good at, I think I'm not perfect, but I think I can hold my own, is actually predicting what the underlying pathology will be, you know, that's what I'm good at. Stephen Wilson 16:07 Yes, definitely. And I want to get to that real soon, kind of understanding the pathologies that underlie these different syndromes. So you're making the point that, you know, these aphasic and apraxic symptoms can occur as part of a spectrum of language and non-language deficits and corticobasal syndrome or PSP syndrome. And then you also we also see relatively pure speech language cases, right? Keith Josephs 16:37 Correct. Correct. And it's not just based on disease duration Stephen. So some people may say, well, of course, if you see them very early, they're going to be pure. And if you see them very late, they're going to be, you know, the speech and language problem will be buried within the context of a more widespread neurological condition. That isn't the case. I don't, I don't pretend that I really understand it. But that isn't the case. You can present very, very early with a progressive supranuclear palsy syndrome, and no speech or language problems. And you can present very early with a speech and or language problem without any neurological problems. Or you can present later with a mixture of both. So it's not, you know, when we see these patients, it's not simply Oh, you've had it for one year, so you're going to be pure. You know, it's that's just not not what we're seeing. It probably depends on where the the predominant, where the fire is in the brain. Stephen Wilson 17:31 Right. Keith Josephs 17:32 Did the fire start in the kitchen? Or did it start in the bedroom? And and so, you know, when you get to the home, you know, where exactly will the fire be? Stephen Wilson 17:32 Mm hmm. And how good are the fire doors? Keith Josephs 17:38 Yeah, yes, exactly. (Laughter) Stephen Wilson 17:46 So, I think one of the things that's unique about your work is that you do distinguish primary progressive apraxia of speech as a separate clinical syndrome than primary progressive aphasia. I'd like to talk more about that in a moment. But within and within primary progressive aphasia, many people recognize a non-fluent variant, a semantic variant and logopenic variant that you mentioned a moment ago. Do you, do you also see those three variants? Or do you think that there are more than three variants? Or do you think it's just like kind of a free for all? Keith Josephs 18:17 No, I want to clarify that, you know, at least hear at Mayo, we never use the term non-fluent, you know, we never did and we still don't, and we can get into that later. But the way I would say it is that, there tends to be agrammatic variant and, and the logopenic variant. And then, you know, I also sort of disagree with the field that there is a, a semantic variant of PPA, which we can get into, but but but I think for the for argument's sake, I would say that there are at least three variants. But you know, I do see patients sometimes, that do not fit into any other variants, either they have a, they don't have all the features that you'd expect. In fact, I just saw somebody we just reviewed somebody on, yes, on Wednesday, Wednesday morning, that did not have the classic features. And, you know, we were pushing the speech and language pathologists come up. What do you think? What do you think? And you know, they were pushing me What do you think? What do you think? And we really couldn't pigeonhole the patient. Ultimately, we went with speech and language disorder, unclassifiable. In fact, you know, when we talk about these disorders, there's a paper that's published in cortex by my colleague Hugo Botha and in the paper we talked about the PPA-U, you know, we had this class where PPA unclassified. We couldn't classify these patients. We also had this category progressive fluent aphasia, Stephen, whereby these patients, now I said, we don't know them as non-fluent, but but but these patients were just fluid. We heard nothing, but when you ask them to name things, you know, in confrontation naming, they did, they did relatively poorly. But that's all we saw. We didn't know what these patients had or where they're going to go. We suspect now that the majority of them will progress into either the logopenic or the semantic variant of PPA. So definitely here, we do see the the agrammatic aphasia, the semantic and the logopenic variant. I think though, maybe where I differ is in the frequency of diagnosis in the syndrome. So the agrammatic variant, the true agrammatic variant, where aphasia, in our opinion is the dominant feature in, in my opinion, is actually very rare. And in fact, even the folks that don't agree or, or will argue with with a term apraxia of speech, if you look at the research that they publish, there's a paper by a woman, I think it's [Jenny] Ogar is her name about 15, 20 years ago. And if you look at the paper she published, the majority of patients that were diagnosed with agrammatic, I think they call it the non-fluent variant of PPA, indeed had an apraxia of speech or a motor speech disorder. Stephen Wilson 20:48 Yeah, no, I, I mean, I, I did my postdoc in that lab. I mean, certainly, you know, as you know, from the consensus guidelines, you can be diagnosed non-fluent if you were either agrammatic or apraxic. And in my experience, the majority, they were much more apraxic patients than they were agrammatic and it was, you know, they did kind of tend to fall into those two distinct groups. Keith Josephs 21:11 Yeah, that's an interesting comment that it's something that, you know, for years and years, I have had concerns with the consensus criteria. It is probably one of the biggest concerns I have the consensus criteria is that you can make a diagnosis of, of non-fluent, or agrammatic or well, it's called non-fluent PPA. If the patient has just an apraxia of speech, and I'll tell you why, why I have a problem with that. The term PPA when Mesulam coined that term, he clearly said that you cannot have, it should not be characterized by phonetic disintegration. And you can ask Marsel, I think what he means by that, is that the patient cannot have a motor speech disorder. So if you really follow the consensus criteria to the tee, it says, first you meet criteria for PPA, then if and only if you meet criteria for PPA, you should be able to classify these patients as you know, a grammatic, logopenic or, or, or semantic, but most people 95% I think of researchers do not do that. They go straight to the logopenic, the agrammatic and the semantic variant, and ignore that first part, but if you really do not ignore that first part, I think what he says, maybe they don't agree with him, but what Mesulam says is, PPA primary progressive aphasia, you know, look at his definition, going back to when was it 1982 If you go back there, apraxia of speech or you know, what he he calls phonetic disintegration, which again, I'm not sure what the right term, but but but you should not be able to then make a diagnosis of non-fluent PPA, if you start off if you just have a phonetic disintegration so that's my, my pet peeve I have with a consensus guidelines that the second part, you know, making a diagnosis non-fluent using apraxia of speech should not be able to be possible, because they shouldn't be meeting criteria for PPA in the first place. Stephen Wilson 23:04 Interesting. Yeah, it's it's a slightly different perspective than a lot of the field has, but I think it's well grounded in the data. I always, I thought that apraxi, progressive apraxic patients were, you know, somewhat different than the agrammatic, even though many of them would evolve to, to have the other symptom as well, you know, that it seemed that one or the other would be pretty dominant in many patients. Keith Josephs 23:33 That, that is correct. If you start off with just what we define as apraxia of speech, you know, the majority of patients with the, with the phonetic type, will develop an aphasia probably within five years, I think. And, you know, but but I don't know, you know, the other way around, though the patient's you know, it's interesting, right, the patients that we called, you know, agrammatic aphasia, so they're pure, the relatively pure, or, or at least, the aphasia is really prominent in the apraxia of speech is minimal. You know, those people, they don't. They look very different from the people that starts off with the, with the apraxia of speech, and even when we follow, you know, progression of the brain, it's very different those patients the atrophy or metabolism tends to, we see it going sort of inferior and anterior affecting the inferior into your frontal lobe on the left side, it's very different where the patients we see with apraxia of speech, you know, the problem actually, we see this focal starts involving the supplementary motor cortex or the superior premotor cortex, they, that over time, the progression if anything, is is backwards into into the motor cortex, it starts off in supplementary motor area, and then we set, tend to see this progression going into motor cortex. So, again, you know, a little different at least in my hand, or in my opinion, and you know, I can only tell you what my opinion is. I know there's a lot of people that that don't agree with me, but I see If you look at the literature and really separate these patients with the pure agrammatics and the pure apraxics, follow them over time and see see where they where they end up. The other thing, Stephen that you know I didn't touch on is you don't want to be when I was in I studied actually Queens Square with, with with Martin Rossor and Elizabeth Warrington and a bunch of you know, wonderful people there and, you know, one of the things I remember learning about them was something called this Luria dynamic aphasia, which I won't even pretend that I truly understand still, but I see these patients that just, you know, you ask them a question, you know, tell me about your family. They'll say, Susie, Martin, and that's it, you know, and you say, but you ask them any questions, you brush your teeth with a toothbrush. You, you you cut the grass with a lawn mower. So don't answer specific questions. But when you ask them open ended questions. They're very, there's a poverty of response. Yeah, those people are little bit different from the agrammatics, but the involvement, the brain area that's involved is kind of the same area except the kind of maybe spirits Broca's area, but we see that inferior anterior frontal lobe being been affected in those those patients, too. Stephen Wilson 26:13 Right. And that way they can repeat okay, right. Like they can repeat a sentence just fine. But they're just not going to want to come up with one by themselves. Keith Josephs 26:20 Exactly. Stephen Wilson 26:22 Yeah. Keith Josephs 26:23 Exactly. Stephen Wilson 26:24 That's really interesting. So, can we talk more about, you know, you kind of started to touch upon the brain regions that are associated with each of these different neurodegenerative syndrome syndromes? Can we kind of flesh that out of it for our listeners? Keith Josephs 26:38 Yeah.. Stephen Wilson 26:39 So you talked about, let's, let's start with progressive apraxia of speech. Because, you know, as you said, that's the syndrome that you spend a lot of time documenting and arguing for the distinctness of it. So So you see it as being sort of supplementary motor area and maybe more lateral premotor areas as well. Like, what how would you characterize that? Keith Josephs 27:00 Exactly. You know, we see involvement, you know, and this is on fluorodeoxyglucose PET scan that seems to be very sensitive and so when we tend to see hypermetabolism, we see this very focal area, and it's almost, it almost always affects the the supplementary motor cortex and the premotor. What confuses me, though, and I haven't put a get a good grasp on, is it can be right side, left side or bilateral. I have that Oh, yeah. I've been looking at that for 10 years. Sometimes it's right. Sometimes it's left and sometimes it's both sides. But we we never see involvement of Broca's area in these patients. Stephen Wilson 27:41 It's more dorsal than that. Keith Josephs 27:43 Definitely, definitely very, very focal. Stephen Wilson 27:45 Yeah. And I've noticed, you know, in all of your papers, the the essential bilaterality no matter what the methodology is, you I mean, you mentioned pet, but also on voxel based morphometry, Keith Josephs 27:55 Yeah. Stephen Wilson 27:56 Whether it's grey or white matter, you always show it to be rather symmetrical. Keith Josephs 28:01 Yeah. Stephen Wilson 28:02 But that's so that's like an interesting contrast with what we see in stroke, right? Because we don't really get apraxia of speech from right hemisphere strokes. Keith Josephs 28:10 Actually, actually, no, not really, if, I know the original, the original paper, the Nature paper, be careful here who's listening. But the original nature paper by by a famous person actually published that was published argued that the anatomic correlate of apraxia speech and stroke is the insular cortex. But, I think that has been refuted. In fact, I don't if you know Argye, but Argye Hillis at Johns Hopkins, followed up and found that it was not that area that was the anatomic correlate. And then since then, there are two or three papers, one, I think, from colleagues in Japan, and one from Jonathan Graff-Radford here at Mayo, where we found the patients that we thought had truly diagnosis with apraxia speech that had a stroke and when we went back, that the lesion was in the supplementary motor area, it's published in I think, I think the journal is I think it's stroke. Stephen Wilson 29:06 Yeah, I know the paper that you mean. Yeah, um, but the latterality, right. Um, so yeah, I agree with you that and sorry, Nina, I do love Nina. So if you ever listen to my podcasts, (Laughter) Nina, she was one of my most precious mentors. But I do agree that maybe the insula finding is, is not where it's at. But, you know, the the lateralization seems much stronger in stroke, right. So you know, very commonly see apraxia here with our left hemisphere stroke patients and although I don't study right hemisphere stroke patients, we kind of like encounter them incidentally. And we never see apraxia in them. So what do you what's up with that? Like, how come that doesn't match? Keith Josephs 29:48 Yeah, remember, I don't you know, honestly, it's, it's interesting and I haven't figured that out as yet. But one one thing that is which may, which we may need to look at is that you know the patients that have the opraxia of speech with stroke, Stephen, they tend to have the phonetic type. These are the patients that have the sound substitutions and the distort the you know, distorted sound substitutions, etc, the groping and the trial-and-error articulatory movements, the prosodic type, where the problem is with a segment in either crosswords or within words, you don't see that in the stroke literature. And what I don't know is, you know, when we see these patients, even though we haven't really seen that is maybe, maybe it that when we see the right side involved, it's predominantly because of the prosodic type of apraxia of speech as opposed to the phonetic type, which, again, is going to be more vocally involved on the left. And which would make sense because remember, I said, that's the variant that everybody talks about, that's the view that's going to be associated with with apraxia of speech. So the the non-fluent PPA, when you're talking non-fluent PPA, and you mentioned, Ogar's study, you know, a lot of her patients, it was 85 or 90% had an apraxia of speech, I would bet that those patients had the, what we call type one, or the phonetic type, not the prosodic type. And we're seeing a lot of differences between those two types. Stephen Wilson 31:13 Yeah. Okay. So I think we should talk a little more about that, because, um, it kind of came up. So this is in your 2013 paper, you first put forward this notion, I think there's definitely hints of it in some of your earlier papers, but you really flesh it out in this 2013 paper and I think neurology, that there are these two types of AOS apraxia speech, one new type one you call it, dominated by distorted substitutions, and you know, articulatory issues and then type two, dominated by sort of what you call say syllable segmentation. So they kind of each syllable being isolated and kind of gaps between syllables. And, by the way, if anybody's interested in hearing examples of these, you've got videos of them on in the supplementary material for that paper, so I think you can get a pretty clear sense of what you mean. I don't know I mean, in my experience in Marilu's lab, Marilu Gorno Tempini's lab, I feel like our patients that you know, we would call progressive non-fluent which would encompass your PPAAOS and your agrammatic. I feel like they had both types of AOS to different degrees, you know, I do get it, I see what you mean about the two different types. But I never I wouldn't have seen them as like, two distinct entities, I kind of see them as like maybe ends of a spectrum. And maybe maybe in stroke too, like I see stroke patients that that I don't entirely agree with you that stroke patients only do type one, I definitely see that sort of syllable segmentation in stroke patients as well. Keith Josephs 32:45 Where do you see the lesion? Stephen Wilson 32:47 I haven't been able to make a distinction between the lesions that are associated with different kinds of AOS yet. I mean, I, I think your work gives us a really great place to form a hypothesis. Yeah, that's not something that we've analyzed yet. Keith Josephs 33:05 I was hoping you'd tell me the answer. Because I, you know, I had just had a paper published last year and looking at the pathology in the two types and it's, I don't think it's simple. I was really curious, you know, because we don't, you know, we don't in fact, there's a paper again, published by a Japanese group where they also argued that they weren't seeing it in the stroke literature, they weren't seeing what at least what we're describing as the prosodic type. So I, you know, if you, I mean, be happy to have any patients and you have video samples and MRI or FDG-PET, you know, be really happy to look at those patients with because I just, it's something that I've spent a lot of time just sitting down home trying to figure out, you know, where, why is why do we see see these patients and I have to say, you know, the prosodic type, I don't know, you know, I, I read Marilu's work and I, one of these days, I need to, I'd love to talk with her about one of her there's a paper that she published. Actually, the findings are very similar, almost identical to the findings that I published last year in terms of PSP and CBD. But the difference is that the the her patients with PSP had predominantly dysarthria and the patients with corticobasal degeneration had predominantly an apraxia speech and so here, the patients that we see with a phonetic type, the apraxia of speech type, which I know everybody recognizes also tend to have corticobasal degeneration so it fits. But the prosodic type we're seeing is really strongly associated with PSP. And I wonder if we're using two different terminologies. I mean, I don't know but I wonder if Yeah, I call it is what I'm calling, you know, prosodic apraxia of speech. Different or the same thing as what, as what Marilu's calling dysarthria. I don't know. Stephen Wilson 35:03 I mean, certain kinds of dysarthria. I mean, yeah, these because these things are not easy, obviously. Right? I mean, and yeah, I do think like, you know, like having trained in Marilu's lab, and then reading your papers, I see so many concepts that are similar, and I just labeled differently. And, and, you know, it's like, the data is the data, like, we're all we're all like, you know, trying to understand the same set of, you know, people that we just kind of, like, give different names to things. I mean, you know, you you happen to work with Joe Duffy, who's like, you know, one of the greatest legends of motor speech, that's quite fortunate. So, Keith Josephs 35:41 Yeah, I was really, really lucky. In fact, one of the first papers I did you know, when I started learning about this, because I came into this sort of as a movement disorder expert, you know, was sort of stumbled upon this apraxia of speech, entity in terms of pathology, so long story, and sort of, you know, not look back, I've been working with Joe for 20 years, and, you know, I still learn a lot from him. So I'm blessed to have him, you know, still participate in, in, you know, in these meetings that I have. But, but yeah, there could be, it could be that, the other thing I've wondered about is, you know, are we seeing like, a different population of patients? Because, you know, like, I know, I don't know, actually, but But I sort of make the assumption that we see a lot of patients with a Scandinavian background, and I don't know how, you know, in California, how frequent those patients are seen? And could it be that there's just a difference? You know, I remember you, I don't know if you know, John Hodges, but I remember, John, before he retired, you know, saying, Ah, Keith, I think I've seen, I think I've seen what you're talking about. And I was saying to myself, you know, John is a very smart guy. Are people just really not seeing this? Or as you said, or is everybody seeing it and it's just not, I'm not being called that. The first time I saw this, honestly Stephen, you know, I said, this is, I thought it was a phonological problem. I didn't, we didn't think it was was an apraxia of speech. In fact, you know, we I remember Dr. Duffy, taking it to a motor speech conference and showing it to his colleagues and saying, hey, you know, we think this is a type of apraxia of speech. We were we weren't sure in the beginning but what do you think? But it just, it doesn't fit it does not fit into, it is not a hyperkinetic dysarthria. It has different characteristics from all the dysarthrias that are out there. So if somebody is going to call it a dysarthria, then it would have to be a different kind of dysarthria because it's not hyperkinetic, not flaccid, it's not, you know, it's none of those and it's not ataxic, it doesn't have those characteristics. So, I don't know. I think it's interesting though, and I kind of wonder though, when I read, read her paper I wondered, and I have never asked her you know, are we seeing the same thing? I'm using a different term, but I don't know. Stephen Wilson 37:58 Yeah, that's really interesting. I don't know for sure, either. But I do think it's hard to make, I mean, you know, just all three of us as apraxia, it's not always easy in PPA especially or PPAOS. Even in stroke sometimes. Keith Josephs 38:15 Yeah. Stephen Wilson 38:15 Okay, so we talked a bit about how PPAOS, primary progressive apraxia of speech kind of has this pretty dorsal bilateral neuroanatomy in your work and can we kind of contrast that with you know, what do you see for agrammatic PPA or and maybe even the other PPA variants? Keith Josephs 38:37 So in the in the agrammatic variants, when when we call a patient agrammatic PPA, we see posterior inferior frontal involvement, Broca's area is involved. We, we always see that it tends to be very unilateral and over time, the, the involvement in my opinion tends to go more sort of inferior frontal, and maybe a little superior. So you think about like, a 90 degree movement of change over time, but the, but most of that movement is occurring anteriorly so we don't see involvement of the supplementary motor cortex or the posterior frontal area as we do in apraxia of speech. We, we always see involvement of Broca's area, and it almost always is unilateral. For this, for the semantic variant and I won't get into the difference between you know, semantic variant PPA and again, you know, trained with Elizabeth Warrington who described semantic dementia, you know. So I think about it a little bit different, I think, but but I know what everybody calls semantic variant of PPA. In those patients, what we will see is involvement of the anterior of the left, anterior temporal lobe, the fusiform gyrus, the inferior temporal entorhinal cortex, hippocampus is completely shot on the left depending on the length of time that the patient has the syndrome. And over time, it tends to progress more posteriorly involve the lateral temporal lobe and, and the posterior aspect of the temporal lobe over, you know, 10, 12, 13, 14 years. And then the logopenic variant, which, you know, something, you know, I learned about from reading Marilu's work, you know, we see exactly what she sees, and, and that is involvement of the, the posterior temporal area. I won't pretend because I'm not an expert, when it comes to logopenic aphasia. I think I confuse myself more than than, than I should because, you know, I kind of learned about this from reading her work and then, you know, I don't know, later on, I wonder if I began seeing these patients that would have more parietal involvement. So not so much of the, the involvement of the Angular Gyrus and sort of the posterior temporal area, but, but but more, but some involvement of the parietal, even the superior or inferior part of the superior parietal. And again, it's not bilateral, it's not posterior cortical atrophy. This is unilateral. And so, you know, I wasn't separating those patients in the beginning and I wonder if, if, if my LPAs or my logopenic PPAs, are dirtier, more dirty than hers? Because, you know, I don't know if again, you know, when you have that superior involvement of the superior parietal lobe, you know, we have I have colleagues here at Mayo Clinic that will say, you know, if you see that, and there's an involvement of the frontal lobe, you're probably dealing with something called dysexecutive Alzheimer's disease. But these patients aren't presenting like that. They're presented with, with an aphasia complaint, they present just like the logopenics. So, you know, I do see that focal involvement that everyone else sees, but occasionally, you know, I'll see a bigger lesion that involves the parietal on the left. Stephen Wilson 41:56 Yeah, I mean, we, yeah, at UCSF, we saw patients like that, too. And, you know, we we would call them AD, well, I don't know, if we all called them this, but I in my databases, they're always called ADa, for Alzheimer's disease with aphasia. Keith Josephs 42:10 So you do separate those Stephen? That's interesting. Stephen Wilson 42:13 Yeah, like, I mean, these were people, they could be really flagrantly aphasic, you know, they would have like, spectacular phonological paraphrases and, and, you know, very clear aphasic syndrome, but like, they would also be, I mean, maybe you're talking about pure kind of people, but I'm thinking people with like, you know, dysexecutive, and, you know, kind of other Alzheimer's like symptoms. Keith Josephs 42:35 Right. Stephen Wilson 42:36 And, you know, they tended to be young, they were almost always like, in their 50s. Keith Josephs 42:39 Right. Stephen Wilson 42:40 You know, and they would, and they would be PiB-positive and, you know, so yeah, now we see those too. Keith Josephs 42:50 We use, I think we used to call those aphasic dementia. And, you know, I'm Rogalski, who works with Mesulam, I think now uses the term you know, Alzheimer's, I forgot I don't want to, to to misquote her, but I think she calls them, is it a, what she called it Alzheimer's, Aphasic Alzheimer's or something like that. But, as I think I think I, you know, my, the patients that I, I recruited initially, with LPA, sort of, I wonder if, you know, we have the the true LPAs, but I don't know, because clinically, I can't distinguish them. You know, I'll be honest with you, like, imaging wise, you can see the parietal involved, and, you know, or not, but but clinically, sometimes they really, you can't distinguish them. At least I can't. Stephen Wilson 43:35 Yeah, yeah, these syndromes can kind of shade into one another. Hmm? Keith Josephs 43:39 Yeah, for sure. Stephen Wilson 43:41 Okay, so you know, we started by talking about your first love, which is neuropathology. So, let's kind of circle back to that. I mean, that's the, that's the place where you've done the most work on these phasic patients, I think. So can you kind of tell us about the spectrum of neuropathological processes that underlie these various speech and language syndromes that we've been talking about? Keith Josephs 44:00 Sure. Oh, absolutely. So, let's maybe maybe we just go through each syndrome and talk about the most common pathology that we're seeing. So if, if a patient has an apraxia of speech in our hands, do you know, pure apraxia of speech, I'm going to say that probably so far, we're about 98 and 99% accurate in terms of what the underlying pathology will be, it's going to be a 4-repeat tauopathy. And, if they have the phonetic type, you know, there's a very high probability that they're going to have the corticobasal degeneration subtype of 4R-tauopathy. If they have the prosodic type, they tend to be older, and there's a high chance 70, 80, 85% probability that they're gonna have progressive supranuclear palsy. So that was the paper I mentioned last year. In our hands, I'm going to skip the agrammatics. Stephen Wilson 44:57 Can we just I'm sorry, can we just dig in a tiny bit So, um, so, you know, a lot of people listen to my podcast or like linguists and okay, and whatnot. So I mean, I think they'd really appreciate a basic explanation of what a tauopathy is. Like what's literally going on at cellular level? Keith Josephs 45:12 Absolutely, absolutely. Okay. So tau is a protein that's in cells, it binds to microtubule. And it stabilizes the cell. And tau, the tau protein has different isoforms, there are six of them. And the I'm just going to break them into two groups of threes. One group has four binding domains. And it's because of, I am sure you know, genetics. An exon, exon 10 is spliced in. And the other group has only three binding domains because exon 10 is spliced out. So you have, tau that is characterized by having four binding domains or three binding domains, the ones with four binding domains, we call them 4-repeat tauopathies and the ones with three binding domains, we call them 3-repeat tauopathies. Now, Alzheimer's disease will have both. So if you look under the microscope, and you look for this protein, tau, so you try to detect it, and you see it, the tau there is going to be characterized by having both types of isoforms, both isoforms three and four-repeat tau. But in neurodegenerative diseases, we have disorders, we have these diseases that can have just 4-repeat. For example, progressive supranuclear palsy is a type of neurodegenerative disease, and corticobasal degeneration. So those two neurodegenerative disorders are tauopathies, like Alzheimer's disease. But unlike Alzheimer's that have both the 3- and 4-repeat tau, they tend to just have four. On the other hand, there's something called Pick's disease or Pick body disease and Pick body disease is characterized by having just or mainly, 3-repeat tau. So I'm sorry, I should have said that for so with that in mind, apraxia of speech is highly, highly, highly predictive of 4-repeat tauopathy. You can, you can, if you are going to bet if you had $1,000, I would say bet it. You have pure progressive apraxia of speech. I don't think you could be more certain of anything else that the underlying pathology will be 4-repeat tauopathy. Stephen Wilson 46:53 Yeah, that's an incredible finding. I think it comes out first in your 2006 Brain paper, right? Keith Josephs 47:14 Correct. Stephen Wilson 47:14 I mean, and then it gets kind of solidified over the years after that. Keith Josephs 47:19 Correct. Stephen Wilson 47:19 So, so why does tau, why does it go wrong in so many people? Like, why is this, you know, why tau? Like, why? Keith Josephs 47:27 I don't know, you know, that's a, that's a, that's a great question. You know, I, we don't know the answer to that question. You know, we see it in the brain, we know that it it is in an abnormal conformation in the brain. And we know that it there's, there's this phosphate that's, that's, that's funny, that shouldn't be there. And because the phosphate is there, so we refer to tau, abnormal tau as being hyperphosphorylated, meaning there's, there's too much phosphate, or it's too phosphorylated. That tau does not bind to the microtubule. The microtubule then becomes, you know, sort of is like you have railroad tracks and, you know, you don't have anything stabilized on the track. So then the trains can go go up and down the tracks. That's kind of what's happening. But, you know, I don't I don't know you know, why. These, these proteinopathies seem to target very specific areas and consistently so. I have often wondered, if I had to retrain, I need to go back and do embryology, because there must be something about how the brain was formed, why, you know. Why does four tau, target this axis, you know, this sort of pre, premotor, motor, basal ganglia axis, while you know, something like picks, pick body disease or picks three-repeat tau targets, you know, anterior fronto orbital frontal and anterior temporal. Why does TDP-43, you know, in young people target the entire brain and old people, we are only seeing it mainly in the, in the hippocampus and amygdala medial temporal, that, that is something I don't get. Why? But there is a strong association between where the protein is going to be and the protein. Stephen Wilson 48:57 Okay, that's a really important concept, right? So you're saying, you know, for each of these different underlying nerve pathologies, they all have kind of the anatomical signature of what which brain regions, they tend to affect, and that in turn, causes the clinical syndrome with which whatever speech and language as well as non language aspects it's going to have right? Keith Josephs 49:34 I think that's a reasonable statement. It's not perfect, but you know, it's not perfect, but, but I think that there is there is something to that, that there's a tendency, definitely to see that, you know, and it gets much more complicated because each of these pathologies can have different subtypes and you know, but but I think overall yes, you know, you just, you don't see PSP for example, presenting with, you know, visual, spatial or perceptual deficits and changes in the occipital lobe. Why is that? You just you? I don't I mean, I can't think of a case in the literature of, you know, a visual variant of progressive Supranuclear palsy, it just, you know, it doesn't happen. I don't know why. Stephen Wilson 50:16 Okay, so yeah, that's a really fundamental question. And I'm glad that you don't know why cause I certainly don't know why. I thought you might know or have some idea. Keith Josephs 50:23 I don't know, I have conversations with with Bill and a glass of wine. Because, you know, it's it's good to, like talking to him, because I think we see the same things and we don't know why, but you know, there's something to it. Stephen Wilson 50:38 Okay, so you told us about PPAOS having the underlying tau pathology, how about some of those other primary progressive aphasia variants? What kind of pathologies do we see with those? Keith Josephs 50:49 I think in the classic logopenic variant of PPA, there's probably a 90% probability that the underlying pathology is going to be Alzheimer's pathology. So you're gonna have that three and four-repeat tau. But one of the things that I think people have to realize is that even though it's, it's the same pathology that you see in, you know, the brains of patients that have the amnestic variant of Alzheimer's disease, the distribution of the lesion, the pathological lesions tend to differ. So in, for example, someone like Ronald Reagan that had an amnestic, and a memory problem, you tend to see the hippocampus really, really affected with the deposition of these proteins. But if you look at patients with logopenic progressive aphasia, for example, there's actually relative sparing of the mesial temporal lobe, hippocampal regions don't have as much tau as the cortical regions of the brain. So but, but again, the take home message is logopenic progressive aphasia, think Alzheimer's disease 90% of the time, probably the other 10% is going to be you know, maybe the other 9% is going to be this TDP pathology, I mentioned T as in Tom D as in donor P, as in Peter TDP-43. And then very, very rare, maybe 1%, you're going to have something else Lewy Body disease or Pick Body disease. So that's, that's what you'll see with with, with with logopenic. With the semantic variant of PPA, the majority of patients will have TDP-43. So the tau DNA binding protein from 40 kilodaltons, probably again 85%, some patients will have Pick Body disease, Pick's disease. And then you know there's some other rare entities are some other rare tauopathies something called globular glial tauopathy that sometimes can present with, with, or present as semantic dementia. And it really doesn't matter if the right side or the left side is involved, which is why I have some issues with you know, saying semantic variant and ignoring the right side of the brain. But that's a discussion for another time. Stephen Wilson 52:46 Yeah, that's a whole nother can of worms. Keith Josephs 52:48 Now and then lastly, Stephen the agrammatic. Stephen Wilson 52:51 Of course. I have been waiting for that. Keith Josephs 52:51 So the agrammatic varaiant, yeah, you know, honestly agrammatic variant is complicated. We don't have a lot of patients that have gone to autopsy honestly with agrammatic variance. But what what we see here with the ones that have gone to post is that the majority of them have Pick's disease. So it's a tauopathy, too, but they tend to have Picks. So agrammatic Picks, progressive apraxia of speech, four-repeat tauopathy, PSP or CBD, semantic dementia is TDP-43 and logopenic progressive aphasia is going to be you know, hippocampus-sparing Alzheimer's disease. That's kind of the associations, the strong associations not perfect, but strong associations that we're seeing. Stephen Wilson 53:33 I think in one of your papers, it's a review paper from 2011, you talked about how progressive aphasia without AOS was associated with TDP. Keith Josephs 53:42 Yeah. Stephen Wilson 53:42 A bit of a different type than the semantic, then the type that's so strongly associated semantic dementia? Keith Josephs 53:47 Correct. Stephen Wilson 53:47 Is that not part of your current thinking? Or... Keith Josephs 53:49 it is, but, you know, I've evolved, hopefully. I think when you, I think those patients will have an underlying mutation. I think if you have a language presentation with an aggramatic variant, and, and TDP, you should be looking for a programmable gene mutation. I think it's the it's the, you know, the, the description that I gave you first, I think, are in the patients that have a sporadic variance, you're not seeing a mutation. But I think it's the mutation patients with agrammatic presentation, those are the ones that are going to have TDP-43. I think that I can't prove that right now. But, but, I but, that's what I think I was seeing and, you know, Julie Snowden from Manchester actually had a paper, where she also saw the, the, you know, saw the association between the non-fluent or aggramatic variant and TDP-43. And I remember talking about, I think, a paper in archives of neurology, I remember talking about that, but, but but now we know much more about the genetics and I think, same for corticobasal syndrome. I'm not talking about that, but I think you know, those people, if you're really seeing that, you know, you, you had aggramatic presentation and you see TDP, you should go back and check for family history after the patient passes, passes away. And you should check for a programming gene mutation. I don't think its sporadic folks, you're going to see sporadic... And by the way, when I mentioned a specific type of TDP, I should clarify that I think it's going to be TDP type A. So there, there are five types of TDP. Pathology, the three common ones, A, B, and C. A is the one that you're going to see associated with aphasia. And that's the type that's also associated with programming and gene mutations. B is associated with ALS or motor neuron disease. And then C is a type associate with semantic variant PPA. Stephen Wilson 55:34 Got it. Okay, yeah. Okay, so I see that's really interesting that it's gone in that direction. So just to kind of like summarize, you've got most of these progressive speech and language disorders are being caused by either tau, or TDP-43, that you got several different types of tauopathies, and several different types of TDP-43-opathies, if that's the right way of saying it. And then each of those types for reasons that we don't really understand yet, targets particular neural systems or circuits, which then in turn gives rise to distinct clinical syndromes. I bet there's a lot of mess. A lot of messiness. Keith Josephs 56:17 A perfect summary. Absolutely agree with you. Stephen Wilson 56:20 Okay, cool. I'm glad that, that fits the bill. Okay, so I've taken a lot of your time, if I could just ask one more question to finish up. This is obviously a very multidisciplinary kind of work that you do. You're a neurologist but you know, a pathologist, first and foremost. If people are listening to this and thinking ah, this sounds like a really interesting field that I like to get involved in, like, what are some of the kinds of skills, backgrounds and what kinds of people are needed to do this kind of work? And what kind of people do you need to collaborate with in the future in the next 10, 20 years? Keith Josephs 56:54 I mean, this is you definitely won't be able to do everything on your own and you have to collaborate and I think, you know, speech language pathologists are very, very important. In neurology, you know, we tend to sort of work in a silo sometimes and I think we need, you know, the Ogars, the Duffys, people like that to help us with the speech and language. Because we're not trained, we're not well trained, other than, you know, knowing Broca's and Wernike's and conductionists. That's about the level of training that we're honestly going to get. So we need speech and language pathologists, absolutely, absolutely, absolutely. We also need an experienced radiologist, someone who has experience in, in different neuroimaging techniques. Maybe you need multiple people who I happen to have Jennifer Whitwell here that, you know, did a PhD in imaging in neurodegenerative diseases and FTD, in particular and so you definitely need someone like that on your team. Now, you can be like, you know, Bill and myself who train us neurologist, but, but our, you know, degenerative neuropathologist, you know, the best at it, really. But you need a neuropathologist as well and you do need a geneticist. So, for people that are thinking about, you know, I'm going to, you know, University of X to start a research program to do this kind of work. You think about the people that have done this, you know, it's not in a silo, it's, you know, we've been successful, because we've had wonderful team members in these different, different areas. I don't think I'm missing anyone, of course, I mean, you can get up you know, if you want to go further, if you want to try to understand, for example, the paper I published last year, you know, to understand the biochemistry now you want to get at, well, you know, is it you know, are you seeing 64, 68 Kilodalton bands on western blotting these patients, and does it look like just in CBD? You probably need a, you know, a bench scientist too. And if you want to go further, you want to develop some sort of model, then you're gonna need experts in that area. But I think for what I do for what, you know, we do, Stephen, I think, you know, speech pathologists and don't forget a neurologist, you do need a neurologist, because remember what I said, a lot of these patients will present and it's different, you know, because, you know, you talk to people, they'll say I have a patient with apraxia speech, and they have a look, they have ALS and ALS is TDP-43 and I'll say sure, but was the primary problem apraxia of speech or was it dysarthria. So what I'm talking about here, you know, does not take into account people that present with a dysarthria that then we'll have apraxia of speech, because that's a totally different beast, and the underlying pathology will not be four-repeat tauopathy. Just throw that out there. So you need a neurologist as well, you know, rule out the, you know, there's no fasciculations, there's no Babinski sign, etc, etc. Stephen Wilson 59:39 Yeah, so there's many different ways, many different opportunities for people to get involved in this line of research. Keith Josephs 59:46 Absolutely. Absolutely. It's a fun, it's a fun area, you know it and there's you never stop learning. You know, I mean, I, I have a meeting every month probably 150 meetings now since I've been doing this and every single meeting I learned something you just, you know, as a scientist, as a clinician, as a physician, you really have to have an open mind. And, you know, something you published 10 years ago, may not be correct 10 years later, and you have to just, you have to have the mindset of you might not be right, you know, this is what you see, but you might be wrong. But but that's what makes it fun. Right. That's what you keep learning. You knew everything at the time. Yeah. But then what's the point? Stephen Wilson 1:00:26 Yeah, well, then it would already be known wouldn't it? Keith Josephs 1:00:28 Exactly. Stephen Wilson 1:00:29 And you would get your reviewers would inform you that you had not done something novel. (Laughter) Keith Josephs 1:00:34 Yeah. Stephen Wilson 1:00:35 Cool. Well, thank you so much for talking with me. I really enjoyed. I really enjoyed our meeting. Keith Josephs 1:00:39 Yeah. No, it was wonderful to be talking with you too and, you know, sort of knowing your background Stephen and you know, I, I, the work that you do the work that UCSF does, the work that I do, I think are all important and you know, you know me calling something tomato (American pronunciation) , and you call it tomato (British pronunciation), we might be talking about the same thing after all. So, you know, we just have to. Stephen Wilson 1:01:03 Yeah, no, I think, yeah, no, we're all studying the same patients. Well, thank you, and I hope to catch up with you in real life sometime soon. Keith Josephs 1:01:12 Yep. Can't wait for this, this pandemic to end. Stephen Wilson 1:01:15 Hear, hear. Keith Josephs 1:01:15 All right Stephen. Stephen Wilson 1:01:16 See you later. Keith Josephs 1:01:17 See you later. Take care. Stephen Wilson 1:01:18 You too. Bye. Keith Josephs 1:01:19 Bye, bye. Stephen Wilson 1:01:20 Okay, well, that's it for Episode 19. Thanks to Keith for taking the time to come on the show. And thank you all for listening. I've linked the papers we talked about in the show notes and on the podcast website at langneurosci.org/podcast. See you next time.