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Primary Progressive Aphasia: Advances in Diagnosis, Prognosis, & Treatment

A review of recent advances in diagnosis, prognosis, and treatment of variants of Primary Progressive Aphasia.

Argye Hillis

DOI: 10.1044/cred-pvd-c15002

The following is a transcript of the presentation video, edited for clarity. Click the PDF icon to download the presentation handout and references.


Thank you so much. It’s great to be here. It’s great to be here especially because I see a lot of friends here. There are people in this room I’ve known for more than 30 years. And when I was a speech pathologist for– for more than 10 years and it gives me a great pleasure to be able to share with you today and I’m more than happy to answer questions along the way.


So I’m going to be reviewing the clinical syndromes of primary progressive aphasia. And that’s very important to think of them as clinical syndromes. They’re not diseases and I’m going to get back to that. That reflect the areas of brain that are most affected by pathology and grossly correspond to a particular pathology.

So this is the number one point I like to get across to patients when I diagnose them with primary progressive aphasia. I try to tell them it’s not a disease. No one dies of PPA. If they come to autopsy the pathologist never says this person had primary progressive aphasia and that was the cause of death. PPA is the clinical syndrome. It’s a collection of symptoms. And it reflects a neuordegenerative disease that causes that. And neuordegenerative diseases that cause primary progressive aphasia are pretty few. But they can affect different areas of the brain. And just like stoke that causes very different syndromes depending on where it is in the brain. These diseases cause very different syndromes depending on where they are– they first start in the brain. And it happens that these diseases have a predilection for certain parts of the brain. Some affect more frontal areas. Some reflect more parietal areas. One affects more inferior temporal and anterior temporal regions. And so the syndrome grossly corresponds to a particular pathology. But there’s no one to one correspondence.

But giving somebody a diagnosis of one particular variant of primary progressive aphasia can be helpful and I’ll try to show you that because it can kind of give them an idea of what problems might come next, what the course of their condition might be, what other problems they might develop, and so on. Now I’m going to be also describing some advances and diagnosis. I’m going to talk about some recently developed tests and imaging for identifying particular variants. There are three main variants of primary progressive aphasia and describe advances and prognosis, some imaging data that may help predict the rate of decline and describe advances and treatment, talk about some emerging investigational treatments for at least temporarily delaying or declining– delaying the decline or possibly then improving at least temporarily, language performance.

Before I go on, I want to disclose that I don’t have any financial relationship to disclose other than I get some financial support for some editorial activities. But mostly, I want to disclose that most of this work was done by my students and post-docs, and research assistants. And I just– I mentor them in this work. And all of this work was supported by NIH mostly NIDCD.

Primary Progressive Aphasia

So, primary progressive aphasia is deterioration of language for at least two years before decline in other cognitive functions, and that was the original description by Mesulam in 1982. Now Mesulam doesn’t really require, no body requires two years before you can make a diagnosis now. So, most of the time people come to us, after they’ve had symptoms for nine months or a year or something, you don’t have say that to them, “Well, I can’t tell what you have, we have to wait another year.” You can say, “I think this is primary progressive aphasia” if they’ve really only had a decline in language.


There are three main variants of primary progressive aphasia, as I mentioned our clinical syndromes or collection of symptoms that frequently co-occur. But that means they don’t always co-occur. We see disassociations, we see some people who just have one or two of these symptoms and so they don’t neatly fit into one of the categories. So, we have a lot of studies that have a group called unclassifiable because many patients come to me with just naming problems and spelling problems. And they may have naming and spelling problems for a year so. Those– That doesn’t meet criteria for any of these three variants because all three variants have naming and spelling problems. So, also at the end of the disease, some people don’t come to us until they have very severe language problems in all domains. And so, you really can’t classify those patients either. Sort of the end of any neurodegenerative disease is pretty severe impairment. It’s affected all of these areas of the brain. So, you can’t really tell except maybe by history sort of where they started.


So, I mentioned, the main variants reflect the area of the brain most affected by disease and give you a clue to the underlying pathology. The underlying disease often determines what problems the person may develop in the future. So, some of the diseases are associated with motor problems or swallowing problems, and we’ll talk a little bit about that.

Variants of PPA

So, the three main variants of primary progressive aphasia distinguished by the distinct patterns of language impairments and supportive pattern of atrophy on imaging. All three variants, as I mentioned, have prominent naming impairment. So, we’re going to talk about each of these three variants and they– these are described in a sort of consortium paper, a consensus paper that was the result of a three or four meetings of people who were doing research in this field from a number of different centers. And Mary Gorno-Tempini is the first author of that paper.

Nonfluent/Agrammatic Variant PPA

So, nonfluent/agrammatic variant primary progressive aphasia is really characterize by effortful halting speech with inconsistent sound errors or apraxia of speech and or agrammatic language production, difficulty in producing complete grammatical sentences. Now, these two things do dissociate and Joe Duffy is going to be talking this afternoon about primary progressive apraxia of speech, when that’s the only problem, you can’t call them primary progressive aphasia because they don’t really have a language problem. They just have a motor speech problem. And so, it’s just the syndrome that he will be talking about. But if they also have aphasia, they have some spelling problems, they have naming problems and they have apraxia of speech, then it’s likely, it’s nonfluent/agrammatic variant primary progressive aphasia. Some supporting features are that they have impaired comprehension of syntactically complex sentences. Now those of you who work in stroke aphasia say, “Gosh, you know, some of these components sound a lot like Broca’s aphasia, effortful halting speech, agrammatic language production, impaired comprehension of syntactically complex sentences.” So, it’s not surprising that they also have spared word comprehension, spared object knowledge. And it’s not surprising that they sound a lot like patients with Broca’s aphasia. And they– I’ll show that area of brain is very similar.

Now, the pathology underlying this variant is usually tau pathology. Now, tau pathology is also seen in Alzheimer’s disease but this is a different isoform of tau. And the disease when they come to autopsy is almost always one of these three diseases; corticobasal degeneration, progressive supranuclear palsy or frontotemporal lobar degeneration caused by tau. Now, frontotemporal lobar degeneration can also be caused by TDP-43 which we’ll talk about can be caused by Pick’s disease or argyrophilic grain disease. Does everybody know what argyrophilic means? Argyrophilic is literally silver staining but philic means, “friends with”. So, argyrophilic is friends with Argye.

So, the cortico– this is important because these patients later in the disease, after a few years of having primary progressive aphasia, if they have corticobasal degeneration, they often develop symptoms as the disease spread of other symptoms of corticobasal degeneration which is often, in the case of nonfluent/ primary progressive aphasia where it starts on the left side of the brain, it’s right hemispastic, hemiplegia, a rigidity of the right– usually the right arm because that’s closest to the speech area. So, they have apraxia of speech and then, also apraxia– ideomotor apraxia. Then they develop rigidity of the right arm very often. They have some Parkinsonism. They may have tremor. They can develop gait difficulty particularly because of rigidity of the right leg.

Progressive supranuclear palsy is a very closely related tauopathy and in fact, it may very often has the same genetic mutation underlying these two diseases. So, you can have one person in a family with this genetic mutation who has corticobasal degeneration or corticobasal syndrome at least and another person who first presents with progressive supranuclear palsy syndrome and another person who first presents with a primary progressive aphasia. Just depending on exactly where the disease starts in the brain. So, lots of people think that corticobasal degeneration and PSP or progressive supranuclear palsy are really kind of the same underlying disease because they can be caused by the same underlying mutation. Now, progressive supranuclear palsy, many of you speech pathologists may see because of swallowing problems, when it presents with the PSP syndrome the main problems are swallowing problems, falls, and eye movement problems, particularly difficulty looking up. So, someone whose underlying disease is PSP may develop these problems later on after their apraxia of speech and speech– and language problems. They often develop eye movement problems, swallowing problems and falls. So, it’s important to look for these problems and be aware of them, especially the swallowing problems.

Frontotemporal lobar degeneration is also caused by tau. And it can cause changes in behavior and personality. So, if the disease is moving forward in the brain, particularly affecting orbitofrontal cortex, then they may develop more behavioral problems later on. Change in personality, comportment problems that we often see in behavioral variant frontotemporal dementia.

So, one of the problems you may see why this can be confusing to families is that, in neurodegenerative disease often the same word is used for both the pathology and the syndrome and that probably started with Alzheimer’s disease because Alzheimer’s disease is used for both a syndrome and a underlying pathology. So, it would be great if we got away from that and starting saying, “Alzheimer’s dementia” for the clinical syndrome of memory, primary memory problems and impairment, progressive impairment, in at least one other cognitive domain. And use Alzheimer’s disease for the proven pathology. The same thing with corticobasal degeneration, the syndrome of having rigidity on one side, Parkinsonism, apraxia is often or should probably best be labeled corticobasal syndrome. And corticobasal degeneration probably ought to be restricted to the pathological disease.

There’s no real PSP syndrome other than PSP. But it should probably be called exactly that, PSP syndrome. Again, Pick’s disease and argyrophilic grain disease are really just pathological diagnoses.

Less commonly, the nonfluent variant– nonfluent/agrammatic variant can be caused by TDP-43 or even Alzheimer’s disease pathology. Alzheimer’s disease can start anywhere in the brain. So, it can cause, as you may know, a primary visual problem. It can cause rare cases — this, any of the variants of primary progressive aphasia.

Semantic Variant PPA

So, a semantic variant primary progressive aphasia has two core features and both of these must be present, as supposed to the core features of nonfluent variant. And that is impaired naming of objects more than actions and impaired single word comprehension. So, they have to have impaired naming and difficulty with word comprehension but supporting the features are impaired object knowledge, particularly for low frequency or low familiarity items. The reading or writing is often impaired but they make regularization errors. So, what some people would call surface dyslexia, surface dysgraphia. So, they read the word yacht as yacht and so on. They read by phonics, spell by phonics. They have impaired reading and writing comprehension. Their repetition is generally spared and they have spared grammar and motor speech.

They have paragrammatic speech like patients with Wernicke’s aphasia. But they’re not exactly like patients with Wernicke’s aphasia. Their language can sound very similar with extended English jargon. However, what’s different about them is they all eventually do have impaired object knowledge. So, with unlike a patient with Wernicke’s aphasia, who might speak in jargon but behave perfectly, normally, may be able to cook, may be able to mow his lawn, maybe– uses objects appropriately. This eventually affects both temporal cortices, left and right, and they have difficulty really understanding the meaning of an object. So, they put orange juice in the coffee maker. They– One of my patients boiled pizza for dinner. One patient spread peanut butter with a can opener. They use objects inappropriately because they don’t understand them. And one of the really key features of semantic variant, primary progressive aphasia is they’ll often say– repeat a word that you said and say, “I don’t know what that means.” So, they’ll say, “The glove, glove, I– that sounds familiar to me. I know I know one. I know I’ve had one. Yes, I think that’s one that I’ve done before. But the glove, glove, I don’t know what that is. I don’t know the glove.” And that they’ll say that very frequently in conversation.

So, this is a patient describing the cookie theft picture, or not. I’ve seen this so many times. I can tell you what she says. It’s very fluent speech. So, she’s a girl and he’s a girl and she’s– I know he’s the one that I did before. She was the one– she’s– I like that one. That’s the sort of thing they say. So, it’s mostly extended English jargon, lots of errors, like he’s a girl. And areas that are involved are mostly the anterior and inferior temporal cortex, more than a posterior temporal cortex that we see in stroke and it is bilateral but it’s more on the left than on the right.

The most common pathology is frontotemporal lobar degeneration caused by TDP-43. TDP-43 is tau DNA-binding protein, a 43 kilodaltons and it is less commonly caused by Alzheimer’s disease, dementia with Lewy bodies which you all may know Robin Williams just died of, he had at death and CJD, other mixed pathologies and so on. CJD is Creutzfeldt-Jakob disease. Usually, that’s a very rapid deterioration in cognition.

Logopenic Variant PPA

Now, logopenic variant primary progressive aphasia has core features of impaired word retrieval in both conversation and naming task. So it’s very prominent. They’re very, very anomic. They also have impaired repetition of sentences and phrases. They have impaired working memory. They sound very much like conduction aphasia. The supporting features are speech sound substitution errors in conversation and naming tasks, spared single word comprehension and object knowledge, and then absence of difficulty producing grammatical sentences. Although, they do produce sentence fragments because they’re so anomic, especially later in the course. They’ll say, you know, “That’s– the boy is climbing the– I can’t think of it. And he’s trying to steal, you know, the things from the, you know–“. So, they don’t really produce complete grammatical sentences but they start off and they– till they get to a word they can’t think of.


And the most common pathology is amyloid plaques and neurofibrillary tangles of Alzheimer’s disease pathology but it’s not in the same distribution of typical Alzheimer’s disease. It usually spares mesial temporal structures, at least until late. Although eventually, these will be involved and they will eventually have episodic memory problems.


So, they’re– a group of us who study primary progressive aphasia we’re asked to get together, supported by NIH, to come up with a bunch of tests and also it’s supported by the FTD association– association for FTD, to come up with tests that would help identify some of these patients with primary progressive aphasia, as well as behavioral variant FTD and distinguish them from Alzheimer’s disease. And, particularly, to use these in the Alzheimer’s disease research centers. And so, we came up with a module of tests.

Now, these are just sort of ones that we– they had to be given really quickly and they had to be the ones that could be used very easily in a research center across the country and they aren’t perfect. And I’ll talk about some of the problems with them. But the idea of some of the language tests was specifically to try to distinguish between these variants. And so, this is a work in progress as I mentioned. Some of the things that were included were letter fluency and this is really used as an executive function test to evaluate for frontotemporal dementia, word and sentence reading, to look for that surface dyslexia. Semantic associates, and that’s just identifying which pairs of pictures are semantically associate– associated to identify patients with semantic variant primary progressive aphasia.

A sentence anagram test was used to evaluate sentence– a grammatical sentence production was the idea to try to identify those patients with agrammatic variant and I’ll talk about some problems with that. And the reason for using a sentence anagram test is, many of these people, as you heard, the first patient really couldn’t talk at all. So, how could you tell if she’s agrammatic? Now, she did write and she was agrammatic in writing. She had good single word writing. But if they can’t write, and sometimes they can’t, sometimes they can’t even use their dominant hand. We wanted something that could look at on a sentence, grammatical sentence production and we thought this would be a good idea. But it turns out it also requires semantics and executive function and is hard for all of the variants.

Sentence repetition, obviously, to identify the logopenic variant, noun and verb naming, some of the patients, as I mentioned, with nonfluent variant are only impaired in verb naming, and not in noun naming. Then there were something to– somethings just to make sure that they didn’t have a more global impairment. So, things like a Benson complex figure memory test. Then there are caregiver scales for observation of key behavioral variants to identify patients with behavioral variant FTD because remember, their problem is really a problem and deterioration in comportment and behavior. So, there are really good tests for that. It’s really observational scales that pick this up, and a neurologic evaluation and standardized diagnostic lists for symptoms.

And this is just really to show you, you don’t have to read any of these scores. Just to show you that it has been tested in a fair number of people so far with all of these variants and with FTD as well as normal controls, 160, this was actually a year ago and patients with behavioral variant FTD. And so, those tests are available if you’re associated with any Alzheimer’s disease research center, if you’re interested in giving them.

Refining the Battery

But I do want to talk about the fact that battery needs to be refined. There are some problems. So post-doc Rajani Sebastian had noticed that the sentence anagram test which involves unscrambling words to produce– actually the way it’s– it is in the NACC module is to make a question about a picture and that turned out for our patients to be too difficult. Most of them just couldn’t get the idea of making a question about the picture. So, we changed that a little to make it a sentence about the picture. So, half of the sentences are just subject, verb, object sentences and half of them are passive sentences but they’re still fairly simple like the horses ridden by the girl. And they have to– they’re given scrambled words and the idea was to detect agrammatism independently of apraxia of speech. And she hypothesized, really, that all variants of primary progressive aphasia are impaired on the syntactically complex sentence production with anagrams because this task requires semantic processing and working memory. So, she tested 63 patients with primary progressive aphasia on this test. What she found was that there was really no difference across the variants even though the variants were not different in terms of at least time post onset of symptoms. It’s really difficult to have a measure of severity because the semantic variants always do worse, some things like the many mental status exam because they have comprehension difficulties. So, we don’t have a good measure of severity of primary progressive aphasia, we could possibly use total brain atrophy or something. But we used time post onset, they didn’t vary. The nonfluent variant patients actually did the best on average, although, there was no significant difference in this test, logopenic variant and semantic variant really didn’t show any difference.


So, they all had impaired performance. And the performance on the anagram tests correlated with performance of semantic processing. And we used the Pyramids and Palm Trees test that I’ll talk about and working memory, it’s a correlated fairly highly with repetition as well as disease duration. So, it seems to really be sensitive to just all problems in these patients. So, the ability to produce grammatical sentences with anagrams to match pictures is impaired in all variants of PPA and really doesn’t seem to distinguish between them. So, we’re currently working on a more reliable assessment of grammatical sentence production in connected speech.

Development of a quick Test that Reliably Identifies svPPA Across Cultures

So, we also wanted to develop a very quick test that would reliably identify semantic variant PPA across cultures. And many people across the country had been using the Pyramids and Palm Trees test which is a test you all probably know about that involves matching one of two pictures to a picture at the top. It’s a nonverbal semantic association test, originally, described by Howard and Patterson. There’s 52 items on this test. So, it’s a pretty long test. And this is an example. And this is one of the good examples, I would say. So, the person has to identify which of these items is most associated with the picture at the top, the glasses. And, you know, we wear eyeglasses on our ears. So, if you were just using episodic memory, you could choose either of these. But eyeglasses are mostly meant for the eyes. So, the correct answer is eyes. Now, there are some items we objected to. And people in Baltimore, and I don’t know about other cities, can’t answer this question. I can’t answer this question. Which is more associated with a rooster, a snake or a worm? Well, in the United– In, you know, Maryland, chickens and roosters eat corn. Corn is our number one product. So, they– we don’t think of them as eating either worms or snakes. As it turns out, I looked this up in Google and they will eat either worms or snakes. So, there really isn’t a correct answer to this. But according to the test, I think, worms is the correct answer. And I’m told by my friends in England that they taste much better if they are worm fed as opposed to corn fed and I don’t believe that. Another item that we– people tend to get wrong is which is– goes better acorn, a pig or a goat? Now, in the United States, most of us think of squirrels as eating all of our acorns. So, you know, it turns and I Googled this too, that pigs and goats will eat acorns. I mean, that pigs and goats will eat any thing you give them, right? But apparently, in England, there’s– pigs eat acorns and maybe it’s associated with a kid’s story. So, maybe Winnie the Pooh, does the piglet eat acorns? I don’t know. But that’s the correct answer.


So, they selected 14– we selected 14 items from the Palm Trees and Pyramid test that seemed to be more culturally unbiased. I.e., you know, we could answer them. But also, that we thought people in other cultures could also– outside of England could also answer and we also wanted a much shorter test. And we tested these people in age matched controls in the US, Greece and Argentina just because I happen to have collaborators in those countries. On this short and, we hypothesized that the short version of the Palm Trees and Pyramid test could better distinguish normal from PPA patients better than the 52-item version. And that it could distinguish semantic variant primary progressive aphasia from other variants and would correlate with atrophy in the left temporal pole where semantic variant patients have atrophy.


And so, what we found was that a score of less than 12 on this 14-item version had a specificity of 100%. It’s not terribly sensitive because remember early on, somebody can have PPA without having object semantic impairments can– they can have– be labeled with semantic variant if they just have word comprehension deficits and not picture comprehension deficits. Score of less than 13 had a specificity of 96% and a sensitivity of 71%. So the area under the curve was quite high. So we used a score of less than 13 to identify semantic variant primary progressive aphasia. And the– we scored scores of– sorry. We used score of less than 12. And 12 to 14 was considered normal. And zero out of 50 controls scored outside the normal range on the short-form. But on the longer form of 52 items using the norm– published norm, 60 out of 20 Argentineans, 7 out of 12 Greeks, 5 out of 18 American controls. So really, you know, close to over a third of the patients scored outside the normal range on the full PPT. So, controlled performance was significantly more frequently classified as normal in the short-form versus the full-form. And we found that the correlation between volume of the– volume in particular of voxel regions correlated with the performance on the short-form of the Palm Trees and Pyramid test. And those areas were in the inferotemporal cortex on the left as well as in orbitofrontal cortex on the right where they also seem to have atrophy in some of the white matter tracts.

Short Form of Pyramids and Palm Trees Test Effectively Discriminates svPPA From Other Variants of PPA

So then some– Murray Grossman who is a collaborator at University of Pennsylvania and Chiadi Onyike who’s one of my collaborators in the psychiatry department and directs the behavioral variant frontotemporal dementia clinic at Hopkins and some other colleagues at University of Pennsylvania all got together, decided to see if this could really effectively discriminate sort of pathologically proven semantic variant primary progressive aphasia from other forms of primary progressive aphasia. And so we evaluated initially 50 primary progressive aphasia patients who either had pathologically confirmed diagnosis or pathology confirmed by proxy based on either genetic mutation or CSF correlates of pathology.

And they were fairly mild. This is their mini-mental status exam score which really didn’t vary significantly across the variants. And as you can see, this is really mild for a patient with aphasia. They tend– Patients with aphasia tend to do very poorly on the mini-mental. They had similar degrees of education and age. And what we found was there was a significant difference across groups on the 14-item Palm Trees and Pyramids. And even though they were very mildly impaired, semantic variant had significantly lower scores compared to logopenic variant and compared to the nonfluent/agrammatic variant. Logopenic variant did not differ from the nonfluent variant. So this just shows the performance on the 14-item Palm Trees and Pyramids in semantic variant versus nonfluent/agrammatic and logopenic variant.

So this 14-item test which is much faster to give seems to provide a rapid test of nonverbal semantics that can distinguish semantic variant from healthy controls and semantic variant from the other variants and correlates with anterior temporal and orbital frontal atrophy. And so may distinguish frontotemporal lobar degeneration pathology from other pathologies relatively early in the course.

Advances in Early Diagnosis of svPPA

So any questions about anything before I go on? So, now, I’m going to talk about some work by David Race, he’s one of my post– was one of my post-docs on another sort of early diagnosis of semantic variant primary progressive aphasia. This is unpublished work using eye tracking. Hopefully, he’s going to submit it very soon. And it is– I think it’s fascinating. So he’s– he has a background in eye tracking and we decide– he wanted to evaluate initially the semantic deficit in patients with different variants of primary progressive aphasia. And so, he used eye tracking to evaluate different trials of a word-picture matching test. So the patients heard a word and then they had to identify the picture that goes with the words. But he also evaluated the amount of time they spent looking at each target in the array. And there were four different arrays. Some of the arrays had coordinate semantic foils like dog, cat, rabbit and the foil is, you know, one of those. And then others had associate semantic foils so the target is dog and then the foils are things like bone and collar and leash. And then there were linguistic associates. So the target is dog and the foils are things like ears. So there’s words like dog-ear. And another example would be butter and a fly so– because butterfly is a word. And then there were filler trials which turned out to be the most interesting. And the filler trials are unrelated foils. So, the target is dog and the foils are coffee and chair and things like that.


So, we– he had three controls and nine participants with primary progressive aphasia. Eight had semantic variant, four nonfluent/agrammatic variant and three with the logopenic variant, four who are unclassifiable. And again, unclassifiable in this case meant they just had anomia and/or agraphia, so spelling and naming problems. They all showed a high level of accuracy on the task and especially the fillers, almost 100% accuracy in identifying the target on the filler task. And so that’s the offline performance or it’s the performance on the online task but it’s when they actually have to match the– eventually choose the target. But the eye tracking performance turned out to be what was interesting. So the eye tracking was they looked at the measure of the proportion of looks to each target and how long it takes to look at the target more than to the unrelated pictures.


So this is an example. The target is camera. So he measured how long it took them to look more at the camera before they actually choose it than to look at these unrelated pictures. Now here’s the control. A control almost very quickly looks more at the target and he collapsed all the unrelated foils because they were also very similar. And they stopped looking at the unrelated foils and just choose the target. This is another control that shows very similar performance. And this is the time it took, less– about 600– 700 milliseconds to look more at– significantly more at the target. This is the patient with logopenic variant primary progressive aphasia, shows very similar performance to the controls, very rapidly just looking at the target. Another– This is the patient with nonfluent/agrammatic variant. Again, they don’t have semantic deficits and almost immediately looks only at the target. Semantic variant were very different. So, even though they eventually chose the target, they kept looking back at those unrelated foils. They weren’t ever quite sure they had chosen the right thing. They kept looking back, “I don’t know if this is right. That could be, you know, could that be a camera,” looking back at all of them. They really were never sure of their answer. This is another patient with semantic variant. Again, just never really was sure of his response. Kept looking back at those unrelated. This is a patient– the ones who are most interesting with unclassifiable patients who just had anomia and agraphia.


So, he tested them two years ago and now we’ve– they have come to a diagnosis. And– Actually, almost three years ago, he tested them. And many of these now have a diagnosis. And this particular patient, when he was tested, was unclassifiable. But now, he has semantic variant. So back when he was tested two or three years ago, he already showed a pattern that was similar to semantic variant primary progressive aphasia where he was kind of looking back, he never got to 100% looks at the target. He was only about 60% looks at the target and the rest of the time, he was looking at those unrelated foils. This is another patient. So even before he met criteria for semantic variant primary progressive aphasia was showing this pattern on eye tracking, where he kept looking back at these unrelated targets. This is patient who was unclassifiable initially, but later developed problems with repetition, not semantics. And he had a pattern when he was unclassifiable that looked just like the normal pattern and looked like the pattern of logopenics, where he looked almost immediately and eventually 100% just to the targets. And this is a patient who’s kind of remained unclassifiable, who has remained unclassifiable and showed a pattern that was more like the controls and logopenics. And so, if we classify patients as having less than 80% looks to the target by 1200 milliseconds, so they were never really sure of their decision even though they eventually chose their target. And the accuracy task, all of those were semantic variant primary progressive aphasia eventually and there was one patient– sorry– all but one, and if they didn’t show that pattern, none of them semantic variant. And then we looked at the correlation between the level of atrophy and the time it took them to look mostly at the target. And that correlated with– you can see in the areas in red, so only areas in the anterior temporal pulse bilaterally, so here on the right as well as the left, and in the temporal pole. So, this seems to be eye tracking using word picture matching even with unrelated foils seems to be sensitive to semantic variant PPA, even before individuals meet criteria of impaired word comprehension in offline tasks and seems to be correlated with atrophy in left and right temporal pole. So it may improve early diagnosis and suggest an early marker for this FTLD, frontal temporal lobar degeneration caused by TDP-43.

Predicting the Course of Decline

Now I’m going to switch gears and talk a little bit about predicting the course of decline. This initial study is by Donna Tippett who is a speech language pathologist who’s recently been working with me half time in research at my lab and she’s also is a clinical position in otolaryngology doing speech language pathology. So she– She decided she was very interested in answering a clinical question, how quickly is this individual going to progress to a severe level. And this is an important question to families because they want to know, you know, how soon is he going to have to move to assisted living, how soon are we going to have to do– you know, get help in the home and so on. And we– It’s been noted by many people and particularly by the Mayo clinic group, who published particularly in logopenic variant that patients with PPA showed variable rates of decline in language from one to two years till the time of death to two decades or more. I’ve been following some patients for more than two decades. So, we hypothesized the rate of decline that is the change in score divided by months since onset may be influenced by primary progressive aphasia variant, age, education and language rehabilitation. And studied 46 patients with primary progressive aphasia over 11 months and then looked at the variables that independently determine the rate of decline. Now we are doing this, we are repeating all these– the study. I have to tell you in over 200 patients now and using much more sophisticated statistical analysis. But I’ll just give– there are some conclusions I think that can be drawn from this preliminary study. And this is just the breakdown of patients, there were fewest patients with nonfluent variant and then similar rates in the others and 14 patients were unclassifiable.


And then most interesting finding to me is that there were patients who had just slow rate, very slow decline and patients who showed very rapid decline in all the variants. But they showed decline on different tests. So the nonfluent/agrammatic variant showed the most rapid decline on the HANA, which is the Hopkins Assessment of Naming Actions. So a more rapid decline than the other variants on this test. So, remember I mentioned they often have difficulty with verb naming. The semantic variant showed the most rapid decline on the short version of the Pyramids and Palm Trees test, that 14-item version. And that’s not surprising. They’re the only ones who showed really significant deficits on that test. And they showed the most rapid decline on that and they also showed some, you know, decline in naming. The logopenic variant patients actually showed the highest or fastest decline on the Boston naming test except for the unclassifiable who actually showed the highest rate of decline on the Boston naming test.


So there were, as I mentioned, rapid decliners and slow decliners in all of the groups. And the only variable that really significantly associated with PPA decline was the type. The semantic variants did show the grade– fastest decline in this group compared to the other variants. There were some tendency for patients receiving speech pathology to show a slower rate of decline than those who receive no therapy. But this is difficult because they receive very different therapies, very different amounts of therapies and so on. And so it’s really hard to look at. But there is no association between age or education and rate of decline.


So we decided to see if we could predict the rate of decline using imaging instead. So we’ve been doing imaging a little different than other people by looking not just at how people’s brains compare to normal controls, but how they compare to one another. Now we do take each brain and try to register it to an atlas using a very technical, this LDDMM process of normalization. But– And we use high resolution scans to do this. But the most important thing that we do is we register each scan to the individual’s owns scan so that we can look at which voxels in that individual sort of disappear over time or atrophy over time.


So one of our first studies looked at longitudinal imaging of patients with PPA. And there were five patients with logopenic variant, eight patients with semantic variant, and two with a nonfluent variant who had longitudinal imaging at least six months apart. Again, I’ll show you these early studies although we have a lot more patients now. And so I think the published work will include a lot more patients. We looked at Spearman correlations between change in regional volumes and change in functional scores.


What I’ll show you, this is– on the top line shows you the patient’s first MRI, the second line shows you the patients MRI six months later. And the third line shows you the difference between the first and the second. And what I really like about this is you can use it in an individual to show them where there’s change. And if you just looked at these two MRIs, it wouldn’t be obvious where there’s difference. It’s really hard for the naked eye to see. But when you compare them, once you’ve registered them to each other, you can show in blue the voxels that have disappeared at time two that were there in time one, or the voxels that have gotten smaller. And red are the voxels that have gotten larger where there’s– there are new– there’s new space. So the ventricles get larger over time in these patients. They are showing atrophy. But what we see in this patient is that there is atrophy in this area in the posterior temporal cortex and inferior temporal cortex, more on the left than on the right, but bilaterally. What we see in all these patients is there’s bilateral atrophy particularly when we compare them to themselves and not to age-matched controls. And we see this to some degree in a temporal pole but much more sort of in posterior temporal cortex more inferiorly.


And then what we saw across– this is a group data. This was just an individual’s data that the change in word comprehension and correlated with the volume, with change in the volume of the middle temporal gyrus and change in the volume of the angular gyrus. So, it is– and this is just one patient who had semantic variant primary progressive aphasia and she– her word comprehension deteriorated from 73% to 0% between these two time points when she showed atrophy as we can see in the posterior temporal cortex here.


You know, just to look at something completely different is Trail Making test, you’ve heard Frank talk about as an Executive Function test and you all know it well. The Part B performance correlated with change in the volume of the inferior frontal orbital cortex. And we can see that this patient who had semantic variant primary progressive aphasia. But remember, I said that most of these patients with semantic variant have frontotemporal lobar degeneration, TDP-43, which is associated with the behavioral variant. So every often, late in the course which this guys was. They– As the disease moves more frontally and orbitally, they start to develop more symptoms of behavioral variant frontotemporal dementia with both deficits in executive function but also behavioral problems and he did have some behavioral problems. You can see his atrophy, he has a lot of atrophy in the anterior temporal pulse as you would expect from his diagnoses of semantic dementia or semantic variant primary progressive aphasia. So he has no anterior temporal pole. But if you compare him to himself over the six-month time period, where he’s now showing atrophy is orbital frontal cortex primarily and some even in frontal cortex, dorsolateral prefrontal cortex bilaterally. And so he deteriorated on the Trail Making test Part B. We allow them up to 300 seconds and so he took 84 seconds and then really maximum time. He couldn’t really do it.


So, progressive decline in specific tests is closely related to progressive atrophy in focal areas providing further evidence that these areas are critical for associated tasks. So, another example I didn’t show you is less supramarginal gyrus seems to be critical for working memory and it was also correlated with atrophy– atrophy and supramarginal gyrus was correlated with performance on repetition tasks. As I showed you atrophy in left orbital frontal cortex was associated with changes in executive function. So individual longitudinal imaging might provide some clues to where the disease is progressing or spreading.

Predicting Decline with Imaging

And then, I’m going to talk about some work now on imaging to help us with prognosis. And this work is really by my colleagues, Susumu Mori and Andreia Faria who are terrific collaborators in the radiology department. And we initially studied 16 patients with primary progressive aphasia using structural imaging resting state fMRI and DTI nine months apart and looked at their performance on naming test, the Boston naming test and Hopkins assessment of naming action to see if we could find any imaging predictor of– that could predict the decline in naming. And lots of people have shown that imaging– changes in imaging are associated with changes in performance over time, particularly decline in various things and I showed you that already. But that sort of the Holy Grail is that you want something that at time one can predict where they will be 9 months later or 12 months later. So we looked to a lot of things. We looked at volumes of gyri. We looked at various DTI measures of white matter tracks. We looked at correlations between homologous cortical regions on resting state fMRI. And the reason we looked at homologous correlations because these are the most stable over time that we lay you in the scanner and evaluate the correlation between both response in homologous regions between left and right and prefrontal cortex and superior temporal gyrus and any particular area on the left will be highly correlated with the right. And that’s really stable over time. And so we looked at those areas on– and that’s not as true with primary progressive aphasia in part because they have atrophy more on the left than on the right. So I’m not saying this as something, you know, deeply theoretically important, but it is a marker that might be able to tell us what’s happening in the brain.

So we found that baseline atrophy in any particular area really did not correlate with subsequent decline in naming. It did correlate with current decline and the change in atrophy in that– in specific areas as I showed you, did correlate with change in naming but at time one atrophy could not tell you what was going to happen nine months later. The initial structural MRI didn’t offer direct markers of subsequent decline in either the Boston naming or the HANA, using DTI measures also.

The decline in volume of diverse brain regions correlated with the degree of decline on the Boston naming and the HANA and I’m going to show you those data. And that’s just consistent with things I’ve already shown you that progression of atrophy correlates with progression of functional deficits. The initial volume of the left inferior frontal gyrus and ventricles correlated with their further degree of atrophy and enlargement. So it could predict if you’re– the amount of atrophy you had in those areas could predict that those areas were going to show further atrophy. But that didn’t correlate with performance on naming. So that wasn’t as useful.

So this is just to show you the areas on– that were associated where change in atrophy or a change in the volume of these areas was all associated with change in the Boston naming test. So again, it’s not just the temporal– anterior temporal pulse but remember I said that all variants are impaired in naming and all of these areas were significantly associated. Atrophy over time was significantly associated with change in the Boston naming test over time in the left– sorry. This is actually the right obviously and this is the left. So, almost all of the temporal areas and the post– inferior parietal cortex as well as inferior frontal gyrus to lesser extent, just this pole area in the left. For the HANA the verb naming test, we see a lot more– the same regions in the temporal cortex and inferior parietal cortex on the left. But also a lot more in sort of Broca’s area here and that’s been shown in a number of studies of healthy controls. And in stroke patients, that inferior frontal gyrus seems to be strongly more associated with verb naming than with noun naming.

But that’s still not what we are most interested in. What we interested in is prediction of subsequent decline and the only baseline parameter that significantly correlated with the rate of subsequent decline in naming after correction from multiple comparisons was the resting state connectivity or functional correlation on resting state between homologous prefrontal cortices. And so we did this twice, the first time was even higher was the correlation of 0.80 and then the second time was 0.69. So these are two different populations of PPA patients. And so it seems to be really stable. And so the correlation– how– the bold activity at rest in the left versus right, how well they’re correlated could predict the rate of change in Boston naming test. And this just shows you, in 30 healthy controls, this shows you the– all of these 185 regions of interest that we look at. On the left, it shows you that 185 regions of interest on the right and the color depicts how well they’re correlated. The red is very strong correlations and blue is very strong negative correlations and brown or gray is weak correlations.

And so you can see homologous regions are strongly correlated in healthy controls. This is very stable over time. And this is what we find in PPA patients. This is a group average. And what we find is much less strongly– strong correlations between homologous regions. There are some areas that are highly correlated but others that aren’t. And we also find that sort of language cortex, the areas in green frontal– sorry– inferior frontal, Broca’s area, prefrontal cortex, all of the temporal cortex and inferior parietal cortex are strongly correlated with each other even at rest in healthy controls. Whereas in PPA patients, the frontal regions are not correlated with temporal regions. Temporal regions are not correlated with each other.

So this seems to be something promising. We’re going to continue to look at but it may tell you that, you know, give you an idea of how quickly the person is going to decline in naming. Now it may be that it just depicts. We don’t control for the degree of atrophy in the prefrontal cortex. So it may just reflect that there’s an imbalance in atrophy, that there’s more atrophy in the left is more neuronal dropout in the left compared to the right. So there’s less pole signal in the left compared to the right. But it sort of doesn’t matter what it reflects because this is just a very easy thing to measure. You stick someone in the scanner. They don’t have to do anything. They lie there for 10 minutes. If you can get a measure like this in 10 minutes, that can predict something later on, it’s really nice no matter, you know, why we get this.

Advances in Treatment: Augmenting Language Therapy with transcanial Direct Current Stimulation

So I’m going to end by talking about advances in treatment. Now, I will point out these are investigational. We are using the main– really the only treatment for primary progressive aphasia is speech language pathology services, so language therapy. I refer all of my patients for language therapy and it can be very helpful, both in treating patients to use compensatory strategy, sometimes augmentative communication strategies are particularly helpful for patients with nonfluent/agrammatic variant. But there are many other things that can be useful, something direct treatment is most useful, using word communication notebooks or picture communication notebooks or all kinds of things that can be useful. But there’s no disease modifying treatment. There’s no proven medical intervention that reduce the rate of decline in PPA. And so, even temporary improvement or stabilization can improve the quality of life.


Language therapy as I mentioned, has been the focus. There’s been number of studies showing that language therapy can be useful. And these have been published. But we decided to try TDCS which– Transcranial Direct Current Stimulation, which is the safe nonpainful, noninvasive electrical stimulation that has been shown to augment language therapy and particularly poststroke aphasia. Although the studies have all been fairly small and there have been relatively few randomized control trials. We hypothesized that unaffected brain regions might be recruited by enhancing neuro plasticity. And, you know, if you look at the literature, both anodal TDCS and cathodal TDCS using 1 to 2 milliamps over unaffected brain has been shown to result in temporary subthreshold change in membrane potentials when paired with behavioral task. And animal studies suggest that it really influences long-term potentiation and long-term depression of neurons in the entire network that’s affected by the TDCS. So wherever you stimulate, as long as you stimulate over part of that network, it really can change the– that the probability that that network will be activated by the same stimulus later on.


The area affected by TDCS is really very coarsely localized. But it can be further localized by pairing the TDCS with the behavioral task. So it’s the task itself use a naming task, it activates the naming network in inferior frontal gyrus, superior temporal gyrus and so on and really bilaterally. And if you– if you stimulate an area of that network, the entire network will have some change in membrane excitability. Now numerous studies have demonstrated that TDCS alone, without concurrent behavioral task, really doesn’t affect language. And that– So we decided to use TDCS with the two augment language therapy. As I mentioned, and I’ve just listed a few here, aphasia therapy alone does result in some improvement in primary progressive aphasia. So we thought we might obtain even larger effect sizes or large– with a TDCS but we would need fairly a large number of participants to show a difference between TDCS and sham because these patients do show an improvement with language therapy.


So we actually are very thankful that NIDCD has funded a randomized control trial with Kyrana Tsapkini as the PI. She had published a preliminary study that was funded by the Science of Learning at Johns Hopkins. And she is now started this randomized control trial and we just have patients flocking to this study. She has people lined up. So far, I’m going to present some– the first 19 studies. I don’t want to take away her thunder, but she’s presented some of these already at Academy of Aphasia. But she has found some improvements for trained items. She initially reported in just six patients improvement with trained items with spelling therapy with or without TDCS and improvement on untrained items and maintenance of gains only with TDCS. So she hypothesized that improvements in spelling would be obtained and really oral naming, too, she’s studying now. So both oral and written naming could be obtained with combined intervention. TDCS plus language therapy and that would be greater than language intervention alone. And also hypothesized that differences would persist at two weeks and two months postintervention even though this is the progressive condition. And she also hypothesized that improvements with TDCS plus language therapy, we generalized to untrained items. And so she’s study– patients with written language difficulties as I mentioned both– she’s studying now both oral naming and written naming. But patients can have two different types of written naming problems. And their spelling can be treated with either a phoneme to graphing conversion treatment or a lexical treatment depending on which one was impaired. And she stimulates over the inferior frontal gyrus.


So far, she’s looked at 19 patients, 5 with logopenic variant, 11 with nonfluent variant, and 3 with semantic variant. And these are just some of the characteristics. They all get 15 sessions of sham therapy or– and then– and 15 sessions of real TDCS. All of them are accompanied by language therapy and there’s a two-month washout period in between the therapies. And they are randomized to whether they get the sham therapy or the real TDCS first. They get evaluations at two weeks and two months post treatment and it is a double-blind control trial. So this is just the treatment for phoneme to graphing conversion. It’s based on some old studies of basically treating phonics using keywords. And the lexical treatment is basically a copy and repeat. They have to spell it five times, trying to teach them spellings of irregular words. And this just shows the study design. As I already mentioned, they get 15 sessions of sham or 15 sessions of stimulation over left IFG or the opposite. So she did some statistical analyses to try to separate out the effects of treatment and the effects of a period.


And I’m not going to go into detail about the statistical analyses but what she found was that there was an effect of the TDCS versus sham, particularly at time one when there is the greatest effect. And I’ll just show you some examples of patients. So, all 19 patients have improved but they do improve more with a TDCS. So TDCS is in blue. So this one patient, for example, who first got TDCS and improved and this is at the various evaluation periods. And this is immediately after treatment, that’s two weeks after treatment and this is two months after treatment. So the patient received TDCS first, improved with TDCS and kind of maintained the gains and then when the person received sham, it lost a little bit of gains and really didn’t improve very much over time. This person received sham first, improved a little bit on the trained items, didn’t really show much change over time. And then when he received TDCS, improved even more and mostly improved– maintained those gains. This patient again, when he received TDCS first, improved quite a bit, pretty much maintained to those gains. When there was a washout period, he did deteriorate more and then showed a little bit of improvement with sham. This patient improved a little bit with sham and then, showed a little drop and then improved with TDCS. So, this shows the change with untrained items for all 19 participants. And there was a significant improvement at period one with the untrained items. And there was significant improvement at two weeks and two months with the untrained items. And so, similar results are seen for the untrained items with TDCS. So TDCS plus spelling intervention was more beneficial than the spelling intervention alone. Treatment effects seem to be better retained at two weeks and two months post-TDCS.


Again, these are preliminary data. She just started her trial back in the spring and it’s going to be going on for five years. So we hope to have much stronger data at the end of five years. But we’re excited about the preliminary data. So the mechanisms by which TDCS seems to augment language therapy are really not known well. Some– There have been some preliminary results with magnetic resonance stimulation that suggests that the synaptic plasticity, which results in a change in metabolites may be responsible for the effects of TDCS. And there are some changes also in resting state connectivity that are seen in stroke patients but this has been shown– demonstrated much less frequently or not at all as far as I know with PPA patients. So Kyrana hoping to look at resting state TDCS or she is looking at resting state TDCS before and after treatment, both before and after sham and before and after real TDCS to see if there’s greater changes in connectivity with the TDCS compared to the sham.


And I presented these results yesterday. These are actually just from a patient with stroke but this is the kind of thing we’ll be looking for in the PPA patients. This is a patient who received TDCS and during the four weeks, she had no treatment with TDCS. She really didn’t show any change in connectivity. And the changes in connectivity are shown. This is the correlations between areas– between homologous regions again and these various language networks. And these are changes in correlation– homologous regions in motor and default networks. And if there’s a increase, it is red. If there is a decease, it’s dark blue. If there’s no change, it’s kind of yellow or green or light blue. And for most areas without TDCS, there’s really not much change. When she received TDCS, she did show a change to high correlations in the inferior temporal gyrus and superior temporal gyrus pole into a lesser extent in inferior frontal gyrus. Whereas the control during the same time periods showed no change and she also showed very little change and maybe a little decrease in these other areas, non-language areas. So we think that TDCS may have an affect on connectivity, particularly in a language network. Again, we think TDCS, if it’s paired with a language task, will only affect changes in the language network.


So in conclusion, primary progressive aphasia is a group of clinical syndromes. It’s distinguished by language characteristics that reflect different locations of atrophy and usually distinct pathologies. There are tests being developed and standardized to efficiently identify these variants. The short form of the Pyramids and Palm Trees tests or even possibly eye tracking with word picture matching with not– unrelated foil seems to identify semantic variant primary progressive aphasia patients early in the course. And the rate of decline varies widely across tasks and in individuals across all variants. But it might be predictable using this resting state functional connectivity MRI, particularly looking at the degree of connectivity in prefrontal cortex or other homologous regions. Language therapy seems to slow the rate of decline on some language tests and it might be augmented with TDCS. The results are preliminary. There’s a study currently in progress. We are also doing a large study of language therapy alone, which is in progress. We’re collaborating with the Georgetown University on this to see if we can reduce the rate of a decline in all variants of primary progressive aphasia. And what we’ve seen is there is– that different variants respond differently. The semantic variants seem to improve most on the trained items and less on untrained items. Whereas logopenic variant and nonfluent variant can show more generalization to untrained items.


So I’m going to end by thanking all my collaborators. You can image this work takes a lot of collaboration. There are people in my neurology department. These are all my colleagues who refer patients and have been great support but particularly in neurology. I’ve had pretty wonderful collaboration with Andreia Faria and Susumu Mori in particular on this PPA work and the biostatisticians. The resting state fMRI data can be analyzed in many different ways so we’re still going to be looking at these data in a variety of ways with these fabulous biostatisticians. And then my laboratory is filled with graduate students and undergraduate students, medical students and postdoctoral fellows who do all these work. As well as some faculty collaborators like Donna Tippett and Marlis Gonzalez-Fernandez. And then, we have– I have a number of collaborators across the country, who’ve been working with me and even in England, Jenny Crinion has been a great collaborator in the PPA work. And my friends Julius Fridriksson and Chris Rorden have been collaborating for a long time as well as Gregory Hickok and Mary Grossman at Penn. And Rhonda Friedman and Aaron Meyer at Georgetown as well as other collaborators at Johns Hopkins. And finally, I’m very grateful always for funding particularly from NIDCD and the Science of Learning has funded by grateful patients. So here’s some of my collaborators and thank you to all of you for listening and I’m more than happy to take questions.

Questions and Discussion

Audience Question

First of all, it’s about identifying these people with PPA in places where there is not as center or a lab dedicated to this. The first video you showed reminded me very much of a client who actually came to us with a vascular stroke but has declined so, so much, and so one part of my question is: Is that a common characteristic or a finding that you would see?

Sure. I would say about half of my patients come to me with previous diagnosis at least somewhere with a diagnosis of stroke. But what tells you it’s not stroke is their MRI and the fact that they’re getting worse. Now, I did present some data that some patients get worse after stroke. But usually, they don’t decline to the degree that these patients decline. And it’s usually not really in the deficits caused by the stroke. It’s not specifically language. If stroke patients decline, it’s sort of more generally in the cognition. It’s not specifically in their aphasia. So if you see really worsening of aphasia, it’s usually primary progressive aphasia but look at their– somebody needs to look at their MRI. Often, they’re read as normal.

So neuroradiologists, and I love neuroradiologists, I couldn’t deal without them, but they’re very reluctant to read focal atrophy. And the reason is there’s a huge amount of variation in what’s normal. And so they won’t– they’re great at telling you what a lesion is. They’re much better that I am at saying, you know, this is a stroke or this is a tumor or what kind of tumor it is or they’re terrible at telling you where that is in the brain. So sometimes, they will say it’s on the parietal lobe and it’s really in the temporal lobe or, you know, it’s– so don’t just read the report if you want to know where something is. But they don’t read focal atrophy. So they’ll usually say it’s normal if it’s PPA. But if it’s a stroke, they’ll say it’s a stroke though. And occasionally they will– if it’s late PPA, they will misread it as a late– as chronic stroke. Because if there’s just encephalomalacia in a focal area, it looks kind of– it could be a stroke particularly if it, you know, if it’s in Broca’s area, there’s just kind of missing tissue in Broca’s area which there is in some of these nonfluent patients. They might read it as stroke but then if they get another scan, a CT or MRI and it’s bigger, it’s less– a whole lot less likely to be a stroke. So– Or if you see a lot gliosis around it and it’s not in vascular territory, it’s not a stroke. So, vascular lesions or vascular territories.

Audience Question

Thank you. The second part of my question is: I was encouraged that language therapy at least at some level seems to be helpful in slowing progression. And I work in a college based clinic and that seems like a good place for some of these people to come if we can find them and get them there. I’m wondering if you have any suggestions about how to do that, how to outreach, who to outreach to if we’re in an area without a known center that’s working with these patients?

So, I think university clinics are great. These patients are really informative, they teach– they teach the graduate students a lot and I always tell my patients, you know, graduates students provide really great therapy because they have the most time and they’re– you know, they’re being graded for their performance and they, you know, they’re innovative and they think about this and they don’t have 10 patients they have to see that day. So, I usually refer my patients to university clinics. One of our university clinics has just decided to do something brilliant which is to provide a support group for families of people with PPA. And I think that’s going to get them millions of referrals because these families really want support and they don’t get it because they don’t really quite fit in the Alzheimer’s disease support groups. There are some FTD support groups out there but they’re mostly filled with families of people with behavior variant and a lot of these patients don’t have behavioral problems. The problems are communication. And so, they’re going to have, I think a lot of people show up who– we did have a small scale which is [inaudible] for aphasia life enhancement had a support group for a while for people with PPA and people loved it but it was just– it was so hard to continue that for the people who were organizing it. So, I think, you know, if you’re willing, if somebody has time and it is effortful and time consuming to have a support group that would bring people in.

Audience Comment

I just want to say, in follow up to that, I was at poster that I did yesterday and this man came up and said, “I’m really no one” and I was, well of course you’re someone. But what he was the husband of someone with PPAOS. And he said just what you just said now is, there’s no place for them to go to be with people that understand them and can help them and he’s linked in to some good places where they are but you’d spoke directly to that. So, I think that really does seem like a very good direction. So thank you for that very much.

Audience Question

I’m Fatima from Ohio University. My first question is regarding the core features or the associated features for the different types of PPA, do you have any specific reading or writing features that can be related to the different types of PPA?

So the question was, are there specific reading or writing features related to each of these variants? I actually published a paper on this a long time ago and, well, I don’t know, couple– several years ago on the spelling types associated with different primary progressive aphasias. There’s not a one to one correlation. The most strong association is that, the semantic variants have this sort of surface dyslexia and surface dysgraphia and that patient with nonfluent variant have agrammatic writing very often. They often have more trouble with verbs than nouns as I mentioned. But they can have a variety of types of spelling problems and reading problems. Sometimes we see and I– you know, maybe Joe can say more to this but I’ve seen a couple of cases of deep dyslexia in patients with nonfluent variant which is sort of surprising. You think, well, they don’t have semantic deficits but they’re– the variant of a deep dyslexia where they say a semantic paraphasia. Like, they’ll look at the word fox and say, woof or, you know, might distort it more than that but say, woof. Or if you ask them to spell fox they’ll write, woof. But then they’ll say, “Yeah, not that.” They know it’s not quite right but it’s similar. So, they’re kind of aware of it and if you give them a picture of fox and woof and say point a fox, they’ll get it right. So, they know the difference but they do have these semantic problems and sometimes. They actually read and write. There have been several cases where they– their reading comprehension is better than their auditory comprehension. So, it’s fairly late in that course. So, Audry Holland actually published a paper ages ago on this where a patient with Pick’s disease had– could write but couldn’t speak and could understand written language more than he could understand spoken language. And I’ve seen a few other cases like this but they often do actually make semantic errors in auditory comprehension and auditory– and if you give him an auditory word they might even write a semantic paraphasia. But if you give it to them in writing, they understand it much better. So, they have some really interesting disassociation. There’s not single– there’s not a single pattern in the nonfluent variant and logopenic variant, I think.


Well, in that case, how significant is it for the clinicians to really identify the variants in order to plan for therapy?

Argye Hillis:

I think it’s less important for you to identify. It’s just this– I would say the same as for vascular aphasia syndromes. It’s less important to identify the variant or the classification than to identify the problems that the patient is having. That’s really the important thing is to characterize the best you can of what problems the patient’s having. If they have apraxia of speech, they have apraxia of speech and you should treat that. If they have agrammatic speech production, you should treat that. If it doesn’t quite fit because they also have word comprehension problems, treat the word comprehension problems and the agrammatic speech production. You don’t care that they don’t fit into– into a category very nicely. These are not perfect. Like I said, they are sort of clinical syndromes and not everybody is going to fit. Half of our patients– it’s just like the Boston diagnostic aphasia examination, half patients are not classifiable and half the patients or at least a quarter of the patients are not classifiable using these categories I just described.


Lastly, it’s just my curiosity, with the TDCS, how feasible it is to be used in clinical setting?

Argye Hillis:

So, it probably shouldn’t be used in a clinical setting just yet. We need more data. We need more evidence that it’s useful, particularly, in this condition but it is not difficult to use. So, I think if we get enough data, there’s a lot of evidence that it works, that it’s more useful than language therapy alone, then it should be use in a clinical setting and if it proves to be, it’s very easy and very inexpensive.

Audience Question

My name is Jordan Green. I’m from MGH Institute of Health Professions. And maybe I miss this but for the TDCS, was that anodal? And if so, what’s was the rationale for using that over cathodal?

I maybe didn’t say it. It was anodal. And so, they’re just seems– there’s evidence in poststroke aphasia for both anodal and cathodal TDCS plus language therapy. Most of the time, the cathodal has been over the right hemisphere and the ideas that cath– so anodal has very predictable effects on membrane excitability. It increases membrane excitability. Cathodal has very inconsistent effects in language. And so, it can either increase or decrease membrane excitability. So, we thought anodal just had– was a little bit more predictable, that it might improve language therapy. But certainly, empirically, there’s almost as much evidence for using cathodal in the opposite hemisphere. It would make less sense in the PPA patients than in stroke patients because in PPA patients they have atrophy. You don’t know that that’s an undamaged area in the right hemisphere. They do have some disease in the right hemisphere. So, even if you think cathodal is inhibiting something in the right hemisphere, you may not want to do that in PPA patients because there is disease in the right hemisphere too. So, it’s just– seems like there’s less evidence for doing it. As somebody pointed out yesterday, you know, we don’t know if you inhibit things in the right hemisphere. You might be inhibiting things that are good in the right hemisphere. So, people need to study that a little more. So, we just thought this would be a better approach.

Audience Question

My question is, if the TDCS studies used any social validity measures to measure the life parts patient functions of people that the primary progressive aphasia. And if yes, what were the assessment measures that you used?

So that’s a great question. And the answer is no. Sorry. We have added in the current trials some quality of life measures. And a lot of these patients are not participating, to be honest, very much in society. So, they just start. Some of them are though. And so, it would be a great idea. But right now, we mostly have quality of life measures.

Audience Question

I’m Isabel Hubbard from the University of California, San Francisco and University of Texas at Austin. I’ve been thinking a lot about TDCS and its effect on disease process and primary progressive aphasia. And I was wondering if you could tell me a little bit more about what you think the simulation is doing to the tissue that is unaffected but as you point out time and time again, beautifully in stroke, aphasia that unaffected tissue, is it necessarily health tissue and if may be vulnerable to disease. So, do you have a theory for how the simulation maybe positively or negatively impacts its vulnerability especially in your language network?

Well, so there are– you’re right. There are neurons that drop out but there are also neurons that are alive. You know, these people are producing speech and language. So the network is there and then we have done fMRI, test related fMRI studies. I mean it’s a great question but they’re– we’ve done some test related fMRI studies and they do show, you know, a network associated with language production. So there’s still a language network in there. So those neurons are working together to produce language. So we think if you stimulate, as I mentioned, stimulation is very broadly localized. So we think if you do the task at the same time and you do TDCS. The TDCS is going to change the membrane excitability over that network wherever it is. It’s finding those healthy neurons that still exists in our– then are doing language when they can do it. So I think that that what’s its doing, is that they’re making those neurons that are still there and still healthy and still able to produce a direct response more able– more likely to fire the next time they get the stimulus. So that’s what’s LTP is. It’s– you just, you know, makes it more likely to fire with the same stimulus the next time.

Isabel Hubbard :

Thanks. And where was your cathodal placement?

Argye Hillis:

So, we do one– so, what, Kyrana Tsapkini who’s my colleague that’s actually carrying this out. She does IFG and then the control is actually on the jaw. And she’s worked with Miriam Begsun [unsure] who’s localized this now to show that that actually does show most active change or just the most activity in kind of Broca’s area.

Audience Comments

I run a nonprofit organization for people of aphasia. And our goal is participation. So we actually have run primary progressive aphasia groups. We used to put the people with PPA into the regular aphasia groups, and that didn’t work. We had to separate that group out, and then we have to further separate it now to a lower level group and a higher group because people that are more recently diagnosed are freaked-out by people that had started to have some behavioral components. So that’s one issue.

The second issue is that [the patient has] usually seen another neurologist who has either not known what it was or said. Yeah, you have PPA and I’ll see you in six months or a year, and doesn’t make any other referrals. Or we have issues — we don’t do individual therapy at the nonprofit, so, I refer out for speech therapy — and the speech therapists are very concerned about the insurance okaying therapy because it says “progressive” and they need a quicker battery than, you know, some of the testing that you had suggested. But could you identify maybe some of the tests that they really should kind of rise to the top — and then, how to reassure them that this therapy is doing some good and especially in collaboration with a nonprofit like us.

So, all of these are good, good points. And think the– we also see, you know, such a difference between sort of very high level people who are still participating in society. And actually I tell them that is the most important thing that the can do. That I think that that is what predicts whether they’re going to decline, at least in some cases, decline quickly versus slowly as if they’re still try to participate. I have one patient who even actually was mute. He stopped working in a– his previous job which was like as a lawyer or something. But he was delivering flowers because it was something he could do. He didn’t actually have to talk to people when he delivered flowers. He just wanted to keep participating in society. You know, if they have that drive and they do things, you know, one of my patient still runs marathons and, you know, they– if they still do things and do a lot of activities they’re interesting and require some contact like, you know, they just have to keep talking the best they can. I think they do better. Your other question on was about a quick battery. And, you know, identify their– it doesn’t take that long to identify the– some of the core features. So I did this, told you about the 14 item semantic test. Joe, I think, will probably tell you a little bit about the rating scale for apraxia of speech that they use and it doesn’t take a really long time to do that. Grammatical speech production, the best thing you can do is listen to them, I think. It’s really hard to quantify. But I think, well, we’re trying to develop a way to quantify that a little bit better than– or more quickly. There’s lots of analyses but they take forever to do. And maybe some of the things that are coming out of aphasia bank for analyses are going to be the most useful there that you don’t– that are sort of automated analyses. So we’ve just given some a lot of our PPA analysis to the– to one of our collaborators who’s going to have them analyze using some of the aphasia bank analysis. So we’ll see if we can find something that evaluates that. Since repartitions is very rapid the NACC subset– subtest for since repartition takes, I don’t know, two minutes. But you could have them repeat sentence from the Boston Diagnostic Aphasia examination or whatever aphasia test do you like. So none of these things take a really long time. So I wouldn’t– you know, there is no PPA battery that I know of but I think you can evaluate for these core features.

Audience Comments

This is wonderful. My name is Becky Khayum and I collaborate with Northwestern and I see most of Dr. Mesulam’s patients. And to answer the last question, I bill Medicare all the time. So this is what I’ve found to be helpful. It really depends if you’re a speech language pathologist if you’re going to be doing for diagnostic purpose or if you’re really going to be doing this for treatment. And if you’re on a team helping to diagnose someone for PPA, obviously then you’ll be doing a lot of standardized tests. But I think most of the speech therapists in the clinics, they’ve already gotten the diagnosis. So what I find is most helpful is more of a life participation, person centered approach. So I will really focus the evaluation on just talking with the person and their spouse and finding out, you know, what their frustrations are. And I completely agree that subtyping and focusing the treatment strategies on the subtyping. To me, I don’t do that either. I look at the clinical profile and what their strengths and weaknesses are but even more importantly what’s frustrating to them.

How you get reimbursement for that is all in how you write the goals. So Medicare is very, very concerned about functional goals and meaningful goals. They’re focusing more on person or the patient rated outcomes. And so if you were focusing all of your goals on their frustrations and what they want to work on and then you make them measurable and you make them attainable. So even if they need a moderate level of queuing to use a communication book, that’s OK. That’s increasing communication. In that way, we can document that and show Medicare that absolutely we can very much show a level, you know, on functional progress. A lot of standardized tests would not reflect that progress. So what I’ll do is throw in a couple of subtest at the end of my evaluation, just what Medicare is auditing. They will see the subtest on there but, well, how I’m proving medical necessity as to my functional goals and outcomes.

Thank you so much and I was curious to hear, is the language study that you’re starting with Georgetown is it opening soon or is it already in rolling right now?

We’ve actually been going on for five years. It’s really to improve or maintain naming. So it’s with all variants. And it’s using a lot of repartition and copying and so on. So it is– we will be submitting competing renewal but it is currently and its fifth– or it’s about to be in its fifth year.

So thank you very much for your comments. And Medicare, I’m sure you all know this. But Medicare did make a decision a couple of years ago that you don’t really have to show progress or improvement in people with neurodegenerative disease. That it is OK to show the people with neurodegenerative disease are just maintaining improvement. As long as your goals reflect that and you show that they are maintaining improvement despite the fact that they have neurodegenerative disease which would otherwise deteriorate then they supposedly will continue pay. It’s not an excuse to say that they’re not improving if they have a neurodegenerative disease. So I really appreciated your comments.

And the other thing about the variants, I think there is usefulness of the variants but they are more for research and for helping us identify more as– perhaps as a neurologist. But you all also– for projecting what other problems they might develop. So, you know, if they have nonfluent variant they might develop problems with– And you can look for this too– for problems with swallowing problems or problems with using their right hand. You know, it kind of predicts the next things that might come up because of the underlying disease. They have semantic variant you might look for behavioral problems. It might not surprise you that they have poor insight and comportment problems that might interfere with their ability to carry out your goals for interacting in society. They become disinhibited and that kind of thing. So, it can help you adjust your goals if you know what to expect.

Argye Hillis
Johns Hopkins University

Presented at the 25th Annual Research Symposium at the ASHA Convention (November 2015).
The Research Symposium is hosted by the American Speech-Language-Hearing Association, and is supported in part by grant R13DC003383 from the National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health (NIH).
Copyrighted Material. Reproduced by the American Speech-Language-Hearing Association in the Clinical Research Education Library with permission from the author or presenter.