2.. Overview of Atypical Parkinsonism | Atypical Parkinsonism (DLB, PSP, MSA, CBS/CBD) Symposium

\ :13 well good morning how are you energized 0:18 God well first of all thank you robbing thank you all of you for coming here 0:24 today it is just delightful for me to be here you can't imagine how much energy 0:31 we get as clinical research from all of you in fact you were the ones that kind 0:40 of took me through the path that I'm in I wasn't planning to study PSP I wasn't 0:46 planning to study all day typical parkinsonian disorders it just happened 0:51 that as soon as I would do one study my patients will call me and say it's quite 0:57 the next what's the next so with that and with all the questions that each 1:03 study has I keep going and going and going and the questions continue to 1:08 multiply so today I'll be giving you an overview of what we think today with our 1:16 own doubts so you may see why take some how long to get the diagnosis and all 1:24 the features that at times comes to be a disease and more importantly that even 1:31 when that happens that we can still make mistakes because really only when 1:38 someone passes away and we get the 1:43 autopsy results is when we truly know what is the real diagnosis so even if 1:50 we're careful we still can make mistakes obviously that if we're careful we make 1:56 less mistakes that we were not so we tend to do long exams and some of you 2:02 may know that so I'm sorry for the lengthy time but we want to try to take 2:08 care of all the aspects from the patient as well as from the caregiver point of 2:14 view so let me start by telling you that first I'm gonna just go with a 2:20 definition what is parkinsonism what is a typical 2:26 and then go on into what are the clinical characteristics of the 2:32 disorders and what are the overlapping features why some are more confused with 2:39 others and why son may stand out more than others as well as what are the 2:46 markers that can help us make an early diagnosis that that is truly what we all 2:52 want an early diagnosis so we have a peace of mind we know what to expect we 2:58 know how to prevent complications we know how to try to get into clinical 3:05 research studies and try to learn more about the disease so we can eventually 3:10 hope what you'll hope cure or even not have it at all so that's really the main 3:21 reason of early diagnosis so we try to 3:26 provide the best care possible we try to get the maximum possibilities for 3:34 research regarding understanding and disease as well as understanding what 3:40 are the possible ways of either prevented or stopping it most of the 3:46 studies do show that when we look at the pathology there are certain diseases in 3:52 which major errors are committed the major one is corticobasal degeneration 3:58 that is where most of the errors occur then there are others and dementia with 4:04 Lewy bodies I would say is the second one and perhaps multiple system atrophy and as well be SP but what is it that is 4:16 parkinsonism is a major question so what you see here is someone walking with a 4:23 small step gate without associated arm swing and that is kind of the 4:30 characteristics I would say of what slowness and low amplitude of movement 4:37 is and that is a key feature for parkinsonism that feature also 4:44 associate with either having tremor addressed that has a certain frequency 4:52 or may associate with stiffness or with postural instability that really is 5:00 whole category like if you were to call furniture but what is the furniture that 5:07 I have is it that a chair a desk so 5:12 that's kind of what all the different disorders are and so we first characterize them as secondary to 5:19 something secondary to drugs secondary to strokes 5:24 secondary to infections and once we ruled those out then there are these 5:30 progressive disorders that happen as we age and those are the neurodegenerative 5:36 diseases this is in which cells in certain areas of the brain die and most 5:43 of the time we don't know why so why is it that some of them are Parkinson's 5:50 disease and the other ones are the atypical well the parkinsonism that is 5:57 the slowness the rest tremor or the rigidity that kind of get us to the 6:05 Parkinson's disease type with a very excellent response to topham energy 6:12 medication and none of the other features that we call a typical so let 6:18 me go there those atypical features are those that are not in Parkinson's 6:26 disease and that's why they're called typicals and why is that classification or why is 6:32 that name what the name is because Parkinson's disease end up being the most frequent one and they wanted most 6:38 doctors diagnosed many of you may have been diagnosed as having Parkinson's disease and eventually you are told oh 6:46 this does not seem like it and it may be this is and one of the ATP comes 6:53 so a typical series because there is false early on in the course of the 7:00 disease because there is no response to dopamine because there is a rapid 7:09 progression and someone may be very early wheelchair-bound that doesn't 7:15 really happen in Parkinson's disease and because there could be some problems 7:21 when you stand up and the blood pressure Falls or because there are urinary problems early on even before all the 7:29 symptoms occur or because the walking is very white based or because there is 7:37 some tremors when you move your arms or because there is dementia early on some 7:44 lack of memory that is significant or difficulty with planning and 7:52 multitasking that that's kind of what Robin was saying the planning of a trip 7:58 right sure her dad had been traveling 8:04 before and knew that he had to have money but there is a lack of planning and so you kind of do the things and 8:12 think that they're going to be all there when in fact you cannot really plan ahead that's truly what an executive 8:18 person do and that's why those functions are called executive functions it is 8:25 also difficult at times because there is other problems such as 8:31 visual spatial problems and/or their difficulties handling things or there is 8:37 some jerking that doesn't exist in Parkinson's disease so let me give you 8:46 an example of what Falls are we ask you 8:52 all the questions when we are doing our examinations regarding when the the 8:58 things happen because when they happen allow us to make a diagnosis if also 9:05 her very close to the starties first symptom pretty much within the first 9:11 year of the symptoms that you identified on something new that makes this thing 9:17 right away is his PSP if the Falls occur but not immediately within the first two 9:25 years that still allow us to think on PSP but MSA comes more into our thoughts 9:31 as well if if the Falls are there but 9:37 it's not really necessarily the first symptom then corticobasal degeneration comes there and dementia with Lewy 9:44 bodies come there but we certainly don't expect Parkinson's disease patients to 9:51 fall early on and that's how we divide and we start thinking about it when you 9:57 are telling us a story another thing is well we see someone 10:03 already coming with a fracture and that's kind of the first doctor that sees or many others have seen this 10:10 person has been falling and comes with a fracture and comes in a wheelchair we already are thinking this is not 10:17 Parkinson's disease to start with I'm already thinking my index of suspicion 10:22 is already very high you may have heard 10:28 about the oculomotor problem so what are they here is the first patient that 10:34 still Richardson and on Celski so and you can see that this person can horizontally follow a pen but not 10:43 vertically and that is the supranuclear gaze palsy the difficulty to look up and 10:50 down and the difficulties that that leads to is really difficulty reading 10:58 because to read you need these rapid eye movements going up and down and that's 11:04 why reading is also an early feature and people just think that I lost my 11:11 interest in reading well it goes a little bit beyond that 11:16 in fact the difficulty is voluntarily moving the eyes and that's why this 11:23 person wants to look at his watch and cannot do so and so the examiner comes 11:31 and helps but truly is difficult for the person unless they really raise their 11:37 hand to look at his own watch this 11:44 supranuclear gaze palsy we said oh now we know that's PSP well not always 11:51 not always at times these are other diseases so as neurologist that's our 11:57 task not yours you're the ones to tell us what are the problems we are to try to put it in 12:03 context so at times it happens that this happens in families and they have a 12:08 familial disease that is the frontal temporal dementia with parkinsonism that 12:14 can pretend like PSP but then there is a family history or it could be that 12:20 there's people that may have an infection and that's Whipple's disease or may be that they living one and they 12:28 have the one little body disease as it's calling one but these are the classical 12:37 features of PSP when we make that diagnosis and when all these features 12:43 are the disease has progressed for at least three or four years that's a lot 12:49 of time we want to make that diagnosis so much earlier than that so yes that's 12:55 how it was described and that's what we call it classical PSP or Richardson 13:01 syndrome or SR or whatever you want to call it everybody calls it a different 13:07 name but basically is the presence of this false a posture instability the 13:12 vertical supranuclear gaze palsy the difficulty speaking the difficulty 13:17 swallowing early on as well as this frontal disturbances that is our 13:24 executive dysfunction our difficulty in planning multitasking 13:29 having an abstract thought we become much more concrete so early on we 13:39 realize that there were things happening before that and that is if I probably 13:45 should go I cannot see my my slice here well so let me explain to you what I'm 13:52 gonna ask you right ask you to see we realize that before those symptoms occur 13:59 there were other symptoms occurring with the eye movements that would allow us to try to diagnose the disease earlier and 14:06 those are the circuits so what are the circuits rapid eye movements between two 14:11 stimuli in which we see the eyeball moving so fast that we see the starting 14:19 of the movement and then the end of the movement but we don't see pretty much 14:25 the I will moving from one side to another so if someone had an infection 14:31 and encephalitis that's not had problems with hallucinations early on without any 14:38 medication that's not PSB either if they have a clear dementia with language 14:45 difficulties or significant memory problems that's not PSP if they had significant 14:53 symmetries one side more dia than the other we thought does not PSP in fact we 15:00 thought that having the symptoms of not feeling well when there were two sides 15:08 being stimulated or having difficulties manipulating objects that is the apraxia 15:16 when there is no problems methodically or having the dystonia all those were 15:24 real exclusionary criteria because those were the typical features of 15:29 corticobasal degeneration but now nowadays that is also a form of 15:36 presentation of PSP so before we thought oh we exclude those 15:42 because they are that's the way to exclude ESP patients that have the real 15:51 disease versus those that have CVD well nowadays that's not so clear some 15:57 patients with PSP may have the corticobasal syndrome in fact there are 16:06 other presentations of PSP that's why that criteria we put forward is what we 16:12 call specific very once we say that they have someone has the presentation of PSP 16:21 Richardson or PSP classical that is PSP 16:27 almost all the time almost all the time but if they have something else we were 16:35 not able to diagnose and that's why the criteria was not sensitive enough there were people that had PSP and we were not 16:42 able to diagnose so that's how in over these past few years all the other 16:48 phenotypes all the other presentations came about one of them is the freezing 16:56 of gait people that just have difficulty with getting stuck in the floor when 17:03 they're turning initially and then this freezing gets worse and worse this 17:10 patient had PSP she had it for 15 years she had a pretty much normal life except 17:17 for that and later on she developed the features of PSP later on she had the 17:25 problems falling and she eventually had the problems with the eye movements and 17:30 when she passed away we learned she had PSP and this is another form of PSP that 17:37 is the akinesia or freezing of gait form that has a much better prognosis so 17:45 that's why it's important to know the different types of presentations because 17:50 it have they may have different prognosis another one is the 17:56 go basal syndrome and in fact this is one of the patients of Richerson this is 18:05 in fact one of my main problem is my right hand and arm that I can't use I 18:21 think that that three years ago well I 18:30 went to an arthritis doctor for my graving that it started with my writhing 18:40 I was losing control the writhing then 18:46 it was hard for me to cut my food see 18:52 I'm right-handed and it was hard for me to cut my food and to eat with my right 19:00 hand the hand started to jump not so much shaking as jumping that's my 19:11 line and I couldn't see cross would describe it better do you see that at times they hand would be moving on its 19:18 own yes especially at night in bed I 19:24 would wake up and the hanging would be up you also feel at times that your own 19:33 arm was not her own arm the right arm yes 19:39 so that truly is what we call the alien limb syndrome feeling that your arm is 19:47 not your arm and it does things that you're not expecting that is different 19:52 than having a Dirk as she described it I use this type to teach my students because there's nobody that can be 19:58 clearer than her she clearly differentiates what is a rhythmic movement that tremor from that jerk that 20:05 happens when myoclonus occur she also this Christ she lost her way of writing but she 20:15 could move her hand she couldn't fold things but she could move her hands and 20:20 that is part of the apraxia like if you lose the way of doing things things that 20:29 we obviously all do automatically become quite hard to do even if you know what 20:36 to do you cannot do them so that is the apraxia itself and that's very typical 20:42 of corticobasal degeneration and not these patient truly had cortical based 20:49 on the generation and there is another form that I skip but is the PSP 20:55 parkinsonism that is someone that really starts with Parkinson's disease like symptoms really the tremor the rigidity 21:03 the that stiffness the slowing but then 21:08 years later develops all the other features of classical PSP and that is 21:15 the PSP parkinsonism that we cannot diagnose early on there's no way because 21:21 patients really respond to the medication as it would be Parkinson's disease patients and only later on they 21:28 stop responding to the medication and they start having the eye problems so 21:33 that's when we can make the diagnosis assume diagnoses that we make that is retrospective in some ways we need to 21:40 have had that history so coming back to corticobasal degeneration that's the way 21:48 that he was described in 1969 the corticobasal syndrome as the typical way 21:56 that cortical basal presented but as I'll show you one of the patients that 22:02 still readers and a nurse asking the typical paper when he when they 22:09 described this disease already had this presentation they just didn't pay attention because all the others did it 22:15 is not as frequent but that patient also had PSP so what happens with 22:22 corticobasal syndrome that we learn that there are many other diseases 22:27 that precent like that one is PSP another one is Cymer and there are many 22:34 others that present and are truly forms 22:39 of a presentation of cortical based on the generation but the pathology is the 22:45 one that tells us and that's why I told you early on that's the hardest diagnosis to make corticobasal 22:52 degeneration also presents with other forms so as I was mentioning 23:00 corticobasal syndrome could be corticobasal degeneration PSP it could 23:06 be a table it could be non even a telepathy it could be at Alzheimer's it could be dementia with Lewy body so 23:15 it could be almost anything so nowadays 23:20 this is recent data from the Mayo Clinic brain Bank and actually if you really 23:28 can see the corticobasal syndrome only less than a quarter of the patients had 23:35 truly corticobasal degeneration and almost have high PSP of course this is a 23:44 PSP brain back so there may be some bias there but still dr. Dixon says that he 23:54 gets brains from all over and not all of them have PSP so clearly it does occur 24:02 that not only in his data but in other centers in difficulty with executive 24:10 function but also becoming more apathetic with us if you have less 24:15 interest in fact that is also true not depression but lack of interest in 24:22 things that someone used to have a lot of interested in that not necessarily go 24:28 along with not being able to do them it just beyond that that's what we call 24:33 apathy and as I said the PSP syndrome there are 24:39 some patients with corticobasal degeneration that happy SP presenting so 24:47 this is just from one brain bank and this is the brain bank from the 24:54 University of Pennsylvania and I just marked from 15 patients only four of 24:59 them had the corticobasal syndrome all others had all the other presentations 25:05 that I was just referring to so it is seen in many more places than that all 25:14 the data is showing that so what is the commonality between PSP and corticobasal 25:20 degeneration but it happens to be that they have a lot of things in common not only the yogur lap in history as you saw 25:28 some of the symptoms are the same but also when you look at the brains the 25:34 neurons and glia all the cells in the brain that we can see that are affected 25:42 have a protein that is called tau that is part of the cell part of the 25:48 membranes of the cells part of the pipeline's of the cells aggregates kind 25:54 of agglutinates and so that allows the cell not to receive the proper nourishment and the 26:02 cell dies so those clumps are in the 26:08 neurons what we call neurofibrillary tangles and they form in PSP because in 26:15 the other cells that nourish the neurons that is the glia they kind of clump not 26:21 only the body of the cells but also its extensions is they form this tufted 26:28 astrocyte in PSP and in corticobasal 26:33 degeneration because these these tau clumps accumulate more in the extensions 26:41 of the cells but not in the body they they form what they call the astral siddik plaque and that's pretty much the 26:48 distinction with one and another because as you saw even location can be similar so it end up 26:56 being this what really allows the differentiation when you look at the 27:01 pathology from one disease to another even genetically there are similar 27:07 things so these two are what we call 27:13 normally we have two forms of tau in in 27:18 the brain three repeats and four repeats and here in corticobasal degeneration 27:23 and in PSP the four repeat tau is the one that accumulates the most and makes 27:29 the cell the tau aggregate and that's what this happens and interestingly this 27:36 is different that what happens in Alzheimer's disease and what happens in other frontotemporal dementia so there 27:45 is this overlap we have the clinical features we have the corticobasal syndrome the PSP presentation the 27:52 frontal dementia presentation that both have in common so are they the same 28:01 disease or they're different diseases and that still the judge is to be made 28:08 in the future future we don't truly know I believe there are different diseases 28:13 and certainly it's worthwhile separate them because maybe what happens is that 28:19 these two forms of the same disease or of different diseases may have different 28:26 genetics or different environmental factors and we will not be able to know 28:32 what leads to one disease presentation or the other unless we really study and 28:39 keep them separated so let me go now to 28:45 the other disorders the MSA is the other 28:50 disorder that I'm gonna be touching about now and it's a gradual disorder 28:56 usually the presentation is a little bit earlier what happens here is that we have a lot of what we call 29:03 autonomic disturbances urinary disturbances that are significant 29:08 problems with erectile dysfunction and some of the patients may end up having 29:15 parkinsonism others may have the kind of drunking type of drunk gait this white 29:24 bass gait and that's how we call it a mess a parkinsonism or MSA 29:32 that often not this is one of our patients impotence was that a problem also feeling woozy 29:47 problem your blood pressure was when you were lying down 167 over 79 but then 29:56 when you when you got up your blood pressure came to be 90 559 so it really 30:02 there is a fluctuating a lot so this patient thought he was diagnosed as 30:11 having Parkinson's disease and he thought as he didn't have any other reason to think that all these blood 30:17 pressure problems and impotence were related to something else they were unrelated or he was getting old that's pretty much usually what 30:24 people think I'm getting old and that's why I fall I'm getting all and that's why I have tremors but happens to be 30:30 that these symptoms truly are the autonomic symptoms are the ones that precede even the development of the 30:36 parkinsonism and allow us to separate these diseases so if they present early 30:42 on we think on multiple system atrophy we think on the measure with Lewy bodies but if they present late we think on 30:50 Parkinson's disease and usually the problems particularly with the blood 30:56 pressure not the urinary problems that are for different reasons but the problems with a with a blood pressure 31:03 dropping when you stand up quickly that doesn't happen in PSP that doesn't 31:08 happen in corticobasal degeneration unless you have medications but usually doesn't happen 31:15 so I have them in two different colors and I have them all in red and I have 31:20 them in red the multiple system atrophy the Parkinson's disease and the dementia 31:26 with Lewy body and I have them in red because of a reason they all have the 31:31 same protein that deposits into the brain when you look at the brain and that is alphas in new claim so the fact 31:40 that alpha synuclein is the commonality already gives us some 31:47 sense that they're gonna be share symptoms and of course they are they may occur at different times but the 31:53 symptoms are share and overlap as well so we see that this is from actually 32:01 cases in which we look at the pathology and we could see that MSA even PSP and 32:07 dementia with Lewy bodies all of them had intermediate problems with blood 32:13 early and then intermediate problems with the blood pressure dropping 32:19 but in the PSP cases truly that is only 32:24 by autopsy where things have not been recorded well that is really not what 32:30 happens in our clinical life I have to say the urinary problems yes they do 32:37 exist early on in MSA and as I said intermediate in the others and very late 32:44 in Parkinson's disease so I mentioned the important part of the parkinsonism 32:51 that occurs with MSA one of the major things is that these patients may at 32:58 times respond to dopaminergic medications so it is important that they 33:03 tried even if the blood pressure Falls so that is very very relevant the MSA C 33:12 we said is gait that is very wide base they may have a tremor and this is 33:20 exactly what I'm referring with that cerebellar tremor is a tremor that exists 33:26 you move your arm that makes you have more difficulties when you're trying to 33:32 eat that is different than the tremor that occurs in Parkinson's disease 33:40 cerebellar disturbances also occur in other diseases and finally dementia with 33:49 Lewy bodies in which there are several things dimension parkinsonism 33:55 arbitrarily have to happen within a year or at least when parkinsonism occur 34:01 first dementia has to occur within a year to call it a measure will kill a 34:06 body and later on if it's gonna be Parkinson's disease and dementia but one 34:15 of the major features is the 34:20 fluctuations calculations in the cognition fluctuations in the motor aspects and people really say that the 34:29 fluctuations are very significant and at times my spouse is doing great and at 34:35 times they're not doing so great and they play golf and they did great with her friends but later on they were 34:41 really confused and that's very typical of dementia with Lewy bodies it is also 34:48 typical having hallucinations seeing things that are not we're not scary 34:54 things just things like a dog that passes by or something that comes and 35:00 goes and then he may get worse and they also may have very frequently what we 35:06 call REM behavior disorder that is when you sleep you're having dreams and 35:13 you're acting out those dreams they it's 35:18 important to have these diagnoses very early because patients are very sensitive to medications to neuroleptics 35:27 so they may develop major complications what is called the neuroleptic malignant 35:32 syndrome if they take these medications and that is a condition that is 35:37 life-threatening these are not all the neuroleptics but the old ones like how long so that is 35:45 something that people that have dementia with Lewy body should always say when 35:50 they go to an emergency room because if the problems are hallucinations that would be something that could be treated 35:59 in the wrong way so as I said as the sinew Klain is in the cells in Lewy 36:08 bodies in Parkinson's disease as well as in the cortex in dementia with Lewy 36:13 bodies but in multiple system atrophy it's in the glia in the other nourishing 36:21 cells that are nearby there are several 36:27 things that also overlap here the blood pressure drops the urinary problems 36:33 cognitive problems that may occur the 36:38 parkinsonism that may respond to levodopa therapy so all this the fact 36:44 that it's a symmetric so all these clinical features the fact that the result Ficino claim also in the brain 36:51 also let thing are they different disorders or they're not whether they 36:57 are or they are not is still important because if we do find treatments for 37:03 these proteins that are gluten aid in the cell in the brain then we can treat 37:08 all these disorders those that have the presentation with MS a with treatments 37:15 that would go against that alpha synuclein agglutination and those that 37:20 have PSP or CBD with treatments that would avoid the agglutination of tau so 37:28 that's why it's still relevant to separate them at least in these two 37:33 major groups but there are features that 37:39 do not fit into any of them like the resist onea in that is axial in multiple 37:49 system atrophy there is a scoliosis is what we call enter a colles but there 37:55 is also enter a colles and what we call retro college in PSP so even these 38:01 diseases that have different proteins aggregated in the brain they have overlapping features and that makes it 38:08 difficult there are also other signs reflexes that are abnormal and maybe in 38:14 all of them so what do we do to work up 38:21 and what are the biological markers but unfortunately we don't have biological markers we don't have like in diabetes 38:29 that will draw the blood and we can say oh this is diabetes that doesn't happen 38:36 we have MRIs and each MRI may help diagnose one disease versus another but 38:42 not all of the people do have these abnormalities so in in PSP there may be 38:49 this midbrain where all the lesions are that is small in MSA it may be the 38:56 opposite it is the pons the one that is small but again this is not really a 39:03 complete marker and I'm gonna go over all these different features that truly 39:10 are not of relevance here is just for you to know there are features that may help point to one diseases another up 39:18 that truly what they represent is the anatomy of the lesions so in 39:27 corticobasal degeneration for example one side of the brain is much more 39:33 atrophic than the other and that's what you can see here you can see more black 39:38 spaces the white and is what where the brain is and look and you can see that 39:45 here is much more atrophic than here because the person had the symptoms on 39:50 the other side you know that it's crossed in the what we have in the brain from one we have in the symptomatology 40:00 so there are symptoms as well for multiple system atrophy 40:05 but again all these symptoms just reflect where the lesions are so in PSP 40:14 we have this small brainstem these more small pencil cell phone because this is 40:19 where all the dart lesions that explain the eye movement problems are and where 40:25 the lesions in the substantia are that explain all the problems with 40:30 parkinsonism so they just reflect where the lesions are but they don't tell us what is the protein that is there that 40:38 is what would allow us to really know this is this disease this is that disease transcranial sonography is being 40:47 done in Europe we don't have that they claim it is very good we don't know that 40:53 yet but apparently it may be very hard to learn how to do it the spinal fluid 41:00 there are some studies that suggest that certain protein ratios may be typical 41:08 more of PSP than the other diseases but again these are not really markers that 41:14 we have in clinic they're still experimental so participate participation in studies 41:20 is relevant because it can help get us there get us understanding what is different 41:28 between one disease and the other so this is what I try to tell you that 41:35 parkinsonism is divided in secondary when we do know what is the cause strokes drugs neurodegenerative the 41:45 Parkinson's type the typical ones and all these different disorders that 41:50 usually are sporadic but there are familial are typical parkinsonian disorders they are rare less than 5% in 42:00 conclusion we can say that it is important to know that there is a 42:07 spectrum of symptoms in all these disorders that may overlap but it's 42:13 still important to keep them separate it is still important to try our 42:18 best to make the best diagnosis as early as possible so you can get the best 42:25 treatment and you know what your prognosis is gonna be it also is 42:31 important because the symptoms may lead to having a complete different prognosis 42:36 from one to another we do want a lot of research that can allow us to really 42:42 find markers that could differentiate these different disorders as well as 42:48 trying to find treatments that can really one day hopefully make these 42:55 diseases either slowed down completely or disappear thank you for your 43:03 attention I'm happy to be here and answer all your questions is Randy here 43:19 can we yep can you help dr. Levin get the lavalier microphone working then we 43:25 won't have to share it if any of you have question cards please raise your hands I see a couple over here three or 43:31 four our volunteers can get around it 44:06 was okay great thanks Randy thank you 44:12 okay we've got a few questions already so the first question is where do the 44:18 diagnostic features get decided how does the latest thinking get disseminated to 44:25 clinicians and non-academic settings oh that's a wonderful question 44:32 that's where CMI's are about continuous medical education is about and that's 44:37 what we try to do all the time so I have to say that since I arrived to California a year ago we had three CME 44:46 events in which we teach healthcare professionals that are in the community 44:51 we truly want that the people would recognize right away DC sees but at times it's hard to get 44:59 all these physicians to go particularly because if you do fall you're going to go to an orthopedic surgeon right so why 45:07 would the orthopedic surgeon now in fact I had one of my students going by and 45:12 when he was being taught what parkinsonism was he said oh I was in 45:19 orthopedics like last month and I saw a lot of patients that have what you're telling me but they never were diagnosed 45:26 and that's what happens you know some of the specialties we'll never know so it 45:32 is difficult so if you do have a very good primary physician that truly goes and tries to get the best and more 45:40 up-to-date knowledge then you're lucky obviously how would you know that you 45:47 need to go to a neurologist when you're falling it's really difficult or that you have to go to a neurologist when you 45:53 have an eye problem or that when you have a urinary problem you have to go to a neurologist I mean it's it's contrary 45:58 intuitive so it's gonna take us a while to get there okay next question is are 46:06 these diseases fatal or does the patient die of some other disease or event the 46:16 latter is a truth that is these diseases are not fatal per se what happens is 46:23 that we develop complications of the disease that is we have swallowing 46:29 problems food goes into the wrong pipe we develop aspiration and we may die out 46:35 of that we food can go in small pieces 46:41 into the wrong pipe we develop repetitive no more that are difficult to treat so 46:48 swallowing problem this is a major cause and that's why I always recommend that you truly are looking and seeing if 46:57 swallowing is a problem and how do you know if it is a problem well if you are coughing when you're 47:04 drinking that is a problem so you need to get your doctor to know and do a 47:10 modified volume swallow a study that allows you to learn how food can be 47:16 swallow with different consistency or how different consistence of food are going through the right pipes so usually 47:25 in neurological disorders the major problem is swallowing liquids not solids 47:31 liquids so if that is a problem these studies can allow you to figure that out 47:38 and once you have that problem it's important for you to be every so often 47:44 having that study every six months a year depending on your symptoms if they are stable with whatever it is that 47:52 they're suggesting you to do then maybe you can wait a year so but it is 47:58 important to be really that's what we meant by getting the proper treatment 48:04 really trying to go and try to avoid complications another complication is 48:10 falling so you fall you get a fracture and you get into the hospital you get all the complications that go with being 48:17 lying down and and having a clot in your leg or anything else or having more 48:24 problems because you fall and have a head injury and so on and so forth so it 48:29 is the complications for the symptoms not the disease per se the disease does 48:34 not affect the breathing that's not a fair necessarily the hard per se that 48:39 are would be the organs that would you know most readily make you think that 48:45 you're having a problem with something that is gonna kill you okay the next 48:51 question is when you are Topsy the brain is it possible to have multiple findings for example can one have both PSP 48:59 and dementia with Lewy bodies how subtle are these diagnoses yes that's a very 49:06 good question as well because yes we can have more than one diagnosis and this 49:13 depends on how good our techniques are to look at these proteins that are 49:20 aggregating the cells this gluten aided proteins in the different areas of the 49:25 brain if someone doesn't look for something you don't find it right so here it is 49:31 important that that you look for them so at times there are Lewy bodies that 49:37 accompany PSP so yes they do occur and those are the PSP patients that have 49:43 hallucinations so I've seen those very very rare but does occur so there is 49:49 overlap at times it is said that there is a fatal attraction among proteins 49:55 that ones one agglutinates these two others to agglutinate and that's why at 50:01 times you have more than one protein and lutein ating that's why in dementia with 50:08 Lewy bodies at times you do have Alzheimer's disease in fact at times frequent that that Association may exist 50:16 so that is what is meant by fatal attraction in some ways okay we have two 50:23 questions related to imaging first about MRIs using to diagnose parkinsonism 50:30 atypical parkinsonism and also the new DAT scan all right maybe let's start 50:37 with the dark and that is the easiest the task can only allows you to say that somebody has parkinsonism but it doesn't 50:45 allow you to differentiate this different disorders they pretty much all look alike so do you really need a task 50:53 and not really because whether you have MS a where you have PSP where you have 50:59 the there will all look alike so it's not going to help you at this point if 51:04 you're slow and if you have tremors or stiffness you already know that you have 51:10 parkinsonism so that step is not needed and it's a lot of money that it's not 51:16 needed to be spent on the other hand the MRI it does show some features that are 51:23 as you so somehow pointing or supporting the diagnosis of the disease so in 51:29 Parkinson's disease the MRI is normal all the merese we can do at present are 51:35 pretty much normal but in MSA you saw that there are certain characteristics in PSP there are 51:42 others so it does help to find things that will support your clinical 51:48 diagnosis but as I show you well I don't think I show you but I will show the people that will come to our CBD 51:58 discussion later on that at times even the MRI looks exactly as the patient 52:06 looks and they may have the corticobasal syndrome without atrophy that corresponds to corticobasal syndrome 52:14 contralateral to the major symptoms but then the diagnosis is still Alzheimer's 52:19 disease it's not corticobasal degeneration so what it really points is to where the lesions are in the brain it 52:27 points to the atrophy that corresponds to where the lesions are and the 52:32 shrinkage of that particular area of the brain okay you mentioned you get 52:38 information from autopsies of brain tissue where do the brain samples come from are they are they donated if so how 52:46 do you go about donating your brain would you give the information to the family after the brain has been donated 52:53 well what I mean before was a study we did with multiple centers across the 52:58 world and that each Center gave us the 53:04 pathological samples and they gave us also the clinical information and that's 53:09 how we were able to put together both and we were able to come up and help make the different diagnostic criteria 53:16 so by looking at they are curious in diagnosing when you put both of them together you come up 53:24 with better diagnostic criteria how do you do about that well that is a major 53:31 gift that's a gift of life it's a gift of life for using it of life for us because as researchers we truly value 53:39 knowing what is the diagnosis that someone had and usually all the center's 53:46 can help but if there is not nobody that does I always try to link people with 53:53 the Mayo Clinic and robbing was telling me before that she does that very well so robbing can be a resource I mean the 54:01 internet I can help you as well this is usually something that would help 54:08 researchers always particularly we do have the clinical features from e-force 54:14 so it is usually important that the where you are being studied if it is an 54:19 an academic center that you let the people that are following you to know 54:25 that this is what you want to do I was explaining that for Liza physicians is 54:30 really very hard at times to say well you know we get to the diagnosis when we see the brain and you are feeling like I 54:39 don't want you to misunderstand I don't want your brain now I wanted whenever it happens but it's but it's 54:46 really an odd feeling you're always afraid someone may may misunderstand you and so at times if you can bring it up 54:54 it's so much better you make the physician happy and you make yourself happy and as I said it's a gift of life 55:02 thank you okay thank you and I would also just like to say that brain support network helps facilitate brain donation 55:09 arrangements and there's a flyer on the table outside if you're interested we've helped 125 families successfully donate 55:17 brains mostly to the Mayo Clinic is as dr. Littman mentioned here's a somewhat related question how often is a 55:23 diagnosis of these diseases put on death certificates so it can be followed in a database and is that important 55:31 unfortunately the certificates are not really good because usually what it they have is the cause 55:39 of this but it doesn't really say and the accuracy of those is very limited so 55:45 there has been they have been several studies that try to put together what is 55:51 the accuracy of diagnosis based on pathology versus that that has been put 55:59 into other certain death certificate and it doesn't help physicians that do it at 56:05 the last minute they just put whatever the family says and they're not going to go to look for something that would 56:13 support the diagnosis or may not even put it there so that's unfortunately not a good way 56:19 to go is there any research on possible causes for these disorders multiple 56:27 that's the hope that's the hope that counts there is a lot of research into 56:32 trying to understand the causes of this disease as Robin have mentioned we do 56:38 have a large study it's a NIH funded study in which we are 56:44 collecting the information regarding genetics doing blood drawings and 56:50 environmental factors occupational factors or people that have PSP and 56:57 their loved ones the caregivers as well as a control that they they choose 57:03 usually somebody that is an in-law if possible match by age to the patient and 57:09 we're discovering in fact a lot of interesting and important things 57:16 environmental exposures do count and genetics does count so it is important 57:24 because I envision a world in which we may know our predispositions and maybe 57:32 if we know what is it that leads us to have these proteins aggregate and have 57:38 these diseases maybe we can avoid that kind of a job or that kind of exposure and maybe we avoid a disease all 57:45 together but they studies occur we have one that 57:50 is multicentric in several centers in the United States and there are studies 57:56 for Parkinson's they have been studies for multiple system atrophy I'm not 58:02 aware of any for dementia with Lewy bodies that I am not aware of and the problem with corticobasal degeneration 58:08 is that we don't have an accurate diagnosis so that's why before going 58:15 into those type of studies what we decided to do is let's try to get our 58:21 natural diagnosis and then from then we can move on into trying to get the right 58:27 study so research is limited by the accuracy of diagnosis because if we 58:33 don't know ahead of time we cannot ask you things that are worthwhile because as you know garbage in is garbage out 58:40 so whatever you put in your gonna get out of that and so we need accurate diagnosis to make advances in science 58:47 and if we make if we know the cause then we're so close to get to the treatment 58:54 that's what we really want do all of these disorders include a lack of 59:01 dopamine and is that what causes apathy and depression most of this disorder 59:09 practically all of them include a lack of dopamine lack of dopamine is what 59:16 leads to the parkinsonian symptoms but lack of dopamine dopamine does not lead 59:22 usually to the apathy it is thought that the apathy may be more related to 59:29 serotonin a different neurotransmitter but we don't have a real good handle on 59:36 what causes apathy on the other hand we do have a much better understanding and 59:43 what causes depression and dopamine but more important in noradrenaline 59:49 serotonin really contribute to all of all of these neurotransmitters 59:54 contribute to depression but it's very important to separate what is the and from apathy because if you are just 1:00:02 not doing things and you're kind of sitting there because in part you cannot 1:00:10 do things but in part because you're not really willing to do them you're not having that mmm that made you move for 1:00:18 things but you're not unhappy you're okay your mood is okay you're not unhappy 1:00:25 with the world then you don't have depression and if you're getting treated for depression it's not gonna help 1:00:32 because it's you have apathy and if you have apathy you treated with 1:00:37 antidepressants and it's not gonna go away as most of us here today are way 1:00:43 beyond the early diagnosis stage and associated treatments is there any 1:00:49 reason for us to have continued studies and tests or are we just putting our 1:00:54 loved ones through additional trauma and 1:01:01 this it depends on how you value life and how you value service to the 1:01:06 community and service to science and it's a very hard thing to say certainly 1:01:12 when you have a diagnosis you can help others more likely you're not going to 1:01:18 help yourself and I think all pretty much all the scientific studies do stress that 1:01:25 whenever you're part of a trial we never said this is gonna help you we never 1:01:30 know that and maybe it can but at times 1:01:36 you can't at times we really know that this is not gonna happen and we really say that but do you want to help others 1:01:43 that's really depending on each person and that's you know this is a decision that is more on personality on being as 1:01:51 you are but it's so American to give to others I have learned things here that I 1:01:58 have never never learned them in other places I lived in Barcelona in Spain and I can tell you that Europeans don't 1:02:05 think like Americans they really think more on this is something that we want 1:02:11 to do for ourselves but not really for others so I don't want to be a guinea pig and do this or that and 1:02:17 here I never hear that I mean we would be extremely rare with my more than 20 1:02:24 years of research I would say I never heard it here but I did hear elsewhere I 1:02:30 think Americans have a different way of seeing the world and is so relevant are 1:02:37 any of these for a typical parkinsonism disorders genetically carried on most of 1:02:45 the atypical parkinsonian disorders are what we call sporadic that is non 1:02:52 genetically related so that is one thing that most of you should know if there is 1:03:00 nobody in the family that has this disease or similar very related diseases 1:03:07 you're not gonna transmit that to your kids so that's one thing that gives a 1:03:13 little bit of a relief if you do have multiple family members in in your 1:03:21 family that do have something very similar to what you have it is very 1:03:26 likely that this is familiar and there is a gene that is really determining 1:03:31 that but that occurs in less than 10% times less than 5% of the people so it 1:03:38 is rare it's very frequent do both do all of these disorders have symptoms of 1:03:45 inability to swallow saliva and drool well in more or less degree as you saw 1:03:56 it comes to a point that multiple symptoms go together and swallowing 1:04:04 disorders are common they are as it is 1:04:09 having speech problems and as more problems you have with speech the 1:04:17 likelihood of having swallowing problems is alike so in the majority of these 1:04:23 disorders that is a major even in Parkinson's disease is a major 1:04:29 issue one of your slides mentioned frontal dementia what is this frontal 1:04:35 dementia is when you do have difficulty being CEO we are all CEOs in our world 1:04:46 some of them some of us may be of big company some of us is from our own 1:04:51 houses but still you have a function of planning of multitasking and trying to 1:05:01 do the best with your own finances as possible right so when we lose those 1:05:08 abilities that are located in the frontal lobes that's when we have 1:05:14 executed this function and when those problems are so severe that actually are 1:05:20 impairing our functioning that is when we call it the measure usually it does 1:05:27 accompany some changes in behavior in most of our diseases is apathy there is 1:05:34 also some impulsivity doing things that may not take in consideration the 1:05:43 consequences for example someone that may have difficulties walking and 1:05:51 difficulties with balance may see a little paper in the middle of the of a 1:06:01 room the living room and they say and I'm gonna go and get it and suddenly 1:06:07 when they get up they just fall I said then the clerk in your cousin says but 1:06:13 what why don't you tell me and I think that difficulty with controlling the 1:06:20 impulse is there so you go to the airport you said sit dear I'm gonna go 1:06:26 and get the luggages someone gets up and starts walking and then again there is a 1:06:31 problem and that is truly what we meant by difficulties and some 1:06:39 dysfunctions that are disruptive of life when they disrupt life in significant 1:06:45 ways that's when we call it dementia but it's a different dimension than Alzheimer's disease it's not a memory 1:06:53 problem that keeps asking and so you know what happened that you don't 1:06:59 remember things that it's a different story it's not that you don't remember what 1:07:04 you had for breakfast you may have difficulties retrieving spontaneously the information but the 1:07:12 information is there you're always there so as if for example somebody calls and 1:07:19 you spontaneously don't say who call but then if somebody else ask you who call 1:07:26 then you say oh your uncle call I forgot to mention that that happens to all of 1:07:32 us of course but if it is in significant ways then that is different so is having 1:07:40 this difficulty in retrieving information that is there the difference with Alzheimer is that the information 1:07:46 is not even there here the information is in the brain the difficulty is retrieving it that's all the time we 1:07:54 have for for questions thank you so much 1:08:01 the preceding program is copyrighted by the Board of Trustees of the Leland Stanford junior University please visit 1:08:09 us at med.stanford.edu