 First, I'm going to just state I've got a lot of slides and I made this with the concept that if anyone has sufficient interest, and I think this is a high-interest topic, because like Chris Rock said, when people used to disparage homosexuality and he said everybody's got a cousin, what's the problem? And dementia is sort of like that almost everybody has someone in their family or someone they've known well who have suffered from it. So I made a PDF and it's also listed on the website for Science Circle. And I tried to make these slides as standalone for perusal so that you could go and review them, look up more carefully on issues that you wanted to see a little more information or look at the references for leads or guidance and to finding more information. So I'm going to hit on a lot of things clansingly as I go through these slides. This first slide, I just thought just for semantics, I thought it would be worthwhile pointing a few things out. One thing is syndrome, often hear the word syndrome. Syndrome is not a very strong word, it basically means you see something, you don't know what it really is. Disease has usually a more defined etiology and the symptoms are better understood. The rest of this you can read for yourself. I'm not going to read the slides, I'm going to just paraphrase the points I think are important. On the second slide, it's just a listing of some of the topics I'm going to hit on in terms of etiologies. There are over 400 known etiologies for dementia. Dementia is sort of a syndrome whereas a lot of disease processes will lead to it. There are many conditions that are like this that have degenerative processes leading to common outcomes because when a system gets damaged and whittled down its levels of function become more and more limited and the range of function becomes more similar, I guess. All right, areas of the brain just so that we're talking about the same things. As an interesting point, I thought from the triune brain of in the 1960s, Paul McLean wrote about the triune brain, which refers to, well, some people talk about the head, the head, heart, and gut brain. Also the reptilian brain, the paleo-malian brain, or sort of the limbic brain, and the neocortex. Neocortex is all your thinking gear. The reptilian brain is, this has been tortured a little bit because Carl Sagan made a comment about it, but it's kind of interesting. He talked about nuclear weapons and the reptilian brain that we all carry around deep inside us involving brainstem and cerebellum, but I think it has to include limbic system, a simpler limbic system than in higher organisms, but reptiles are not totally organic machines. The paleo-malian brain includes the limbic system, which is involved with learning along with the hippocampus, and mcdala, and hypothalamus, and a lot of emotions are based or dependent on function in that level, and then the neocortex. The neocortex here, you have all these foldings of the lobes, the frontal lobe, which is where people say you make your executive decisions, and the parietal lobe, you have the sensory motor and the sensory and the motor cortex adjacent to one another, and occipital lobe in the back, and the temporal lobe on each side, and there are a cell site like the lateral fissure and central sulcus that separate the various lobes. The occipital lobe, it's kind of interesting, I just throw in a little story here and there, I had a patient resident came into the emergency room and I was on duty. He had been hit and he was brought in, he had been hit in the back of the head with a baseball bat and he was blind, and he basically had a contusion of his occipital cortex. Next morning he could see that was a wonderful thing, it recovered, but your brain can't take too many whacks like that. You get your oatmeal jarred and you get axonal shearing and damage of all these little fine dendritic connections. Let's see, I gotta remember which button to click here. You have certain areas of neocortex, yes that was a hit on the back of the head, the part of the skull where he would have the skull jolted forward so his occipital cortex would get compressed. You have dedicated areas like Brokaw's area and Wernicke's area for speech, understanding and speech processing, and auditory cortex and some of those can't be made up for if they're lost due to stroke or anything like that. You also have ventricles or fluid filled spaces in the brain, you really don't have lymphatics in that central nervous system, but you have two large lateral ventricles which are in each hemisphere in the forebrain or the prosencephalon, it's actually of the prosencephalon, this is a telencephalon part we're talking about. These ventricles are symmetrical and the embryo doesn't even have defined hemispheres in the neural clump that's turning into brain until two months and it's pointed out because I think it's worth noting that embryos are not babies. Propaganda and false semantics will make arguments about that and you can believe what you want but they're not babies, they're not first three months is the embryonic stage and then it's fetus of second six months of the terms, but any rate on neurons just to talk a little bit about its structure, they have a soma or body with a lot of dintrites that can cook up with a lot of other neurons and take in information and it processes it and weighs it and then it shoots it down an exon, you can trick new neurons into having more than one exon but generally they have just one exon and human anatomy in particular. If it's a myelinated cell it can do it much quicker, it has this deionization process, it runs down the cell membrane but it can jump, the impulse can jump from node to node of these little spaces between the myelin sheath that are created by the oligodendrites, those are called nodes of Ranvier, you get multiple sclerosis, you get autoimmune attacks on your myelin and oligodendrites and it causes sensory and motor dysfunction. The cell types aside from the neurons are very important, these appendable cells, I won't go much about those but they're in the, they're lining the ventricles and ventricles, there's an area called the curate plexus which is where the CSF or cerebral spinal fluid is produced. It's very similar to serum except it doesn't have protein unless you've got an infection, shouldn't have blood or white blood cells or some other things too but and I guess one way to, if you have a leak of fluid from the middle ear to the external ear through a perforation or you know you think somebody has psoriasotitis, just middle ear fluid and you put a tube in and they get leaking and you test that if it has a lot of glucose in it then that's cerebral spinal fluid, it's not middle ear fluid. Microglial cell is a big actor, it is a, it's your killer cell, it's the earner for inflammation so you want them to be doing their job and facilitating but not attacking. The astrocytes a supporting cell and it helps maintain everything that facilitates a lot of functions and the oligodendrite wraps itself around the axons. Here's a slide which defines a little better what each of these cell types. I left off the appendable cells and this hasn't resed for me yet but glial cells are these non neurons in the central nervous system but they are all from neuroectodermal derivatives meaning when the embryo is just a three-dimensional disc shaped thing on the dorsal, it has an orientation ventral dorsal, ventral is the front, the dorsal is the back, it's a way to think of and it that will be maintained to adult form. Epithelial cells on the outside are ectoderm and those infold and form a neural tube and then that undergoes all kinds of morphologic change developing into central nervous system including the ventrigals and everything else. So any questions for the moment at this point? Dementia, what is it? Defining it is a trick. Basically you lose your ability to figure things out and process the way you had been doing. It can present in lots and lots of ways. They're like I mentioned I think 400 plus ideologies for dementia so you can have sort of defining arrays of presentations and a lot of other things seemingly left normal. Categorically cerebral vascular disease which is of which this multi infarct dementia is associated. It's the second leading cause of dementia and Alzheimer's is the most common and Alzheimer's itself is part of another category. This slide just lists some of the main ideologies associated with dementia. I'll point out that AIDS HPV infection untreated can lead to dementia or be associated with dementia and that's accelerated apparently by meth. I'm going to focus on the ones that are in bold print. Cerebral atrophy category that includes Alzheimer's. I should be consistent and say Alzheimer's disease but in this case I didn't. I'm going to tell you about some of these others. Is this pace okay? Anybody? It's the pace I'm going okay? Good. Frontotemporal dementia basically lose cells and get shrinking or atrophy of the frontal and temporal lobes of that part of your neocortex particularly. There's historically a disease called PICS disease. There's been ongoing discussion coming to a consensus that gets revised and re-hammered and classifications is a significant part of the community activity known as science so there are other types of presentations, other terms that are more specific to a specific presentation but would fall under this category of frontotemporal dementia. I'll mention semantic dementia in a moment because I again because I think that's interesting. Cortical basilar degeneration. The basal ganglia are you have the cortex and they relate to clumps of specific cells referred to as basal ganglia which has also been reclassified to include substantia nigra which is down there in the midbrain but there's an interesting word I thought I would throw in here, nosology from nosos for is Greek for disease. I think this came around in the 1700s or so but it's the study of classifications of diseases in medicine is referred to nosology and they talk about it's a nosologic arguments have led to inclusion of this disease in this category so if you'd like words there's one for you it might show up in your next puzzle. So more about frontotemporal dementia I just put that at the top for keeping people on track. Semantic dementia is kind of interesting they talk about loss of conceptual knowledge. I remember I took an abnormal psychology class in college and one thing our professor kept emphasizing and maybe it was in his experience that the last thing people tend to lose is the thing that had been most natural and most deeply ingrained and integrated into their makeup horrible joke about you know brain injury or surgery on the brain that I don't think was told by a doctor I read it once and somebody said there goes the panel lessons but that's sort of a reflex this sort of concept. I don't like jokes about this stuff because I'm not I'm not criticizing anybody I love chocolate I'm not I'm not referring to that I'm thinking of my own personal experience of really coarse things I've heard people say when they were looking at somebody's tragedy it just ticked me off brain MRI I'm going to tell you a little bit more about brain MRI oh I know you weren't joking I would I noticed that just as I started talking about that I was talking about my own personal experience in operating rooms and like a child that had an airway obstruction we hear a lot about obstruction of justice I used to deal a lot with obstruction of airway and this child almost died from a chunk of carrot some my grandmother gave a child a chunk of carrot and she aspirated it and he couldn't get it out we had to shove it down into the right main stem bronchus to be able to ventilator to get her oxygenated better and then got a hold of it and brought it out when she was more stable and this damn anesthesiologist said as she was waking and see if she's going to be a republican or a democrat I just have listened to so much dreck over my years people I would have loved to just punched in the nose if I could have just been dealing with my reptilian brain but you do that you lose it's like when you curse you lose if you get into a discussion well anyway this MRI shows the characteristics this is pretty extreme I've always liked looking at radiologic figures and I go to tumor boards still every Friday and we get scans and CT's and this distinguishing characteristics I would see that struck me was atrophy of the brain with deepened salsa I could see there was less substance to the brain and here you have especially in the front which is at the top loss of substance and the ventricles those big of curved structures that are symmetrical there in the center they're too large in the left one you're seeing fluid is the white so the the dark is fluid in this the two images on the right and not the cellular stuff has grayscale appearance so this is pretty serious loss of brain functioning brain prankama now that's a good point it's easier to spell almond which is where amygdala comes from one point about frontotemporal dementia particularly in these this is one tragic thing that you got families that suddenly have a member that goes crazy becomes promiscuous and spending all the money and just behaving weird or withdrawn or loses their facility with speech and you see mental changes like that it's that's really an important part of figuring this stuff out as good history and especially longitudinal history getting information to figure it out absolutely depends on a good historian and the family who come use the patient because so often patients won't tell you about stuff I'm going to try to talk a little bit about things people might be able to do to improve their chances of staying intact so you see changes in behavior changes in language social and language development go parallel children have language delays often have a delay in social development as burgers and all timers as burgers and autism are example of that and so in decline you can have the same thing um louis body dementia now louis bodies are a characteristic of pathological finding it was first associated with Parkinson's disease and they can happen in number places in the brain but there's a type of dementia that's associated with these abnormal clusters of alphas and nucleon and they look like this this is a creative commons slide so I didn't have to ask anybody's permission it was already granted waiting for it to there it's resed for me these like upper left hand corner of these dark blob that's that's a cell it's intracellular it's a neuron that's full of this alphas and nucleon inclusion and oh one other thing this is actually substantia nigra and if you look at this and you see what look like little dark dots that's a neuro melanin uh is the reason it's it's the area of the brain that is it has a visible appearance you can see it's a little darker so it there's a type of cell that produces dopamine that gets damaged in Parkinson's the synnuclein uh uh s n c a gene for the a is for the alpha at the end uh synnuclein alpha gene finds uh the instructions to make this little protein and uh it is thought to have some role in helping maintain the supply of neurotransmitter that is held in and uh presynaptic of vesicles I misspelled vesicles there but my bed it's not the last time I'll ever misspell anything I guarantee um so these inclusion bodies I'm going to talk about this more generally associated with dysfunction of the cell they actually tend to bugger up the cell by uh blocking axiplasmic flow these synnuclein tends to be uh down in the uh tips of the axons near the synapse and uh it can impair its function it's uh by the way once you run out you don't have adequate uh synaptic synaptic vesicles uh with neurotransmitter you are out of ammo you're not going to get nerve talking to anybody among the other neurons in the area okay alcohol uh alcohol ethanol don't even think about methanol um which like uh sternum like uh built down in elders will drink mixtures that uh is denatured alcohol or whatever just because they're so desperate um but uh alcohol is a neurotoxin and I think you should remember that it also is loaded with calories and I know there's a lot of uh stuff out there um promoting alcohol in a sense saying that uh people drink alcohol tend to hold up better they don't get reservatrol from bedwine and all that but you need to be very careful about ingestion of alcohol and very careful about how much of it you ingest um there's a very serious condition a type of dementia vernicke korsakov syndrome I've seen patients with this uh it has two conjoined findings retrograde amnesia they don't know what they were what they've done in their life or where they came from they can't and that can be a varying uh uh degrees of severity and anterograde meaning they can't learn anything they can't remember anything sometimes there's some of this is reversible if they simply quit uh drinking but these are people who have been abusing alcohol for a good while maybe a decade or two and uh particularly with binge drinking and uh it's some interesting points about it I can get this to res here that's the same slide as I had before I think just about okay if you ever worked I've worked in factories back when I was uh younger also lived in a car and things like this I had no address for times but uh it's hard to do that when you're older I don't think I could survive it now through the winter but uh uh Rebold's law is uh he's uh someone that's uh studied uh the neurology of amnesia but he made an issue of the last and first out just like in factory work the last person hired is the first person fired uh the most recent memories tend to go and there's this old concept that uh uh similarity which when I was young seemed to be the common path in aging uh people became like children again and they remembered their childhood memories and they'd end up wanting to tell you the same stories in and again they were living in those days again they everything else had been stripped away somehow my phone just sang a song um one last point about this kind of uh dementia uh impaired temporal localization of past experience everything runs together whatever they can remember seems like it all happened about the same time and it reminded me of Janice Joplin I played a concert last night uh I did two gigs last night and one of the guys I played with he's a he's a trumpet player but he actually used to do gigs in San Francisco and uh played with Jerry Garcia that and uh Janice Joplin uh knew her and he turned down a job as a drummer to Glenn Miller band point uh this guy's pretty interesting but at any rate um just thinking of that uh when I saw him last night because I put Janice Joplin with all respect to her she was an immense talent but she almost certainly was alcoholic she always had uh a bottle of booze usually whiskey with her on stage and one time I heard her say it's all the same day man it's all the same day and all these people would yeah yeah it's all the same day you know it sounded like a cool thing to say but you know that was probably the experience she was starting to feel that's what has occurred to me in retrospect so there's also something quite sad she was 27 like Jim Morrison and Jimi Hendrix as well she died I didn't even make it to 35 like Mozart um but uh that's her picture when she was a child there's something sort of sad that it can happen when people age and I want to run through something I think is interesting and particularly the V vitamins is to quick jaunt through that and and if people want to look at it more they can go to the website and pull up the pdf but Berry Berry is historically important and was associated with neuropathy and whips and so uh you gotta be one the founder that you have polished rice it takes off the husk and the has the uh vitamins and it's just starch uh so if you don't be one and in other words take be one and your diet especially you'll be stumbling and numb with ataxia or trouble walking and weakness and you have a risk of dying of heart failure also an interesting point was too much coffee or tea can deplete it but Bernice Corsicoff sees binge drinkers they tend to have very poor nutrition alcohol used in that much excess tends to supplant any semblance of a normal diet and it also seems to have impact on health process and even its absorption so they tend to get severe vitamin deficiencies and that causes the generation and death of medial phylamic cells that are needed for processing memory and the cerebellum which is where you get the stumbling around so any rate I thought that was worth pointing out alcohol abuse is a big reason or a big risk factor for be one deficiency I'll just run through the others real quickly and I want you to note in the center column I think as it rest for me but yeah central nervous system problems that can arise from deficiency of the like riboflavin which is B2 brain dysfunction that's a little general B3 which is niacin you can have loss of memory dizziness it's still resing here we go pelagros insanity you have mental changes that are pretty severe it's one of the points in this so never we are dealing with the people so I'm not in practice now but I saw a lot of dementia always tried to see if they evaluated properly but you want to be sure that you're not just shrugging it off and missing something that is treatable I mean that's really a horrible thing if you have somebody that comes to you for help and you miss it so that takes a hell of a lot of time and it a lot of energy and if you really do your job that way as a physician you're tired as hell at the end of the day because it takes so much emotional energy to get into every patient's brain or the family's brain and figure out what's going on okay vitamin B5 these people that designated the B vitamins were apparently didn't like four and eight and things like that but panthentic acid which can cause encephalopathy and behavior change you can get these B vitamins from lots of sources or you can kill sentient animals like this cow I threw this in just as a I like this picture I when I was a kid and I was very isolated on a remote primitive farm and we had a lot of books but I had no kids anywhere no people in sight it was a clear day way down in this valley I could see a little house often the fairly vast distance when I was upset I felt like the cattle were concerned it was a deep instinct in me I think that there's a lot going on in these in the minds of these animals just like they if a if a calf is making noise they want to see what's going on with it they come over to it they I don't know if they can cry but they can sure feel fear and they want to live just like you do so it's easy to eat them I guess if you don't have to see them get killed and slaughtered and skinned and butchered but that's just a personal point so B6 is also associated with autonomic dysfunction and cognitive decline and dementia of alcohol abuse promotes it B7 is biotin which can be associated with hallucinations and seizures and when it's at a low level this is a picture of pig about to get slaughtered so I put that in there you don't have to eat pork to get biotin right you can maybe it'd be good if you had to do it with your own hands but any rate this is something I'm kind of I'm kind of the whole package here I am take it or leave it but B9 is folic acid and it can affect behavior and cause dementia if it's in severe severely depleted and Alzheimer's disease it can be associated with low levels of folic acid B12 there's a lot of ways to get B12 nowadays you don't have to eat meat to do it in the old days like in World War II if you wanted to go in the Navy and you found you were nemic they'd say this is something that happened go eat some pork liver for about a month and then they would get a lot of B12 from that but you got to remember the people trying to go into military in 1942 they'd just come off a depression and there was a lot of malnutrition in the United States but B12 can also be associated with dementia it's particularly associated with megaloblastic anemia and lack of intrinsic factor that helps absorb it in the GI tract and the same cells form acid so you have aclurohydria meaning no acid in the stomach people with that condition pernicious anemia like that tend to get stomach cancers in the long run one point I would make about B6 is that I'm waiting for this to res here it's supposedly potentially injurious to large sensory neurons and so you need to be careful about how much of it you take and I want to point that out because I look at energy drinks and the content and energy drinks seems to be pretty high and fortified cereal I would think so it's fair yeah I would think so these are all water soluble vitamins and if you have a normal absorption if you've got an atrophic GI tract or an old absorption for medical reasons you may have problems no matter what you take orally but for the most part the B vitamins are pretty safe to take I would emphasize also that too much niacin sometimes people take niacin to help reduce cholesterol it's an alternative to statin but you have to take a pretty high dose but it is potentially hepatotoxic so here is a list of the eight B complex vitamins be 1 2 3 5 6 7 9 12 4 8 10 or 11 so anybody ever gives you an IQ test and says what's the next number in the sequence and they say 1 2 3 5 6 7 9 you say 12 so you're memorizing the eye chart okay so again dementia you're starting to lose your stuff dysfunction from the expected particularly the expected for one's age and it can be in varying degrees of severity of course and all that needs to be documented carefully I'm going to go into that in more detail to more formally state characteristics of dementia you got to look at this and think about how would you create oh a screening that would be applicable to any patient any patient regardless of their language usage or lack of ant language or um being of uh having a foreign uh or a mother tongue that's different than the language in which you'd be testing and uh what about blind patients blind since birth of the lost division after um ability to focus and pay attention all these things can vary so much uh one thing that you can use I really don't know of other tests there are other tests by I'm not familiar with them but this one this one I knew of um it's a questionnaire that can be administered to screen for dementia and there's a score that's given even for people in a coma and you think how would you say that somebody in a coma has dementia well you can't specifically uh based on that uh wouldn't want to say they have dementia until you see what their performance is if they emerge from the coma really but there is a score for someone in a coma who has no response there was an old national lampoons which was a spoof type magazine and dan blocker was hauls on bonanza and he was a big guy and died of a heart attack earlier and national lampoons had an interview with dan blocker after his death and they would ask him irrelevant questions and then they would have they had it as a questioner and then his answer every time they showed his answer it was blank and um so it's sort of like testing someone in a coma I guess so any rate that's just for general information okay let's talk about specifics 1906 this guy in the upper left um Alzheimer reported on he was working out of uh Frankfurt I think uh in uh at a clinic and he reported on a patient he had followed for about five or six years um who had a severe dementia and uh she was young like 50 years front set so he reported this to a group um on the 3rd of november 1906 and um I have the the details here the symptoms she she had paranoia that's not unusual and demented people paranoia also guarding and trying to cover up their uh failings especially earlier on when they they have awareness they have some insight and they don't want anybody to see it and sometimes they confabulate they'll make up junk just so that they're giving an answer and they're kind of trying to satisfy the questioner um sleep and memory disturbance aggression confusion all those things are very typical and um oh the one thing I wanted to point out is paper excited little interest a few years later he pointed reported on a few other patients uh later one without some of the morphological changes uh on autopsy um and pathological examination of the brain but uh he died in 1915 never got to know that he was a household name household word uh which is often the case it's like great artists often die and despair and then get discovered so plaques and tangles are the big deal the plaques are the beta amyloid plaques and there are tangled bundles of fibers nft neurofibrillary tangles particularly tal tangles I'm going to talk more about tal and talopathies dementia is associated with uh abnormal tal um protein accumulations major feature in this is loss of synapses even if the cells don't die they just can't function synapses break down and um eventually there's atrophy loss of brain volume and uh uh death at a point um in 1984 uh the criteria for Alzheimer's reflected the viewpoint of the day um it makes me think of um oh politicians uh behaving badly when they're younger without uh any realization of the bigger picture and uh um viewpoints change and sensitivities become more extreme and then they're in trouble as we see in Canada um at any rate um in 1984 memory loss was it if somebody lost their memory that was started that be considered probable Alzheimer's um and Alzheimer's is absolutely confirmed on autopsy most often still is but we're having biomarkers emerged and that's really important and uh I'll talk a little bit about that in a minute 2011 there was a uh another uh nocologic uh um coming of minds uh to try to sort out what should be considered Alzheimer's and so they revised the disease uh criteria and uh getting it up to date they talk about it in three stage in early pre pre clinical stage with no symptoms and have Alzheimer's and no symptoms that's really important that's acknowledging the fact that these changes start or apparent and then middle stage of mild cognitive impairment um where there can be word finding difficulties and um I've got a little bit more on that in a bit but uh uh generally those people can still drive and uh manage their bank accounts and then the when they enter the final stage they become dependent on other people um so word finding as I mentioned down here is one of the other symptoms that can become uh um um noted as and lead to the diagnosis of Alzheimer's not just out and out memory loss okay these are busy slides but again it's uh intended for people to be able to go back to them and get something out of them often slide shows you just get bullet points and you can't go back and read much out of it but um um there they also tried to acknowledge all these other things you can have all kinds of multiple ideologies going on for a presentation of dementia and uh Alzheimer's may not be the whole story just like a person can have umaryngeal cancer and lymphoma at the same time uh vascular disease is a is a big player there as you can often have people with Alzheimer's also vascular disease and it seems to potentiate the problems um any ideas why uh they did not declare biomarkers uh as one of the criteria for diagnosing Alzheimer's and the answer is they don't know exactly what's going on yet I'm going to try to lead you to what the best most intelligible current idea is in a few minutes here but uh I think that's an important point there are no definite biomarkers there landmark changes like the plaques and especially the neurofibrillary tangles with the tau proteins but that's dependent on either brain biopsy which is sometimes done or a an autopsy so here on the preclinical changes you're starting to get amyloid or tau protein build-up and other nerve changes might be apparent if you were able to look at it but uh getting the mild cognitive impairment you're starting to have and um uh their problems are a little bit out of balance with what you would expect for their age and um also their background you have to take into account a person's educational background that they can uh people with more education and uh more uh language usage uh will tend to be able to offset any apparent uh effects of Alzheimer's longer um so earn and read everything you can it's uh every synapse you form helps save your life um finally Alzheimer's dementia is the final stage and that is a lot of damage done by that point okay i'm waiting here for it to res oh in terms of genetic testing this is a review you have early onset and late onset and there's a couple mutations uh in amyloid precursor protein particularly uh that can be detected by uh um testing um and if you have a family history that probably is worth doing but you only you have five percent or less generally is a typical number you see in the literature about how presentations are genetically based uh for late Alzheimer's uh late onset Alzheimer's disease you have this uh apogen on chromosome 19 and um it's uh a gene that is um it's an apolipoprote let's see apolipoprotein e um it's related to or one of these types of proteins that helps carry lipids in the bloodstream so any rate um there are various alleles that can be damaged the e4 um is one of uh interest here uh for this these new criteria they uh don't recommend genetic testing for apol mutations outside of research now i have a friend who's a physicist who's the best mathematician i've ever known um and uh math is dear to my art so i position to appreciate his abilities but uh he was telling me um i could say his name of course but he was telling me uh he got testing and he was found to have positive apo uh a mutation on uh one of the um chromosomes but he was heterozygous um uh was just one chromosome the other chromosome was okay so he was enrolled in a study and they did PET scanning tell you about PET scanning for and um i don't think his testing was 23 in me i steepens vane or something but um uh at any rate um they threw him out of the study um he was somewhat depressed to be in such a study again with but they threw him out of the study because his PET scanning showed no beta uh amyloid uh accumulations so uh that was a good thing i think so i'm going to talk about imaging techniques there is so much physics and so much fascinating history in um uh the development of these things magnetic resonance imaging and anyone know what gadolinium is i was in a conference once with someone it was called pimping they pimped not pimping like on the street yes it's an element and i i knew uh i knew you would know it's a contrast agent when it's uh in uh coordination bond uh system with uh some organic molecule uh sort of like iron in the heme molecule uh but uh it's an element uh a guy asked a bunch of relatives of residents they always talked about MRI with gadolinium and he says what is gadolinium and nobody said a word but it's an element um atomic number 64 uh it's a lanthanide and it's right in the middle of the lanthanides the lanthanides and the um um i want to say actinic uh and atonines i'm shyza but um the uh second the the period seven um actinides yeah i was blocking because i had um other a words popping up in my brain uh those um lanthanides and uh um actinides are uh where the f orbitals get filled um you can figure out the periodic table if you can remember that um there's one s orbital three p orbitals uh five d orbitals and seven f orbitals there are odd numbers there's an easy uh calculation to figure out the maximum number of electrons uh in any shell if you do uh the arithmetic progression of one plus three plus five plus seven uh or um um odd numbers up to up to seven and um double it because each orbital can uh hold two electrons so uh anyway um an element is paramagnetic if it has um uh unpaired electrons it means it can take on uh magnetic properties uh gadolinium in certain situations can also be ferromagnetic but um uh yeah gadolinium's a lanthanide it's in it's in that first uh row of the f group or the uh lanthanides of the um it's it's in the um sixth period i guess sort of right before you get recess you know um anyway um it's great as a paramagnetic uh um uh element because it's got uh like seven uh seven unpaired electrons um now one problem with it it can deposit and rain and other tissues uh and uh there's concern about it damaging the kidneys um they try to make uh don't play that but uh it's not trivial to give someone lanthanide a uh gadolinium contrast there is there has emerged in a bread about this i thought it's a brilliant uh uh uh a ligand and biochemistry ligands are generally molecules that bond uh to another molecule or receptor but uh in this case it's we're talking about coordination or dative bonding uh a metal within our compound and manganese is element 25 it's halfway through the uh d um block meaning um it's got five uh orbitals and so manganese has five unpaired electrons so it's pretty good as a paramagnetic uh element um i guess because of the way the atoms sit together the pure element of manganese is not ferromagnetic but uh they're too close together but um uh manganese can be come a replacement for gadolinium and uh probably will and uh the testing they did it showed no aching and uh or loss of the man of the manganese into uh tissues it was excreted through the kidneys um functional MRI i'll talk about that in a moment um um there's iron iron uh in excess can be dangerous uh um uh potentially toxic too but um manganese is a normally found in human physiology uh the highest uh element that's really a component of human physiology or mammalian physiology is iodine which has an uh it's one short of uh xenon i guess it's it would be um and the uh the fourth i think it's let me the fourth period but um um so i'm trying to think again but iodine uh xenon and then cesium and calcium uh cesium and calcium barium barium uh and barium is a little heavier um but iodide is a um atomic weight of 53 and uh that's pretty dense compared to you know nitrogen oxygen carbon and hydrogen so it's um uh pretty good for absorbing x-rays contrast agents used in ct scans are usually with iodide um uh nuclear medicine techniques are really the thing that are so cool positron emission tomography and these speck scans which i i don't see i i think that pet scanning is going to supplant specks uh or uh single proton emission tomography techniques um just a quick note um another just a salt timer uh didn't get much note of his work uh ct scans are pretty cool um uh acormic i'm not acormic acormic and how holmesfield um are given credit for developing the ct scan um the um um house holmesfield is a really fascinating guy he was uh he's british and he was in the royal british air force i think and then he ended up going to uh he learned about electronics there and radar and uh then uh went to the um uh faraday uh uh school uh college in uh uh i think in london and uh which is respected among engineers though he was uh i don't know some have said he wasn't a certifiable engineer he wasn't that level of training but he was a brilliant guy and clever and he was on a holiday and he had an idea if you had a box you could see what's in it by shooting particles through it and looking at it at all angles and um it was a bit like faraday who was largely self-taught and burned by discovery uh and uh in my thinking anyway so um uh he also created the house felt uh units um house field units i'm going to germanize his name i guess but um um that compares it's a brilliantly simple um linear uh measure of absorption of x-rays and looks at air is negative a thousand and water is zero and um dense cortical bone comes out to about a positive thousand but um at any rate uh iodide is uh or the iodide contrast can have house field units uh over 300 uh and its absorption um um barium is a bit higher but it's a bit heavier so anyway i thought that's another example of this so much interesting chemistry involved in this stuff uh magnetic resonance imaging was uh first reported by uh reyman demedian uh 1971 and he actually did the first whole body uh mr images in 1977 78 one last point i'll make this other i remember the first time i saw a ct scanner and they were just so pixelated they looked like a ti for a um a toy computer which had i think four kilobytes of ram or something and it had games that would show black men like lego men fighting and shooting and um they were slow and the ct scanner was not much better um general electric got involved in that early didn't save them in the long run but uh uh one of the things i admire about humans is they see something and they say we can do better we can make this better uh that along with just the intellectual curiosity and uh discovery and understanding and artistic expression i think all of these of sorry somewhat despicable species were in a rate and you look at all the damage we do magnetic resonance imaging with uh gadolinium that's in in a uh organic molecule uh that no belt price for that went to competing scientists and demedian was totally ignored and um that was uh looked at with some regret in the long run um but it seemed unfair um but uh not that these other guys didn't do good work but um uh i guess uh fair news is nothing to do with it functional MRI i think is a beautiful concept uh ogawa is a japanese researcher he used to work for bell labs i think and then uh he's been directing this uh research facility in japan for a long time now but he realized that uh you know you have hemoglobin at the pulmonary artery comes out of the right side of the heart with poorly oxygenated blood and goes to the lungs and then the pulmonary vein comes back to the left atrium with uh oxygenated blood so you have deoxygenated or deoxy hemoglobin in higher levels going to the lungs and it comes out oxy hemoglobin and uh ogawa recognize that um there are different MRI uh imaging attributes to each of these so uh he exploited that to develop a way to look at blood flow um in the brain and the ideas that areas that are actively um are more more active are burning off more uh um uh energy need more blood supply so uh functional MRI i think is here to stay that's a pretty cool thing and nuclear imaging techniques i'm going to fly i've seen i've talked a long time here uh the positron emission tomography um uh can be used with a CT scanner or they it can be a uh mathematically fused or by algorithms fused with MRI images i spoke with a radiologist yesterday about these things um when i asked him about his current use of spec uh he said that they use uh radioisotopes that are the same as for PET scans they're not using uh for for brain these um gamma emitters like radio i died would be used to uh to image the thyroid gland and and the scans of organs that way using radioisotopes that emit gamma rays that can escape a patient have been used since around 1953 but um uh this i threw in just so you'd have a picture of this is a spec scan just showing how certain areas light up um and in this they were talking about uh this is from an NIH thing they were talking about how uh alter the imaging a little bit and uh enhance the uh resolution but uh you can see where um it detect uh levels of higher metabolic activity with uh these agents now the PET scan has about three times more um sensitivity and higher resolution and you can use the same machine as the CT scanner in a PET scan so you don't have to put them machine take them to another and the um of of of of chlorine uh fluorine team isotope which is produced by a cyclotron cyclotrons were invented in 1925 by Lawrence who uh had element 103 named after him he was at the University of California in Berkeley and he was kind of considered the godfather of grandfather of nuclear medicine uh the technology depends on being able to create a short-lived isotope out of what are normally uh uh normal metabolic components um and uh i list elements that can be used but just to keep going here um the decay is uh involves um a positron and a neutrino being released and the positron travels until it encounters an electron somewhere in the vicinity and uh um an annihilation event results in two gamma ray photons um and the detectors the same detectors for a CT scan are uh encircling so you can get localization assist a diagram to the process um the neutron goes off into the universe so somewhere someone with a neutron uh neutrino i mean um they'll say somebody's doing a PET scan somewhere that's that's flip never mind it but okay the technology for producing these is really pretty cool there's three naturally occurring isotopes of oxygen uh with uh eight nine and ten neutrons they take the heavy oxygen in heavy water and bombard it with high energy protons from a cyclotron or a linear accelerator and they create 18 fluorine in or a fluorine 18 isotope in solution and they quickly bond it with a pharmaceutical and uh they can inject it it has a half life of about uh 127 minutes no i was i was making a joke synergy i was i was thinking that someone on a distant planet who can detect neutrinos might see oh there's a neutrino from earth someone's doing a PET scan so i was i was being probably creating i know it's a real nerd joke uh okay so there's a number of theories about how Alzheimer's comes about uh i'm gonna run through those quickly one is um wrong cholinergic theory the synapses get lost so you can't produce cholinergic um acetylcholine neurotransmitter and they thought maybe that's the cause of it well that's that's or what happens but i just mentioned it or historic reasons in the sense as the depth of understanding became greater uh Alzheimer himself noted these clumps of which turned out to be beta amyloid and it's from breakdown of amyloid precursor protein and um nobody really knows what that does it seems to be uh concentrated in synapses but the pharmaceuticals that have been created to clear beta amyloid or prevent beta amyloid from accumulating and these clumps or plaques uh did not help they were disappointing so people were hoping that these would be uh cures for Alzheimer's or a new major treatment for Alzheimer's but the new refibrillary tangles are the um real key i think um i have a few slides here which people can uh go back to look at as well um if you look at these uh little tear droplet clumps those are uh mostly sick neurons and these larger clumps are um like i don't have a pointer but if you look uh just right at center and and uh uh about three fourths of the way above the center uh you see these starburst deposits those are plaques amyloid plaques this is a normal picture and the whites on the right side you see white matter which is just fibers and on the left you see gray matter which has a lot of neuronal bodies and you don't see any mess everything looks nice and orderly the neurons look healthy the nuclei are not cluttered with junk right there in the center when this gets uh raised uh you can look and you see tangles of filamentous tangles uh forming uh and uh this is one is silver stain of uh showing the tangles uh in uh this is from the hippocampus of um someone with Alzheimer's campus is that primary memory site um so I've got some information here about the beta amyloid i'm going to keep going it can come back to look at it but just about its size and how many um amino acids there are um where it comes from oh it ends up there but here's an interesting point there are three approved um head scan ligands uh on the market for detecting alpha alpha beta amyloid and there are others on the way all of these use this of 18-floor isotope uh they're working to get more specific and more sensitive markers bio markers or tracers now i want to talk quickly about tau i'm sorry i've run over should i keep going reasonably close yay or nay okay thank you one vote that's okay we'll consider your the president of the united states so one vote overrides everything I appreciate that um tau and tau opethes are um a big focus of uh of um research uh tau is a microtubule associated protein map is the uh um acronym uh it stabilizes tubulin that form uh the microtubules now microtubules are really interesting and they are the cytostructure of the of the uh heron but also involved in all kinds of processes especially with actin and amyloid fibers they're always being remodeled every time you make a dentrite or new synapse you are using uh assembly tubules to bring it into service and that depends on um stable system and tau uh apparently stabilizes microtubules and uh there's an interesting history behind the discovery of tau as well but i won't go into that right now um here's the theory in a nutshell you have these kinases here enzymes that are maybe activated by oxidative stress maybe free radicals so uh there's a there are articles that talked about turmeric that i came across that i thought was an i take turmeric two capsules uh twice a day when i can think of it but uh they are wonderful uh as anti-inflammatories i take them in lul of ibuprofen or uh so i broke my back i broke three vertebra in uh 2015 so i get pain uh pretty easily but um i i use turmeric for my pain i never take anything else i don't want my brain cluttered with opiates but in any case these kinases get kicked on they hyperphosphorylate these tau proteins in the axons that leads to them grouping in they're generally uh they come out unfolded and they're hydrophilic they don't seem you know folding of uh proteins uh occurs um so that certain groups in the protein can escape the having to face the water they're hydrophobic so this is uh comfortable just out in the water so it doesn't tend to fold up uh and uh any at any rate um they end up um going from being fairly soluble to becoming insoluble in aggregations uh and the tangles are formed neurofibrillary tangles and uh of course the benefit of stabilizing microtubules is uh affected and if you get a significant amount of dysfunction of microtubules in your neurons your neurons are going to check out they're going to stop functioning and then they're going to eventually die and so that is the in a nutshell the best a statement of the theory i can give you right now this is a now there's been a kind of a holy grail type search for a marker a biomarker a tracer for tau this is a a new molecule that's not approved yet but it's uh there's excitement about it so i just wanted to mention uh floor tau superior um and uh there is a study in the national institute of aging uh as recruiting patients at the washington university for tau pet imaging using this agent and here i'm not going to spend time on this but i just started oh i don't know dwelling on similarities and other between this tracer and other molecules uh so of the possible causes of Alzheimer's these tangles from as a tau opathy may be uh one of the most important leads but it's almost certainly not the only thing going on there's um this is really multifactorial and there's probably going to be a lot of layers if tau is the uh real damaging agent there's going to be a lot of layers that leads to it becoming that that way i'm sure people have argued that gum disease they've noted that people with bad teeth often have dementia and they found components bacteria associated with gum disease and associated with plaques and changes in Alzheimer's and herpes infection as well um generally inflammation in all of this plays a big role once you get the neurons sick and you get uh proglia acrophages that are around the neurons angry they'll start to kill the cell say mutation trim to mutation that's uh appears to predispose the microglia to in um double agents there's also a section here i wanted to talk very quickly about diabetes type three diabetes i'm gonna flip through here uh some things because um it's gotten over but uh um the brain uh was not considered an insulin target organ when i was in medical school um that's langurans um that's uh tooth uh things named after me the eyelids of langurans where the beta cells create insulin in the pancreas uh and uh there are all these other hormones that are secreted such as this gremlin uh grayland um and that was the pancreas and this is a nether diagram with an islet this is another just a diagram showing islets that's the lay of the pancreas it's um back in there um where in um historically if you had an injury back in there you wouldn't make it uh too much vital stuff in there that's a liver that's pulled upwards there and as a duodenum to the left and the spleen and upper right hand corner and the stomach is removed there to see the pancreas is that big yellow um blob these are the guys that discovered uh insulin uh and got awarded the Nobel prize best in mcloyde best as the young men that dog was fed uh or or injected with an x extract of dog pancreas tissue that dog was that diabetic and he lived only trouble is they were they did that in 1923 and 1916 this um uh count dracula looking guy uh actually he looks like a pretty sharp dude for 1916 uh nicholas palatio of romania discovered that he could extract um a material from dogs to treat um uh diabetes and he had it patented in in 1922 but he never got acknowledged or one that Nobel prize for it here's another person i want you to know about and if you go back and look at this take a moment and look at this this is a really remarkable individual dorothy uh um dorothy um pro foot hodgkin uh from um she was born in kairobi she was British very shy uh reticent quiet person she did wonderful uh discoveries developing three dimensional imaging of cholesterol penicillin vitamin b12 and insulin which had a big impact on uh on treatment of diabetes that was her model for um penicillin that she discovered on the e day there's a frederick singer who sequenced diabetes and um radial immuno assay where where they uh uh used markers on uh things to bond to the insulin to uh detect it uh uh was developed by uh rosaline yellow uh breast testing for allergies based on her work and insulin is a big deal this is a gentleman who had um mental illness and other problems and he ended up he had been in the united states living since he was an infant he only spoke english and so ice got a hold of him and deported him to iraq and he couldn't get insulin he died within a few weeks so they brought his body back for funeral and jimmy adoud so it's a sad world okay there's a whole section of this i'm i'm gonna just kind of wrap it up in one uh statement the brain appears to have some insulin production it also has insulin receptors and it can develop insulin resistance and i've heard people describing dementia Alzheimer's as the brain starving for energy unable to utilize uh uh glucose and oh i'm sorry i hit the wrong button stupidly here uh so that's referred to as type three diabetes i wanted you to be aware of it and and uh read more about it um and diet as as well might play a role in there for instance uh high dose corn syrup uh in hamsters uh induces neuronal insulin resistance and the blood brain barrier um protects the brain from molecules getting to it but the olfactory bulbs and the roof of the nose are um well they they have through the little dural sleeves these little um um processes that drop down into the nasal vault so the um kind of bare neurons of the olfactory bulb uh are coming down into the top of the nose and they detect things in solution and that's how you smell things well they can use insulin sprays and there's evidence that it helps people's mentation when they have dementia so um it gives more support to the idea that um there's an insulin um resistance component to dementia um so here's my last slide and i wrapped it up by just thinking it's a really complex arcane thing the brain but it's uh going to be a big thing of study for the this century uh make your best choices and give it your best shot as you go along but be careful what you expose yourself to and um joy learning and sharing and being part of the scientific culture of humanity but don't worry about wealth or fame and life's rarely fair but really it doesn't matter i'm saying that because of thinking of these people that did wonderful work and they don't really get noted for it we're really uh more of a collective than anybody wants to admit we like to make heroes and take it out that uh there's a loner the rugged individualist leading the way but everyone's dependent on uh that makes progress or humanities dependent on uh at least a part of it being represented in a culture in which they make an impact these people may not have had their name known but their work was part of the ongoing push forward so that's it any questions thank you i'm sorry i went over so long that's my um that's my um signature uh mistake i guess thank you mike thanks day and vick bedbrain now i saw someone talk about bedbrain i'm not sure what you're referring to thank you talk to oh no i've um heard of bedroom eyes but i haven't heard of bed bedbrain no problem so um i if you do go back and look at the slides i do hope that was successful in making them so that you can get a fair amount of guidance and information from them just by reading them thank you arian i realized after i'd um i thought this would be a good topic to discuss and i realized uh when i started to make my outline what an incredibly detailed and immense um uh subject it is thank you mike and you know uh i was thinking about and uh i think it was office space where the movie where there was one guy uh uh he was the people person and they were talking to him and he said what do you really do here and he says i'm a people person what's wrong with you people he says i'm the one who explains to the engineers because they can't talk to people it's not talking to the um reviewers of the business very well so he was about to get sacked um but i think that um medical science is so dependent on physics and chemistry uh in particular and um molecular biology of course um it's really more room in medicine for improvement by development of these um other disciplines that have application in it uh then by the practice itself so i guess i'll turn my microphone off now if there's no further questions thank you mike okay thanks for the opportunity to speak to the group