Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 1 of 7

*Note: We still do not have a copy of the powerpoint lecture and I did not know I was suppose to transcribe. I'm going to do the best I can via audio to determine when there are slide changes and I'll try to organize it so it's easily understood. I apologize for the inconvenience.

BG - basal ganglia, PD - Parkinson's disease, SNPC (SN) Substantia nigra pars compacta, SN - substantia nigra, SNR - substantia nigra reticula, IN- interneuron, DA - Dopamine, STN - subthalamic nucleus, NT-neurotransmitter.

I. Introduction a. Good afternoon. My name is David Standaert. I'm from the department of neurology. I am both a physician and a neuroscientist. I run the Center of Neurodegeneration and Experimental Therapeutics, where we study basal ganglia diseases, Parkinson's disease, Alzheimer's, other degenerative disorders and I take care of a lot of patients with PD. So what we're going to try and do today is talk a little bit about the basal ganglia. So some of this will be very straight forward, neuroanatomy and neural circuits. Other parts I'd like to talk a little bit more about the patients since that's what some of you will actually get a chance to see at some point in your career. If we can get through a reasonably expeditious manner, I have a video at the end of a patient with PD I'd like to show if we have time. We'll see how we do on time. b. Just to start out, a couple of things to say. Just a practical thing, you'll notice these slides are different from what was on the website over the weekend, because I worked on them over the weekend, so the new ones should be posted now if you'd like to go and download the new and improved version. They should be up there. Some of these slides are probably missing from what you downloaded over the weekend. The other is the textbook is very heavy on anatomy and description of the basal ganglia and we'll review a little bit of that, but I'd rather talk about the function of the basal ganglia, which isn't really addressed there at all. So we'll review a little anatomy, but I'm going to try and give you some idea of how the circuitry of the basal ganglia works and how they're interconnected at least some of the basic ideas about how people think about the function of these particular parts of the brain. II. Objectives a. So here's our objectives here. We're going to talk about the input and output nuclei of the BG and how they're connected. So this is the circuit. We're going to talk about inputs and outputs. We're going to talk about PD and the four cardinal features, descriptions of PD and what those are. We'll talk a little bit about the role of genes and environment and causes of PD. This is a big area of research. Lastly, we will touch on the role of dopaminergic drugs in the treatment of PD. These are really the four themes. I'm going to try to do it in roughly this order. III. General BG Circuits a. To talk about BG circuits, I know you just spent a lot of time talking about the motor cortex, so the motor cortex circuit is fairly easy to understand. It comes from the motor cortex, there are neurons, upper motor neurons, which project to the spinal cord. These synapse on lower motor neurons that connect to muscles and cause movement or action. b. People always wonder how the BG fits in. Where is it in this pathway between cortex and spinal cord? It's not actually in this pathway, it's a modulatory loop, it sits off on the side. So BG, although very important in controlling movement, has no direct connection to the muscles at all. They do all their work by taking information from the cortex and do various types of information processing sending that to the thalamus and looping that back to the cortex. It's a side loop, it's not directly in the path of information flow from the cortex to the muscle. It is a side loop trying to tell the cortex which movement to make, how much movement to make, but it's not directly connected to muscles at all. That's one thing to appreciate about the BG, even though it's the most important part of the brain in regulating movements, it does not directly connect to the spinal cord or to the muscles. c. Then the second point is that the textbook talks about multiple BG circuits for multiple functions, so we're going to talk a lot today about movement. This is an old classic slide from Alexander in 1986, who parsed out five different parts of the BG circuit and found five parallel pathways. It starts with cortex, they go through the nuclei of the BG and go back to the thalamus, which goes back to the cortex. They all follow this same basic scheme: cortex, basal ganglia, thalamus, back to cortex. They do different things. The one we're going to talk about most today is the motor circuit, so this is as it's being suggested involves movement, it's the one that is involved in PD and other BG diseases. The other circuits, there's an oculomotor circuit here, so I know that Paul talked a lot about eye movements, the muscles make the eyes move, but what initiations the movement is a lot of circuits in the BG. These are analogous circuits. Then there are circuits that are behavior in the BG. This is probably a topic for another day, but parts of the BG particularly the ventral striatum and other regions are involved in the motions and actions and behaviors much more than movement. We're going to focus on the motor circuit, but Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 2 of 7 it's worthwhile knowing that there are parallel circuits regulating eye movements and regulating behavior in the same way they regulate movement. IV. Input a. What is the motor circuit? What are the basic pieces? A lot of this is in the basic text, but let me try to put it in some context. The first piece to understand is what are the inputs. Where does information come out of the cortex? Information comes out of the cortex where does it go? b. It goes to a structure we call the striatum, but it's actually two parts in the human brain: caudate and putamen. So caudate and putamen are very similar parts of brain. They have very similar types of cells in them. They have similar inputs and outputs, they are physically separated and I'll show you an anatomical slide in a second to show you how they're physically separated. In a functional way, you can think of them as the same thing. If you go to a rat, they are in fact the same thing. A rat doesn't have two separate structures, they have one fused caudate or putamen called striatum because when you cut a section through it, it looks striped. There are white matter bundles running through it and it looks striped. V. Output a. The output, there are two nuclei which are output structures. There's the globus pallidus pars interna, substantia nigra pars reticulata. Unfortunately long names, these are also two structures which are analogous to each other. They have very similar types of cells in them. They both are outputs. They project to the thalamus. Straitum is getting input from the cortex. These are projecting back out into the thalamus and the differences between these two structures are not really all that important. it is better to think of these as a functional unit. VI. Intrinsic Nuclei a. The middle part of the inner connections, the intrinsic nuclei, this is globus pallidus and the subthalamic nucleus. These are two relay nuclei. b. The substantia nigra contains all of the dopamine cells. Dopamine is the heart of regulation for BG. I'll walk you through how these are wired and connected. I think it's worth it to think of these in this way. Thinking that the input receiving information from the cortex, the output sending information back out to the thalamus, then the interconnecting nuclei and their very special role of the dopaminergic cells. VII. Name that structure! a. So, I know we're going to use the clickers in a minute, but I couldn't figure out how to make it through this list last night. So we'll do this the old fashioned way and we'll do a little name that structure. Feel free to shout out the structure if you know what these structures are. Let's start with this one up here. this is a human brain slice. There's brain stem down there and cortex up here. He identified the following structures on the slice: caudate, putamen, internal and external globus pallidus, thalamus, subthalamic nucleus, substantia nigra (pars compacta and pars reticulata). The pars compacta are the dark cells here, this black stuff here. These are the dopaminergic cells. Ventral to that is the reticulata. You won't see this too often. This is a slice taken at a special angle in order to be able to see all of these structures. VIII. Input of Striatum a. Let's talk about these pieces a little bit. The striatum is the input structure of the BG and it gets several kinds. One kind of input it gets is from the cerebral cortex. The output of the cortex is mainly excitatory, glutamatergic. It sends glutatergic excitatory afferents to the striatum and excites neurons. It also gets dopamine input from the SNPC. It does get a little bit of glutamatergic input from the thalamus. This is a side loop, the function of that is not terribly well understood. We won't dwell on it too much. We'll talk mostly about excitatory input from the cortex and the DA input from SN. Really what the striatum is doing is taking the excitation it gets from the cortex and the DA from the SN and integrates the information. The amount of information coming out the cortex is really tremendous, virtually every area of the cortex sends an excitatory axon in to the striatum, so it's getting information from all parts of the brain. It's getting information about movements that are occurring, state posture, movement we're thinking about making, integrating all of this through the input of DA, which is controlling how it does that. IX. Striatum a. What's in the striatum. There's two classes of neurons in the striatum. i. 90% are projection neurons also called medium sized neurons, or medium spiny neurons. So they're medium sized neurons (15-20 microns in human). There are a lot of them, they have spiny dendrites. Their axons project out of the striatum down to the downstream structures. ii. The other neurons are interneurons. Interneurons have cell bodies in the striatum, but their axons stay entirely within the border of that nucleus. They don't go anywhere. Probably the best understood of the large spiny ones, which are cholinergic. There are also some other classes here that use nitric oxide and GABA as NT, but when you think about the cellular content of the striatum, 90% of them are these projection neurons sending their axons to downstream structures. Then the other 10% are the interneurons modulating the inner connections. Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 3 of 7 X. Wiring of the Striatum a. This is a little bit about the wiring of these. This is a cartoon of the medium spiny neuron. Here's the nucleus here, some mitochondria, sitting around in the cell body, here's a dendrite with spines. When you have spines, you have synapses. b. Cortex sends its excitatory axons down and synapse on the head of the spine here. c. You have DA afferents that form synapses on the shaft here. This is thought to be important, this anatomic layout where the excitation is coming out on the head. The signal travels down and as it passes the neck, it comes under the influence of DA. i. DA can gate whether an excitatory signal that comes through a spine makes it to the cell body or gets cut off here, depending on the state of the dopaminergic neuron. This structure is thought to be important as an integrating factor in controlling basal ganglia function. Excitatory glutamatergic inputs, DA inputs, there also these cholinergic and things that are coming from the IN tend to come down on the bodies of these cells as well. XI. Outputs a. What about outputs? Where does it go? This is where it gets a little complicated and you have to think about it a little carefully. b. Here's a cartoon of the striatum and I said that there were 90% of the cells were projection neurons, they have a cell body here and an axon that goes out somewhere. So that's these. There are some IN, they stay within the borders of the structure. c. Turns out there are two classes of projection neurons. These are distinguished by different kinds of receptors on surface, different neurochemicals inside, and different connections downstream. i. One class has DA D1 receptors. These are G-protein coupled receptors that bind dopamine. When you bind a D1 receptor, broadly speaking, you tend to excite a cell. D1 turns on cAMP synthesis. It's an excitatory receptor. This pathway is activated by DA. It also has a marker substance, which comes down here an projects to the GPi, SNR and they use GABA as a NT. They send an inhibitory signal straight to the output of the BG. In fact, because they are directly connected from straitum to the output they are called the direct pathway. ii. There's also an indirect pathway, which comes from the medium spiny neurons, but these come from D2 receptors, broadly speaking, these are inhibitory receptors. When they bind DA they shut the cell off, sending inhibitory signals to the GPe and we'll see how this all hooks up in a minute. The important thing to remember is striatum projects to both parts of the GP, GPi and GPe, but it's coming from two different types of cells. Ones that are going directly out have D1 receptors, cell that are going indirectly through the GPe have these D2 receptors. You'll see how this plays into a yin/yang circuit which regulates movement. XII. D1 Circuit Details a. So you can wire these all up in a circuit. This is the conventional way it's wired up. I think this was in the original slides. I don't know if you can follow or not, but they're up there now. You can download these and cruise them at your leisure. b. Here's the cerebral cortex sending glutaminergic signals to the straitum. It's got two output pathways: one goes directly to the output structures GPi, SNR, the other is indirect and goes to GPe, inhibitory, it's projects to STN, which is an excitatory structure which projects to the output. So there's two pathways for information here, one direct through here, indirect through there. They all loop back to the thalamus, and back to the cerebral cortex. c. So let's pull this apart a little bit and look at it one piece at a time. This is conventionally the way people who study the BG think about this, having two motor circuits to the BG, which are balanced against each other. One of them is this direct circuit. D1 containing neurons goes to GPi, SNR, very simple kind of circuit. If you turn this circuit on by putting DA on the striatum. You turn on these guys, which release GABA and turn off the output structure that tends to release the thalamus, it sends glutamate, and turns on the cortex. So the net effect of activating this pathway is to send more excitatory signals to the cortex which will increase the motor output. XIII.D2 Circuit Details a. The other circuit is this one. D2 receptors here. Inhibitory signals to the GPe, that in turn inhibits STN, excites the output back to thalamus. If you turn this one on, how do you turn this one on? DA won't turn this on. DA will shut this off. This is more of what the pciture would look like if we took the DA away, release the D2 receptors, this becomes active, inhibits this, so you have this double inhibitory relay, which allows the STN to become more active, drive the output, shut off the thalamus and reduce movement. So you have a yin/yang here. The direct pathway is driving movement, while the indirect pathway sis inhibiting them. XIV. DA on the whole circuit a. In fact, if you DA on the whole circuit, this is what is thought to happen. You get excitation of the direct pathway, you get inhibition of the indirect pathway, both of these contribute to turning off the output structures. Both of them release the thalamus and drive the cortex. This is in a very simple way how we think about DA driving movement. It works through two different routes: activating the D1 receptors, binding the D2 receptors and Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 4 of 7 turning them off. Both paths end up with a reduction in BG output and an increase of thalamic output and a increase in movement. I know it takes a moment to think through this. That's why I'm glad they're on the website, so you can cruise them at your leisure. XV. Introduction to PD a. Let's talk about PD. That's enough about neural circuitry for one day. So PD is probably the most common disorder of movement, second most common degenerative disorder behind Alzheimer's Disease. Originally, It was described in 1817 by James Parkinson, who published "The Essay on the Shaking Palsy" which is an entertaining small book, about 40 pages long, worth your read if you can find a copy. He told of the shaking palsy or paralysis agitans described involuntary trembling motion, lessened muscular power, parts not in action even when supported, propensity to bend the trunk forward and pass from a walking to a running pace. Kind of flowery language, I'll bring it down to a more practical description. b. It's a very common disorder, 2% of the population over the age of 65. That's about a million people in the US alone. There are tremendous number of people with PD, so it's a serious public health problem. XVI. Cardinal Symptoms of PD a. What are the cardinal symptoms of PD. This is the way neurologists like to put this up and talk about it. i. One of the classic features of PD is shaking or tremors. It's a particular kind of tremor, usually in the hand, usually a rolling tremor, a kind of tremor present at rest. When asked to put their arm up, the tremor tends to stop, it might reemerge right here though. If the go to pick something up, it will be quiet, when they're not paying attention to their hand it will reappear. it is usually asymmetric, it is usually more severe on one side of the body than another. That's one of the hallmark features of PD, this tremor. ii. There's rigidity, stiffness. You can't see rigidity, but you can take a hold of their arm and feel that they're stiff. It's a form of resistance to passive movement. The arm will be tight and stiff. iii. They have bradykinesia. That is slow movement, literally. These are slow movements. PD patients are very slow. Tiny movements of hand are very slow. They might have micrographia, the come in with this teeny tiny stuff and you have to get a magnifying glass to read it because they really don't move their hand very much when they write. iv. The last feature is postural instability, an impairment of balance reflexes. Normally a later feature in PD. Later on they'll develop falling. They tend to fall backwards. They tend to start stepping backwards and they can't stop, called festination. So these are the core motor features: tremor, rigidity, bradykinesia, and postural instability. This is what we look for when we diagnose PD. We don't have any definitive tests for PD diagnosis. We diagnose by looking for these features, no brain scans or blood tests that are practical in a clinical test. It is a clinical diagnosis, which involves looking for those four features. XVII. Pathology of PD a. What's the pathology that goes with this? It's a loss of the DA system. b. We talked a few minutes ago about how DA promotes movement by activating the BG. This is a disease where there is degeneration of DA neurons. So here's a normal midbrain, anyone know what this is up here? Cerebral aqueduct. These? Cerebral peduncle. This is the tectum, cerebral peduncles, cerebral aqueduct. We're in the midline, in the brainstem. What's this stuff right here? SN. This is the black substance, from which SN is named. This is melonin, which is the byproduct of Da synthesis. Neurons that make DA have black stuff in them and it fills them up like this. This is the normal brain. You see this is autopsy. This isn't stained. This is just how it looks. If you do that with someone that has died from PD you get this. And it's a very complete destruction, typically 95-99% of the neurons are gone at the time of autopsy. So there's a very selective degeneration. We can see that the rest of the brain looks okay and the blacl stuff has really wiped out. So that's the core patholoy of PD. XVIII. Cellular pathology a. At a cellular level, you get these round things here. So these are round spheres. You get these pink things in the middle with a clear halo in the middle here. Anyone know what this is? Lewy body. So this is what pathologist look for when they look at the neurons. This is a DA neuron here. This brown stuff is the melonin, which looks brown under the microscope. This is an abnormal inclusion, it's a Lewy body. It's a signature pathology of PD. XIX. Circuit of BG in PD a. Why does PD make you slow? This is back to the same wiring diagram here. What we've done is shown what happens when you remove DA input to the striatum. The slide I showed before was 'What if I added DA to the striatum'. b. This tried to address the question of what happens if it goes away. If it goes away, D1 neurons are less active, they don't have DA to activate them. They're going to turn off. These guys are going to be more active before there's no dopamine inhibiting them. They're going to in turn inhibit this GPe, that's going to turn on the STN. The STN is going to drive these output structures. There's nothing opposing it because the inhibition has gone away, so it's all excitation. So you turn on the GPi and that becomes very active, inhibits the thalamus, and turns Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 5 of 7 off the motor cortex. This is really how people think of it. You will find more complicated versions of this diagram, but this is really encapsulated in a nutshell the ideas people in field have been thinking about. c. This model has been around since 1989 and it has had many additional features, pathways, and concepts added onto it, but this is the core model of the BG function that most of us fall back on when we try to understand the circuit. PD is the loss of DA and produces rigidty and stiffness through this process of inhibiting the thalamus and removing the cortico excitiation. XX. Non-motor symptoms a. One side point I wanted to make is that we've talked a lot about how PD is a motor disease, but as clinicians we are increasingly recognizing that there are many symptoms that are not motor disorders, which don't deal with the basal ganglia, which includes loss of smell (hyposmia), vision changes (double vision), color vision, REM behavior disorder, excessive sleepiness, depression, autonomic disturbances such as constipation, dementia. All of these are part of PD. That goes with the fact we realize that we've talked for years about the DA cell loss, but there is a larger pathology and this slide is meant to illustrate that range of pathology. XXI. Progression of PD a. If you look at a large number of patients with PD, it does start in the brain stem, way down in the brain stem, heavily involves the midbrain where the DA neurons are, but eventually if you follow people long enough the disease spreads to other parts of the brain, allowing you to see a larger spectrum of disease. Once again, i think this is in the updated set and not the other. It's not a key issue, but I wanted you to be aware that the field is moving away from the thought that this is purely a DA disorder. XXII. Causes of PD a. There are other things going on in PD, but we understand what causes PD. There's really only a single slide on this topic, it's a very long topic, we could talk about it for hours about this. What it boils down to is that most cases are unknown cause. If people come to see us in the clinic, and we see a lot of patients, about 5000 a year at UAB, most of them we have to say " I really don't know why you have PD" b. It's typically a late in life disorder. Although as I get closer to that late, I guess it sounds worse and worse to me. Midlife disorder perhaps. Anyway, typically between 55-65 is the typically onset. There is a range, you'll see people in your 40s, exceptional people in their 30s (Michael J. Fox). We have a patient we follow here that developed at 16. We don't know the cause. Most people don't have a strong family history. many times you can't pick any anything specific. c. As far as genetic, genetics is a big area of interest, it's important for patients to know that most cases are not genetic in origin. If you have PD the risk to your children is generally pretty small. It's not any different than the rest of the population. So most of the time, it's difficult to point out a genetic cause. Although we have found genes that cause PD. These have been found in rare families around the world with strong patterns of inheritance. There are about 5 different ones known, depending on how you're counting them. But even if you take all of the PD genes known, they account for less than 5% of all the cases, maybe more like 1-2%. So still 95-98% are unexplained by genetics. It is true if you have early onset, there might be a most genetic nature. This is true of many neurological diseases, AD, ALS, PD, other disorders. If you're talking about someone with PD at 20, 25, 35, the odds that they have a single gene causing that is quite high. But the average person at 65,75,or 80. The odds that there is one gene is driving it is quite small. XXIII. Risk Disorders a. What are the other risk factors for PD? Male gender, it's about twice as common in males than females for reasons that are not well understood. Hormones is the answer that comes to mind immediately, but that doesn't seem to be the answer. Most cases are post-menopausal and hormone replacement although it affects many features of human health doesn't seem to affect PD risk. b. There may be a role of early life estrogen loss. Some studies have followed patients that had surgical removal of the ovaries early in life and they may have a risk that is closer to that of males, not an obvious link. c. It is more common in people that live in rural areas. d. Pesticide exposure, there is a strong link between PD and pesticide exposure. There's been some nice work in California where they keep tract of pesticide exposure and people that live locally seem to have a risk. e. Interesting, smoking protects you against PD and gives you lung cancer instead. We don't recommend it, but it's an interesting curiosity. There's lots of chemicals in cigarette smoke that affect through nicotine receptors. Robin can tell us why it's protective. It is a mystery, but there is a clear link. Studies have shown that people that smoke are less likely to get PD. Perhaps the only benefit of smoking that I'm aware of. f. Caffeine consumption reduces risk. The right dose is between 2-4 cups a day. that's those little 6 ox cups. Not these ones on the counter. XXIV. Treatment of PD a. That's enough about causation of PD. Let's say a few words treatment of PD. So most treatments are based on DA replacement. Our core understanding of this disease is of a DA deficiency. We've come to realize there are a lot of things going on. Treatments are based mostly on replacing dopamine. What do they do? They help the Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 6 of 7 things produced by DA deficiency. They help the tremor, rigidity, stiffness, bradykinsia, postural imbalance, but there's two problems. Over time they are less effective. I'll show you an illustration. The other is they don't do anything by the things not caused by dopamine deficiency. Dementia, cognitive impairment, constipation, other symptoms that reflect pathology outside of the DA system don't improve at all. In PD the first therapy became available in 1969. Before that people died very quickly of PD, they lives 5-7 years and died fairly quickly. So you saw a lot of the motor features. But now that we know how to treat that, we see people living longer and we see a lot more of these other symptoms: dementia, autonomic impairment, which limit the quality of life is not the duration. That's the direction that the field is trying to do, to get beyond DA treatment. XXV. DA Synapse on medium spiny neurons a. How does DA work as treatment? To talk about that we need to review the DA synapse a little bit and the biochemistry of DA. b. In this cartoon we see the presynaptic terminal. It comes down makes a synaptic connection with a post synaptic receptor. So in the BG where is the presynaptic axon coming from? DA axon, so where are the DA cells? SNPC, right? So this is an axon coming from the SNPC and making a synapse on the striatum. So this synapse will be in the striatum, this will be on a medium spiny neuron on one of its spine. It will probably go on the side of the side of the spine though. This is a synapse contained within the striatum, coming from the SN, projecting onto a medium spiny neuron on the post synaptic side with receptors. XXVI. Biochemistry of DA a. DA is made from tyrosine (which is dietary). Tyrosine is an amino acid. There's an enzyme here tyrosine hydroxylase which makes this compound called DOPA (aka L-DOPA, dihydroxyphenyl alanine). There's a second enzyme called aromatic acid decarboxylase which makes dopamine out of that. b. It's packaged into vesicles. There's a transporter here, VMAT1 (?), these vesicles fuse at the membrane, gets into the synapse, binds to a DA receptor which boosts a signal. c. We have to be able to remove the DA from the synapse. It's reuptaken into the synapses as a transporter here, called the dopamine transporter which will take it back there. i. There's a common drug of abuse that blocks a transporter: cocaine. Cocaine is an inhibitor of the reuptake. It doesn't bind to a receptor it just blocks the reuptake of the DA, increasing DA in the synapse. You do get motor behaviors with cocaine, people get restless and move around a lot. The cognitive behaviors are what tends to be noticed, but people get motor behaviors as well. d. The other thing you can do is break it down. There are two enzymes here: monoamine oxidase and catochol-o- methyl transferase and these act in sequence to produce inactive products. So this is how it's cleared. Most of the drugs we have work here by augmenting production of dopamine or binding to the DA receptor. XXVII. Pharmaceutical treatments for PD a. This is a menu of them. I'm not going to take you through all of these various things but we do use levapoda itself, we use agonists, we use inhibitors of the different enzymes, and a few other drugs. I won't go on about this. you can go over it in pharmocology texts books if you want. XXVIII. Levodopa a. Let me just lead you through levapoda a little bit, because it's the most important drug for PD. It's clearly the most effective treatment that we have. One of the biggest guns in our toolboxes when we want to treat someone with PD. It is the biosynthetic precursor. So we've giving the compound which is the intermediate here. The normal precursor of the transmitter, fortunately, tyrosine hydroxylase is found mostly in DA neurons, but AAC is found in a lot of other cells, glial cells, other cells. So if you have PD and you've lost a lot of your tyrosine hydroxylase, you give people LDOPA, they can still convert it to dopamine and they can store it, release it, and reuse it. That works extremely well. It's extremely remarkable. b. If you have the occasion to see someone who has not been treated for PD . Every once in a while you get someone who hasn't seen a doctor in five years, they're in a wheel chair, rigid, shaky, you can give them levodopa, wait an hour and you can watch them walk our on their own accord. It's amazing to see. It's a remarkable therapy. In a way it's amazing that it works. it's amazing that you can take an amino acid like levodopa and just take it, ingest it, and it will get to your brain and it will fix a neurotransmitter deficit. In a way, what we'd like to do for all brain diseases. We'd like to go in there and manipulate the deficits, PD is probably the best example of this. XXIX. Issues with Levodopa (Graph) a. What's the problem with it? Over time, the response becomes more variable over time. This is from a patient of mine. He drew this graph, I didn't ask him to do it, but he did it anyway. He was an engineer, he liked to graph things, his wife said he graphed the checkbook every month. b. This is himself at 7 am. This is the whole day. he has off and on. In the morning he takes medications, which includes levodopa, which lasts for an 1.5 hour, but then it quits on him. takes more pills, takes a while to kick in, goes back down. He rides a roller coaster. When this guy is off, he's frozen, he can't move at all. He can't get out of his chair. When he's up, he has dyskinesias (thrashing away). Neuro: 2:00 - 3:00 Scribe: Jennifer Watson Monday, February 8th, 2010 Dr.Standaert Parkinson's Disease Page 7 of 7 c. For instance, Michael J. Fox at the congressional hearings. Levodopa produces dyskinesias. Our lab has worked on this for a while. it's a plasticity problem, with neural plasticity, that's induced by these large doses of DA, which we give PD patients. This really becomes a problem for people. We have a variety of solutions, some involving even surgery on the brain. XXX. Neuroprotective Strategies a. Just a couple of words about neuroprotective therapies. What other than replacing the DA would we all like to go? Something to protect the brain. We don't have something like this. There are some treatments under study. That's where we have to go if we want to make progressions with the disease. There are features which are not DA responsive. If we're going to treat those, we need to slow the progress of the disease. XXXI. Summary a. To summarize my basic points. i. One of the ideas is that BG circuits are loops that regulator behavior. They aren't in the pathway in the brain and spinal cord, they're a side loop that regulates behavior. ii. The striatum recieves the input. You should try to think about how the striatum is wired: what are in the inputs what the the transmitters there? It gets inputs from cortex, SNPC. The transmitters in play are DA, glutamate, acetylcholine (to some extent from the interneurons) and GABA as the output. iii. Motor symptoms are caused by loss of DA input in the neural circuit. This circuit helps us understand how that works. iv. In terms of causation of PD, there's evidence of genetic and environmental contributions, but bottom line for most patients have unknown causes. v. Current treatments: most involve replacing dopamine. They're effective on the motor symptoms but they don't work very well on the non-motor symptoms. XXXII. Questions

Which is an input structure of the basal ganglia? Putamen, STN, SN, GP? Ans: Putamen.

Striatal medium spiny neurons project to: Cortex, GPe, GPi and SNr, Spinal Cord, and STN. Ans: Globus Pallidus (e or i).

Which is not a cardinal feature of PD? tremor, slowness, stiffness, paralysis, and impaired balance. Ans: Paralysis

In most cases the cause of PD is: Genetics, Toxic exposure, traumatic brain injury, unknown. Ans: unknown

Which are likely to approve with levodopa treatment? Ans: motor symptoms, rigidity.

Watched video.

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