Movement disorders. Treatments

One of the things that has been coming up in the recent literature that I think people should know about is this whole argument that okay you give somebody levodopa. They are going to make dopamine. In the synthesis of dopamine there is the liberation of hydroxyl radicals and other free radicals. These free radicals contribute to neuro-degeneration by oxidative mechanisms. Perhaps they are vulnerable. It’s a vulnerable substrate because their capacity to deal with these kinds of free radicals and other moieties is lowered perhaps. So if we give levodopa to these people they are at greater risk for the continuing degeneration that we are trying to treat in the first place. Corroborated by in vitro data. Oh no, we shouldn’t use levodopa then! But the problem is, levodopa remains our best treatment for idiopathic Parkinson’s disease. Simple. And in the clinical experience that story of greater neuro-degeneration as a result of the use of levodopa has not been corroborated to the degree that we see in in vitro study. So it’s a very controversial area. But the point, the reason I want to bring this up is because it’s the whole issue of oxidative stress, or oxidative neuro-degeneration as a mechanism for this selective cell loss that we see in this disorder. There is the story that the longer people are on levodopa the more likely dyskinesias will happen. For all those reasons they are advocating that the dopamine agonists are the first line of therapy for early disease. In clinical settings this is not what you will necessarily hear. It depends. If it is a 70-year-old who is presenting for the first time, retired and otherwise enjoying his life and wants to maximize the next 5-7 years, yes you use Sinemet. It depends. It depends on many different things.

When we start talking about stroke, for example, when we get into that really dicey area of tissue plasminogen activator for example, know what is not controversial in the literature. Don’t worry about the controversies in the literature. That’s not what the Boards are trying to determine. That you’re aware of a controversy … oh, and by the way, that is especially true in the orals. If you are standing in front of a person whose kids are going to private schools because of dopamine agonists, you don’t want to sit there and say, “Well, I personally think the use of levodopa is very important in the early treatment of disease. I use it all the time. I think this argument on the other side of dopamine agonists are really sponsored by people whose kids are being sent to private schools by …” you don’t want to do that. Say, “I realize that there is a controversy. The Keystone conferences have put up this kind of consensus idea of how we should treat early disease, but it seems to me that it would depend on ….” Now you are vomiting up sort of a stock response. But the point is, there is a difference between… the orals are a different kind of mind set. You don’t want to walk into controversy in the orals. All you want to do is to say, “I acknowledge that there are controversies out there.” There is one guy, M.S. Maven – a real lab rat- said, “Um, there is no differential diagnosis in this case. It must be multiple sclerosis.” He was shot down. He was right but that’s not the time to do that. It’s the time to sort of generate large differential diagnoses. If they don’t like that then you have to rearrange real quick and start talking about something else. It requires a flexibility on your part. It’s very different from what you do sometimes in clinical settings. Which makes the point, all we are doing is preparing for a test. We are not preparing for clinical practice. Clinical practice is something different.
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The dopamine transporter is a transporter thing that allow for the concentration of dopamine and/or metabolites, taken up from the synaptic cleft, taken into the presynaptic cleft. So far so good, right? You know about that re-uptake mechanism. Makes sense there would be a transporter. Except that it also seems to pick up on toxins that may be selectively neurotoxic for those cells. Therefore, the presence of this dopamine transporter may be a marker for those cells vulnerable to selective neuro-degeneration in Parkinson’s disease. It’s either you have more dopamine transporter activity, or DAT activity in certain pathologic preparations, or a decrease in that thing which sequesters either dopamine or toxin in the presynaptic cleft, this entity of the vesicular monoamine transport, or VMAT. Here’s the point: either more of that or less of that transporter will be associated with increases in putative toxin or increases in dopamine in the presynaptic cleft, greater likelihood of neuro-degeneration. That’s the thought behind this whole enthusiasm about dopamine transporter activity. In the next few years you are going to see spec studies trying to quantify amounts of dopamine transporter in nigra etc. So you are going to be hearing this stuff I think in the next few years. There’s a little scientific factoid that I think they might pick up on.

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