June 2004 Issue | Catherine Willner, MD Neurology and Pain Medicine (Board Certified)

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  • June 2004 Issue | Catherine Willner, MD Neurology and Pain Medicine (Board Certified)

 


 

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INTERVIEW TRANSCRIPT

CLINICIAN OF THE MONTH
Catherine Willner, MD
Neurology and Pain Medicine (Board Certified)
130 Rock Point Drive
Durango Tech Center
Durango, Colorado 81301

JB: It’s time for our Clinician/Researcher of the Month. This month, we are very pleased to have not only a primary clinician in the area of neurology, but an individual who has been a consummate educator in this field pertaining to our Applying Functional Medicine in Clinical Practice training program (AFMCP). She is a faculty member of AFMCP and is actively involved at the Institute for Functional Medicine (IFM) in helping to develop the concept of functional neurology. I am talking about Dr. Catherine Willner, a Board-certified neurologist and specialist in pain management.

Dr. Willner is a graduate of the University of Kansas College of Health Sciences and Medicine. She was a Fellow at Mayo Clinic for a number of years before going into her own private practice in Durango, Colorado. We have all been very fortunate to have Dr. Willner as our mentor in helping us to understand what is happening at the cutting edge of neurology and how functional medicine might make contributions to some of the complex neurological disorders. Dr. Willner will be heading up a new module to be offered by IFM—a two-day intensive course on functional neurology starting in the fall of 2004. It is with great pleasure, Catherine, that we welcome you to Functional Medicine Update.

For those of us who are not neurology specialists, let’s begin by having you give us an overview of how you see neurology as a discipline, how it has changed in the past ten years, and the most significant problems you deal with.

Neurology as a Discipline
CW: Thank you for those kind words, Jeff. I really appreciate the opportunity to discuss these issues. This is a very exciting time for neurologists. It is also a very frustrating time because of the amount of research evolving as we begin to understand a lot of the basic science about many of the diseases that have haunted us over the course of our treatments of patients. These treatments have typically been designed to consider neurological diagnoses as the primary problem, even among the neurodegenerative disorders.

In general, neurologists are practitioners who are essentially assessing things that typically have been considered to be episodic disorders like stroke or migraine, but disorders that are also degenerative in nature. Some of the disorders are genetic (present from birth onward) and some may be genetically mediated and develop during a lifetime, but they are usually considered multi-factorial and include environmental conditions in their evolution and progression.

Historically, neurologists were considered to be those who could name things, diagnose disease, and localize pathology in the nervous system, but that did not necessarily mean they could improve the outcome from those conditions. We were quite good, but had a limited armamentarium to impact the course of patients with problems traditionally diagnosed as neurological—things like Huntington’s disease, various dementias, and Parkinson’s disease—the system disorders. Those are very frustrating.

In the late 1980s and early 1990s, things started to change quite a bit, partially because as a profession, we identified things on the horizon that looked very promising in terms of being able to modify some of the things that neurologists did. The 1990s were identified as the Decade of the Brain, but I think this new century has brought even more insight and availability of tools to alter the course of these diseases. As a neurologist, I am frustrated because I can’t keep up with all the literature that’s in the basic sciences these days. At the same time, some incredibly important clinical studies have been done, and it’s our job to make people in the field aware of them. That’s one of the most important roles I see clinicians playing—divulging information about what neurologists can offer to patients now.

JB: As a full-service practicing neurologist, do you see patients with non-specific types of symptoms—individuals in a pretty severe state of pathology—or does it cover the whole gamut?

CW: It runs the gamut. Neurology is one of those specialties where, when practitioners can’t identify what might be wrong, if there’s something that sounds like it might be mediated by the nervous system, we investigate all sorts of things. They range from trying to identify the etiology of spells, unusual sensory symptoms, and changes in cognition, all the way to people who come in with full-blown diagnoses which may or may not be neurologically correct.

I used to joke that I saw more people who were diagnosed with Parkinson’s disease but really only had minor tremor. It was because tremor was always the first symptom presented to the primary care physician. It was assumed that it might be Parkinson’s because they saw a little early tone change or a little slowing in some movement factor. In reality, these people only had tremor. The exciting aspect is that only some of those patients would, indeed, go on to develop Parkinsonism. Neurology practice runs the gamut all the way from seeing people who do not carry a diagnosis. That’s the most exciting part.

In terms of the range of things that neurologists see, there is such breadth. It keeps you on your toes because there are so many areas that can involve the role of a neurologist. You don’t see just one population of patients (with the exception of those clinicians who are in centers of excellence where they only see patients with Parkinson’s disease or movement disorders). One of the nicest things about being in training at Mayo was seeing grass roots neurology at the earliest stages of diagnosis or investigation. We also saw some intriguing and different presentations of a variety of syndromes that some people might spend a lifetime waiting to see one or two cases of. It was a very rewarding experience. As I stayed on staff there, I became more involved in sub-specializing because that’s the nature of Mayo, but I still saw a huge variety of patients.

The most exciting thing for me now in private practice is that people come in with their relatives. I can identify a problem that may be well beyond my ability to make much impact in terms of the pathophysiology, but we know that their relatives may be at risk. A big part of my practice is trying to educate these patients and their primary caregivers about things that might impact their natural risk for a potential problem as they age.

Mitochondrial Connection to Neurodegeneration
JB: That leads to an interesting question which probably relates to the thinking of most of our listeners. If the nervous system is principally composed of cells called “post-mitotic” (not likely to divide and replicate), we have memory of all the things those cells have been exposed to since their initiation in the nervous system. We start looking at the nervous system as a highly active metabolic part of our body in terms of energy production and ATP generation from the mitochondria. Last, we look at genetic inborn errors of mitochondrial DNA, the so-called mitochondrial encephalopathies. Perhaps it leads us to recognize that there is something about the mitochondrial connection to neurodegeneration. Is that partly how you see the evolution of thinking in your field?

CW: Absolutely. In fact, one of the highlights of focus in our field was when people started to realize that some diagnoses were considered ineffective in terms of therapy. When we realized there were some people who had mitochondrial encephalopathies who could actually respond to certain treatments, we began to ask what else might be involved in terms of mitochondrial dysfunction. It gave us a great basis in pathophysiology for other disorders which might not be so severely impacted in terms of respiratory chain function, but had relevance to the model of certain diseases that were neurodegenerative in nature.

Up until as late as 2000 in our literature, you’ll see statements such as “Alzheimer’s disease is a neurodegenerative disease, but the underlying pathophysiology is not really understood.” That’s in our textbooks; it’s in our literature; it’s in our current articles. That has all made a transition. Paramount is understanding some of the unique features of the nervous system. Among those is being highly dependent upon the availability of glucose, and upon the productive ability of the mitochondria to maintain an energy gradient. That’s because the nervous system is an electrochemical system in and of itself. It is highly energy-dependent. Disorders associated with mitochondrial dysfunction gave us great insight as to how the mitochondria, in several ways, may impact neurodegenerative processes. That has been the beginning of so many attempts at research arms of treatment—trying to ascertain if improvement of mitochondrial function could be achieved, and whether or not the cell can be protected from a course of death in terms of any of the neurodegenerative diseases. We used to say these disorders were very different. It is now clear that they share certain things related to the pathophysiology of a post-mitotic tissue.

There is a beautiful discussion in one of the recent Lancet Neurology journals (a relative newcomer to our list of resources) written by people who are involved in the field of genetics. They have studied the issue of whether or not post-mitotic tissue differentiates in such a way that it might actually be able to revert and try to divide. If a post-mitotic tissue like the nervous system starts to divide, it may produce a problem, because it cannot go back through the cell cycle other than impending its own death. It may be one of the triggers for apoptosis.

The requirement for energy in the presence of mitochondrial dysfunction may put a cell at risk because of oxidative stress. People who have attended the AFMCP course have heard that time and again from me during my presentations, but it bears repeating. Because of the risk factors related to mitochondrial dysfunction imposing secondary risk of oxidative stress, both at the level of membrane function as well as energy production, those cells are at risk for certain degenerative properties, among which the most obvious is apoptosis.

There’s an entire cascade now being discussed in terms of genetic risk for disability to de-differentiate and then incur apoptosis, as to whether or not healthy mitochondrial function can protect the cells from that particular demise. That’s where a lot of basic research is being directed—trying to identify genetic risks for that outcome, including mitochondrial dysfunction, but also other inborn errors that may put a cell at risk. Over a lifetime, a cell may not die right away, but it sets itself up for apoptosis because of those risks. There are several good discussions in an article by Zhu et al. in the April issue of Lancet Neurology.[1] They talk about the “two hit hypothesis” of neurodegenerative diseases. Among those intricate to that discussion is the role of the mitochondria and oxidative stress that may arise out of dysfunction.

Neurology and the Blood/Brain Barrier
JB: You have raised some very important points that impinge on our clinical assumptions. One of those assumptions has been the long-held belief that the brain is isolated from the rest of the body by the blood/brain barrier and things cannot cross it. Therefore, the brain is insulated or protected. That model is starting to change pertaining to the blood/brain barrier being a signaling medium. Would you tell us a little bit about how the blood/brain barrier is viewed in the field of neurology?

CW: We see it as a selective barrier. Even as recently as when I trained, it was considered to be an absolute barrier; there is no immune connection; there is no signaling across the membrane. Breaking down of the blood/brain barrier was a clinical concept. That has completely changed.

I don’t consider myself an expert in that area, but we now understand that there are certain aspects of the blood/brain barrier that make our attempts to treat these mechanisms frustrating because we want to get neurotrophic factors across the barrier and we struggle with that. Or, we want to get chelators across the blood/brain barrier and we struggle with that. We don’t know whether or not the ineffectiveness of certain protocols is related to the blood/brain barrier. We also recognize that a lot of signaling occurs at that area and that it is regulated in the normal brain. It begins to become dysregulated in brains that are affected by neurodegenerative processes such as chronic inflammation and the changes that occur at the level of the blood/brain barrier. There are beautiful review essays related to those changes and how our concepts are evolving, as we begin to understand that. Sometimes, the question comes down to something you and I have discussed in the past. That has to do with whether or not diseases that are considered neurodegenerative, or those that have a component of loss of neurological tissue over the course of time, have a common set of mechanisms or whether there is more than one set involved. Is there something going on systemically that might be involved in this process? If so, the blood/brain barrier is not protecting itself.

There is also the question about the underlying pathophysiology of all neurodegenerative disorders. I think the blood/brain barrier concept is shifting, but I don’t think any neurologists would say they completely understand it yet. That’s an evolving concept that will begin to fade in the same way all other concepts have been modified, as we begin to understand more of molecular genetics and the effect of interaction by cell signaling. That remains to be seen. I think we will understand a whole lot more about that in the next decade.

Microglia and Neuronal Function
JB: That relates to another changing concept you know much more about, that being the role of the microglia in neurological function. I recall learning about it some 30 years ago as being pretty much a structural component, the glia being a kind of glue-like substance that ties the neurons together in some kind of a three-dimensional structure. Now, suddenly, it seems that the microglia have a functional aspect that reinforces neuronal function. Would you tell us a little bit about that?

CW: There is an entire literature on that, as well, that is demonstrating beautifully the functional capacity of the microglia, both to regulate cleanup around the brain, as well as immune protection. There is also the intricate role of microglia in the modification of some things that can become chronically problematic to the nervous system. Once the microglia are turned on, that is, they think something is wrong, they have a habit of maintaining a low level of inflammation that can damage neurons. In every single disease that neurologists see where there is a process in which neurons are lost, we originally made the assumption that the microglia did their job—they would come in and clean up. They were called “sleeping giants” to some extent because they were capable of being very dormant cells. When there was an immunological attack, or some sort of toxic attack on the nervous system, they would turn on and act like immune-based cells that would clean things up. We then started to realize that in some of the neurodegenerative diseases, these cells are actually on all the time at a low level, not to the point where they’ll kill you, but to the point that they will maintain a low level of inflammation. Now, one of the ongoing hypotheses about some of the types of dementia, including Alzheimer’s, is that the A-b protein (amyloid beta protein) may be aggregating partially because the glial cells cannot accommodate this protein and they can’t break it down. All sorts of efforts are being made to try to figure out ways of dissolving the protein at the same time the glia are turned off. They may be the main reason the neurons are being damaged, more so than just the aggregation of the A-b proteins, and the aggregation itself may not be the problem. The problem is that the microglia cells are trying to break the protein down and, as a consequence, they are turning on an inflammatory process.
That also applies in other disorders that are much too complicated to talk about in our short time together here, but things like multiple sclerosis and various types of chronic ongoing inflammatory processes that can be turned on intermittently to create attacks. The glial cells play an incredible role. It’s not only the microglia; it’s the other supporting structural glial cells that can inhibit certain activities and can also remain “on fire,” to use Dr. Perlmutter’s analogy when he presented “The Brain on Fire.” It is one of those things thought to be the basics of the pathophysiology involved with cell degeneration in that situation. There is a very intricate connection between neuronal cell health and the actual functioning of the glial cells, supposedly the support structure, which do, in fact, a lot more than support.

JB: That leads to a segue among these factors—the post-mitotic tissue, the blood/brain barrier, and the glial cells. I recall a number of years ago—I think it was at our 3rd International Symposium on Functional Medicine—when Dr. Flint Beal presented his work. At that time, he was at Massachusetts General Hospital; I think he is now at Dartmouth working in the neurology area. He talked about the role that upregulation of the microglia had in the production of high amounts of nitric oxide, conversion to peroxynitrite, and how that related to the production of oxidative stress factors in nervous tissue such as he could measure with 8-hydroxydeoxyguanosine (8-OHDG). 8-OHDG is a breakdown product of nucleic acids that can be seen in the blood as a consequence of neurodegenerative oxidative processes. Has this theme continued to evolve since the early 1990s? Are neurologists generally agreeing with this?

CW: Those who are reading the current literature are agreeing with that. I have seen three separate articles in the last year and a half where those very specifics were talked about. Before, if you looked up things like 8-OHDG, you would be looking in basic science reviews and there would be no clinical applicability. In several recent review articles discussing neuroprotection (an exciting new concept for all of us in neurology), those topics are discussed specifically. It warms my heart because I know those things were talked about early on in functional medicine circles and they are now appearing in our literature. It’s a rewarding sense of a full circle process to show that those things have been determined to play a role.

Neurologists are very cautious. We are very obsessive/compulsive types to some extent. We are very cautious in terms of our conclusions. Right now, if you ask the average neurologist in practice whether he/she is measuring those levels or not, I think you’d find that functional neurologists are doing that (those few who call ourselves that), but you don’t necessarily find that to be the case. There are precautions about measuring those things until we can deliver absolute clinical criteria for their management. The pathology originally presented as playing a potential role is bearing out in article after article in review of the concepts of neurodegeneration, or the concept of neuroprotection to try to slow the course of these diseases. The disease courses are considered to be an unrelenting progression of neurological dysfunction. Indeed, we are seeing things related to the issue of measuring oxidative stress levels, as well as the role of free radicals. That has been quite controversial in our literature, as well, but it is leaning toward the other side of the pendulum in acknowledging that those things do play a role. It is imperative that we identify ways of trying to modify those risks early in life before the natural course of apoptosis has been set in motion.

Neuroprotection and Parkinson’s Disease
JB: Let’s take all of what we have been describing and possibly apply it to conditions some of our listeners are more familiar with, such as Parkinson’s disease and loss of nigral striatal neuron function. In the January 2004 issue of JAMA, there was a nice review that discussed neuroprotection in Parkinson’s.[2] I first recall reading about the concept of “neuroprotective therapy” in a review article written by Clough in 1991 on the management of Parkinson’s disease.[3] In the JAMA paper, I was fascinated with what the authors said about oxidative stress, mitochondrial dysfunction, excitotoxicity, and inflammation being the four etiological contributors to Parkinson’s. You and your colleagues in functional medicine have been speaking to that for the better part of ten years. Would you tell us how you see this article contributing to the general understanding, and its place in the history of the development of neurology?

CW: I wouldn’t go so far as to say that article is a culmination of everything. There have been several articles that have appeared since then that are a culmination, in terms of looking at all the factors. But it brings it to the general physician’s practice. When something that basic gets into JAMA, heads go up, and eyebrows lift to some extent, but it generates a lot of debate. That article contains some beautiful expression of the controversies in our field, and how we can interpret information from our basic science and clinical research. It also contains numerous caveats of caution about interpretations related to whether L-dopa, in the form of Sinemet®, is a toxic product or whether dopamine agonists are a protective product in Parkinson’s disease. In making their conclusions, the authors are cautionary in the sense that they don’t want to say they have identified that these things are neuroprotective, but they are outlining a course for where research should be going. Indeed, I’m pleased to report that it is going in that direction because they are summarizing some of things that have to do with how we will approach interpretation of our literature.

I don’t know how many of your listeners know about the study that was done initially in the 1990s that suggested there was a protective role for the MAO-B inhibitor (monoamine oxidase inhibitor type B). I spend quite a bit of time in AFMCP classes talking about the imperative of these basic and clinical research studies that evolved our thinking about this. There is now a lot of effort going toward trying to identify whether blocking MAO-B as an enzyme involved in excitotoxicity is something that could prove to be protective. That concept has received more attention related to the controversies about what the original drug we tested actually involved. People were given vitamin E or selegiline and vitamin E, at that time called L-Deprenyl. It was clearly shown that vitamin E in isolation really didn’t help people very much. However, there was another smaller study somewhat later that showed that vitamin C and vitamin E may actually play a role. I remember in the mid- 1990s, our movement disorders expert at Mayo told us that when we saw Parkinson’s patients, we should put them on seligiline, 5 mg twice a day, along with vitamins C and E. We gave vitamin C in a gram and vitamin E in 1200 IUs. Obviously, it was a-tocopherol and you could ask all the questions you want about whether those are the most appropriate antioxidant-type treatments, but at least the concept was being studied. L-Deprenyl, or selegiline, had somewhat of an agonist or dopamine protective effect. It might not have been the MAO-B inhibitor effect that actually created the response.

These types of controversies are well discussed in the January 2004 JAMA article. These things might be protective, but there are no large, definitive, long-lasting, placebo, double-blind studies to advise what to do when a patient comes in with early Parkinson’s disease, or is showing the earliest signs of any of the neurodegenerative disorders. In this situation, that article takes us straight to the facts—here are potential things that could impact these mechanisms. The mechanisms are potentially modifiable with evolving drug therapy, but also with other things. The most rewarding part of the JAMA article is that when the four basic pathophysiological mechanisms are discussed, the authors mention a role for drug therapy and also vitamin E or other types of antioxidant therapy. Other things are mentioned that may be more natural in terms of the ability to modify oxidative stress or mitochondrial dysfunction, like coenzyme Q10.

I found it interesting that the authors of the JAMA article refer to coenzyme Q10 as a “drug.” The idea that these basic pathophysiological processes are being investigated from all possible aspects of intervention is rewarding to those of us who have been saying there are other ways to modify these things besides drug therapy. If you start early enough, you can make a significant difference in the course of a patient who has been diagnosed with Parkinson’s disease. A lot of the things being studied about Parkinson’s also seem to have effect on some of the other neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), Alzheimer’s, and other types of storage diseases. This particular focus enables us to have the ability to modify some symptoms.

It remains to be seen where the best place to start is. Does one start everywhere? As a functional medicine practitioner, I think of things in terms of the matrix, and I want to know that I am trying to look at all aspects of a condition. First, look at all aspects that may affect an individual patient, and then make a test to measure it. That article falls short in guiding practitioners in what to do. One of the forerunners in terms of our clinical research has been Clifford Shults, who I think is still at the University of California/San Diego. He did phase 2 of the primary pilot study on the beneficial effect of coenzyme Q10 that was published in the Archives of Neurology in October of 2002.[4] That is always cited as a pilot study in our literature and everyone agrees with what Shults stated at the conclusion of the article—that a larger study is needed to confirm the results.

Even though we know that coenzyme Q10 is probably not harmful for people, a lot of physicians don’t know whether to advise their patients to take it as a supplement or not. But they can show their patients the data from this study and tell them that if they can afford it, perhaps they should take it. All of us are excited about the idea that these things are being looked at in our practice. These are the forerunners to a complete transformation in the practice of neurology. That’s why I’m excited about this.

There were other things that weren’t discussed in that article that Shults points out in a recent issue of the Archives of Neurology. He wrote an article, titled “Treatments of Parkinsons: circa 2003,” and added to the list mentioned in the JAMA article beyond excitotoxicity, impaired protein degradation, abnormal protein aggregation, the concept of neuroinflammation, and the role of the glia.[5] It talks about apoptosis as an early and late phenomenon. If readers are interested in what was started and discussed so thoroughly in the January 2004 JAMA article, they should read the Shults article. Though it is aimed toward neurologists and carries a lot of jargon related to some of our studies, it does very clearly define some of the issues that may also be included in that pathophysiology.

JB: There was another interesting paper on the same theme written by Dr. Bruce Ames from the University of California/Berkeley. Though not a neurologist, he has certainly made some startling and important discoveries about the biochemistry of the nervous system. The paper appeared in the Archives of Biochemistry and Biophysics and in it, Dr. Ames talks about a metabolic tuneup to prevent neurodegenerative disorders, which includes the use of lipoate, N-acetylcarnitine, and N-acetylcysteine.[6] What seems to be emerging is a collection of different antioxidant manipulators that may have an effect on redox of neuronal cells. Is that how you’ve watched the literature evolve into clinical practice?

CW: Yes, and all avid readers of the primary neurological literature are waiting for things like Dr. Ames’ views to get into it. Editorial comments discuss those things, but the primary papers are not yet making it into our literature. I apologize for not mentioning that article earlier. It is a beautiful step forward in terms of opportunities to modify things in ways that we already understand are efficacious. As I said, neurologists are cautious. Until we have a very large, randomized, placebo-controlled, double-blind study on a treatment, with every explanation possible explored as to the efficacy and the reason for it, we tend to be cautious. At the same time, it is so exciting to see. From my own patient population, I know these things work. I do these things on a regular basis and I have some very happy patients who could be a lot worse by now but are not. Taking that full circle, if we look again in a decade, we’re going to see those things in our literature.

I think the rest of the practice of medicine will make a tremendous impact on these patients. That’s the most rewarding thing, along with looking at those things from the perspective of our concepts about what antioxidants are. I don’t remember specifically which conference it was where you discussed mitochondrial function, but there were some beautiful concepts presented at that meeting about what a safe antioxidant really is. There were some beautiful questions posed that are sorting themselves out.

Environmental Effects on Neurological Function
JB: Regarding the management of a complex patient with a set of neurological symptoms, we often go back to what we call our “matrix,” looking at various confounding contributors that might relate to the outcome seen in signs and symptoms. One part of the matrix for neurological conditions which the authors partially allude to in the January 2004 JAMA article on Parkinson’s, is the genes/environment connection. In this case, it’s the genes and uniqueness related to the xenobiotic detoxifying enzymes and how various environmental toxins might be interrelated with Parkinson’s. That brings into play the toxicity argument and unique detoxification capability. Would that suggest that neurologists are going to be looking beyond the brain at other things that have to do with systemic detoxification?

CW: Absolutely. That’s one of the most important concepts. That does not get a lot of attention, but I remember your comments earlier about the blood/brain barrier. I believe those things are all issues being looked at. Neurologists tend to be neurocentric, but we do have models for toxicity that come from the systemic aspect of things. Hopefully, most of your listeners know about the MPTP model of Parkinsonism, which was a Demerol analog. Street use by people who took it as drug abusers caused them to develop Parkinsonism very quickly. That model has gone on to serve us well in terms of primate research related to identifying animal studies that can be done on Parkinsonism. That took us back to an “aha”—this is a systemic toxin that comes environmentally by exposure. There are some patients who didn’t get it and some who did, which took us back to the differences in their ability to detoxify things. That took us to the liver. We are reluctant to admit that any other organ in the body might be doing anything other than serving the brain, but we do understand that now. That’s one of the things that will evolve along with the concepts about protecting from environmental risks versus modifying genetic risk. If you can control either one of those things, but also at the downstream end, protect from the pathophysiology that those two conditions may engender, you have a treatment plan that allows for a lot of areas of entry. I think that’s what’s going to be coming forward in the next decade or so.

I’m really excited about the module we’re putting together. It goes way beyond neuroprotection and neurodegenerative diseases. As a neurologist, the matrix that we use at AFMCP applies to just about every single diagnosis. I’m not a diagnosis-based person in that sense, but as a neurologist, obviously trained to name things, I think about diagnoses. Even in those conditions where you suspect something might be neurological, but you’re not yet ready to diagnose it, that matrix works. The beauty of it is that looking at the environmental risks, the genetic risks, issues related to ability to detoxify, and all of the other aspects of the matrix, it applies beautifully to anything neurological. I’m biased, but I suspect it applies to every other discipline traditionally considered allopathic medicine. I’m extremely excited by the marriage of those two concepts—basic science and neurology coming so far with the pathogenesis of things that are now bearing out to have established abilities to modify genetic risk as well as environmental exposure.

Just to cite something else about Parkinson’s disease, there was another interesting article in the same journal that included Dr. Shults’ update on Parkinsonism. In it, a pilot study was briefly presented in which investigators used an old antibiotic (discarded quite some time ago) that has chelating effects.[7] Neurologists are not strangers to chelation. We have been taught how to chelate related to certain neurological disorders associated with heavy metal toxicity because, as most people know, they are disorders that are easily identified. The fascinating thing was that the investigators looked at the levels of copper and zinc in association with chelation, using a quinone-type antibiotic, clioquinol. They saw a lowering of the levels of the aggregation of A-b, the beta amyloid plaque that we were talking about earlier. The comment was made at the end of the article that it would be interesting if this applied to the genetic risk for Parkinson’s disease from accumulation of beta synuclein (one of the proteins that aggregates in Parkinson’s disease), and its affiliation with iron. We think our practitioners should be assessing these things.

It’s fascinating that things which may be toxic to the nervous system may come from the environment. We have ways of manipulating those things, and clinical articles are beginning to come to the forefront which suggest we take them into consideration. I thought it was incredible that this is making it into our literature. The beauty of that is to identify things that we can modify, and the matrix is a beautiful place to start for any disorder. It helps one to come to grips about asking questions relevant to genetic and/or environmental risks. That’s the teaching that remains to be taken into our primary neurological practices. We don’t typically ask about those things until it’s too late. I’m excited by that concept, the application of the matrix, and the module we’re planning for this fall.

JB: You’ve reminded me of an interesting sidebar relating to an environmental effect on neurological function. A number of years ago, I recall reading about some neurodegenerative clustering that occurred in a geographical area where people were eating sugar cane. A mold was found in the sugar cane that was producing a metabolite (3-nitropropane), a small contaminant of the sugar cane being consumed. 3-nitropropane was found to be a very strong uncoupler of neuronal mitochondrial function and which basically caused peroxynitrite formation and neuronal death. Here is a connection between the environment and lifestyle, and probably some genetic-related effects, that translates into neurodegenerative disease.

CW: Absolutely. The isolated cases where people have been exposed to something that turns out to be toxic and produces neurodegeneration, have been the early, preliminary eye openers for our practice. Our profession has been inundated by such things. It took us a decade or so to figure out what it was. Once we figured it out, we could apply it to mechanisms, and those things are well established in our literature now as being the forerunners of the interaction between genes and the environment and the role that might be modified by changing environmental risk in terms of neurodegenerative disease. Those examples are exciting, but threatening in a sense because it makes us aware of the fragility of the nervous system. People who have looked at those things environmentally and who then went on to look at them from the standpoint of the pathophysiology, added legions to our experience in terms of being able to understand these mechanisms.

Early Warning Signs of Neurological Disease
JB: Dr. Willner, we only have a couple of minutes left. Would you tell our clinicians what early warning signs and symptoms they should look for in their patients where neuroprotection might be of some benefit? You talked about motor system dysfunctions, but are there other hallmark signs and symptoms?

CW: The hardest part about answering that question is that neurologists are trained to pick up things having to do with dysfunction long before people express a disease. We are always examining whether someone has a tone change. From the standpoint of symptoms, it’s sometimes difficult. I personally think that anyone who has a tremor or a change in balance ought to be examined by a neurologist, or someone who has neurological skills that can ascertain that there may be an early problem. But symptoms are sometimes difficult. Any of the early warning signs of any neurological disease should be investigated, and immediately these prophesies that we’ve been discussing should be thought about. There’s a corollary to that. Often, by the time a patient gets to a neurologist, the diagnosis is a little bit in question, but it’s mostly obvious.

Often, patients are sent to neurologists that are far along in treatment. The neurologist may not have chosen that primary treatment for the disorder. The primary example is Parkinsonism, which we were discussing earlier. Patients are often started on Sinemet, or they’re immediately started on the newer medications, the dopamine agonists, because there’s been some early literature to suggest they may be protective. That has not at all been decided among those people who look at our literature with a critical eye.

When such patients come in, the corollary is to ask about their relatives and children, in order to make sure they are aware of things they can be doing now to prevent the possible progression of a condition because of their genetic risk. Oftentimes, they also share environmental risks related to the development of a neurodegenerative disorder. It’s a question of asking a patient whether or not they have relatives who are older than they are who have neurodegenerative diseases. Neurologists are asking their younger patients if there is Alzheimer’s, Parkinsonism, or ALS in their families. What would we do differently in a young person who may have that familial genetic risk?

That’s the turning point. I think that’s what going to be done in the next few years, in addition to looking at biochemical individuality and genetic individuality. We’re going to be looking at risks where we may not be able to halt the disease in the patients who are diagnosed, but if someone comes in, even for a migraine, we want to know whether or not they have Parkinsonism in their family. We want to know if even just one relative has it. We want to know if they’ve been exposed to things. The functional approach to that is beautiful in terms of its ability to identify those things.

JB: I want to thank you, Dr. Willner. This has been a most enlightening discussion, though just touching upon the tip of the iceberg in terms of what you’ll be covering in your two-day, intensive module on functional neurology this fall. Thank you again, and we will be keeping close tabs on your work.

Side 2

It is hard to believe that in just 40 minutes, Dr. Willner presented such a panoramic review of the current state of affairs pertaining to neurodegenerative disorders. I would call that a “tour de force”—a remarkable job on her part. It leaves us with a lot of important questions, many of which will be addressed in much greater detail during Dr. Willner’s two-day course on functional neurology, which will be offered this fall.

Let me give you a sense of where I believe the concepts that Dr. Willner discussed are going. I want to focus specifically on the four areas of the etiology of neurodegenerative disease that were described in the article in the January 2004 issue of the Journal of the American Medical Association—oxidative stress, mitochondrial dysfunction, excitotoxicity, and inflammation. I believe I can add a few thoughts about each of those in the context of the contemporary literature and how they might relate to the management of early warning signs of neurodegeneration—gait disturbances or specific types of functional neurological imbalances.

It is also important to remember, as Dr. Willner so eloquently pointed out, that the matrix—the fundamental lens through which the functional medicine model is focused—tells us that there are many different contributing components of organ-specific or tissue-specific pathologies. In general, a condition of a specific tissue is related to a functional change in the body, not just solely what is going on in that tissue. We are obligated to take a broader look. In functional medicine assessment, we start with antecedents, which include the genetic factors that underpin the relative susceptibilities and strengths of an individual that are modified in their expression by triggering factors—environmental and endogenous factors that can trigger the expression of mediators. The mediators are the signaling molecules that may work locally, but act globally. Last are the specific signs and symptoms of different duration, intensity, and frequency. It is that model versus the traditional differential diagnosis model that characterizes functional medicine and leads to the matrix, a series of interlocking physiological functions that may contribute to a dysfunction.

Let us talk about specific neurodegeneration. We will go back and re-explore the brief discussion we had with Dr. Willner concerning the glia, and the emerging role of importance it appears to play in functional neurology. There is mounting evidence, as described by Dr. Willner, that glial cells, overlooked for nearly half a century, may be nearly as critical to thinking and learning as neurons are.

In an article in Scientific American, titled “The Other Half of the Brain,”[8] Dr. Douglas Fields points out that the mental picture most people have of our nervous system resembles a tangle of wires that connect neurons. Each neuron is thought to have a long, outstretched branch (the axon) that carries electrical signals to buds at its end (the synapse). Each bud emits its own family of neurotransmitters through the synapse—chemical messenger molecules that act across a short synaptic gap to a twig-like receptor, or dendrite, on the adjacent neuron. Packed around the neurons and axons is a diverse population of glial cells—glial from the Greek word for “glue.” They were assumed to be structural and glue-like, attaching the neurons into a three-dimensional space, but research on glial cells faded into the background of science for a long time.

Neuroscientists failed to detect signaling among glia, partly because they had insufficient analytical technology, but primarily because they were looking in the wrong place. They incorrectly assumed that if the glia could chatter, they would use the same electrical mode of communication seen in neurons. They would generate electrical impulses called action potentials that would ultimately cause the cells to release neurotransmitters across synapses, igniting more impulses in other neurons

Over the past 10 years, it has been determined that the glia have their own unique messenger system. This system is not related to the traditional neurotransmitters, but to unusual molecules (not so unusual now, but unusual 10 years ago) like nitric oxide (NO). NO and other neurochemicals are neuromodulators that act like cytokines/chemokines, the messenger molecules produced by the immune system. That is what led neurologists to recognize that the microglia are, in fact, a subtype of the immune system. The brain has its own immune system. In fact, the glial cells are derived embryologically from the same progenitor cells as the Kupffer cells in the liver, the embedded lymphocytes, the circulating white cells, and the mucosal-associated lymphoid tissue (MALT) found in our gut. The gut, liver, systemic circulation, and glia are all communicating one to the other through similar messenger systems.

Once it was known that the glia had their own chemical messenger system (reminiscent of the body’s immune system), it was recognized that it was possibly a part of immunological vigilance and could be activated by the same precipitating agents that activate the immune system at large. These would be things like antigenic stimulants and foreign cells. Viral infections of the brain can upregulate inflammatory reactions through the immune-like process found in the brain, not necessarily occurring only systemically, but regionally in the brain itself, and this could interface with the messenger system of the immune system at large. It is an interesting evolution of our understanding about the other half of the brain, the glia, and how they relate to function and control of immune defense in the brain.

One of the principal agents released by the glia through activation is NO, through upregulation of neuronal NO synthase. Neuronal NO synthase, when undergoing a rapid immunological upregulation or activation, can induce an uncoupling of this enzyme to some extent, producing superoxide. Superoxide chemically reacts rapidly with NO to produce a caustic chemical called peroxynitrite. Peroxynitrite, in turn, can degrade into a nitrosating substance that can injure proteins—nucleic acids—and it is a promiscuous molecule when released into tissues. It does not need an introduction; it does not have a calling card; it basically “nails” anything that is near it.

When peroxynitrite is produced in the nervous system, there is potential for injury to neurons, which can uncouple their mitochondrial oxidative phosphorylation, resulting in neuronal oxidative stress that produces a shift of the neuron toward an oxidative chemistry leading to its own apoptotic death, or cell suicide. Neuronal reserve is lost. Over time, this accelerates the loss of post-mitotic tissues, increasing the loss of cellular reserve, and ultimately decreasing the function of that portion of the brain, leading to decline. This is another example of Dr. James Fries’ concept of organ reserve and losing reserve over time (in this case neuronal reserve), as a consequence of an upregulation of the apoptotic process that was initially triggered through glial cell activation and peroxynitrite production.

One of the interesting things that is emerging related to the control of mitochondrial function, is insulin signaling and insulin resistance, which tends to creat mitochondrial dysfunction. A number of papers have been published on this topic, including one in Science magazine, titled “Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance.”[10] The investigators show that there is an interrelationship between alteration in mitochondrial function, insulin resistance, and lowered energy production, as in mitochondrial uncoupling. As much as a 40 percent reduction can be observed in mitochondrial oxidative and phosphorylation activity when assessed by 13C/31P NMR spectroscopy. The data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly.

Whether it is insulin insensitivity or hyperinsulinism causing mitochondrial dysfunction, or mitochondrial dysfunction causing insulin sensitivity, appears to still be somewhat controversial. It may be a component of both. In the paper I am citing, it appears that insulin resistance is caused by mitochondrial dysfunction that occurs with age. Is it the chicken or the egg? In the functional medicine model, that is always an important question. It is caused either through the mitochondria, or through insulin signaling. The takeaway is that it is possible insulin regulation and mitochondrial support are interrelated in terms of the regulation of cell signaling, and how that influences oxidative chemistry and ultimately inflammation. One of the hallmarks of neurodegenerative disorders is the inflammatory response.

The neurons are “chock-full” (to use the vernacular) of mitochondria. It is interesting to note that the cell type that probably contains the highest percentage composition of mitochondria in its volume, is the cardiocyte (75 percent mitochondria). This heart cell would be visualized as being absolutely chock-full of mitochondria doing all the energy metabolism work required to keep the heart beating for all of our lives.

Similarly, the neurons, which are engaged in oxidative chemistry, are also very dense in mitochondria, not quite to the same extent as the cardiocyte, but still very prevalent. As mitochondrial oxidative phosphorylation decreases, or there is a mitochondrial phase transition leading to increased oxidative release, it leads to neuronal injury and apoptotic death of the neurons, as well as increased inflammatory response in the nervous system. There are now several links between mitochondrial metabolism and hyperinsulinemia/insulin resistance metabolic syndrome, and even to how that relates to neurodegenerative disorders. There may be a relationship between dysglycemia/dysinsulinism, and neurodegeneration.

Examining this from a web-like perspective using the matrix of the functional medicine model, there is a way to connect together what might appear to be processes outside the nervous system with things going on within the nervous system—a shift to inflammation and oxidative chemistry. There is a good review paper on the topic of mitochondrial metabolism and type 2 diabetes that appeared in Diabetes and Metabolism.[11]

One of the other things that increases neuronal oxidative injury, oxidative stress, and the associated inflammation of neurodegenerative disease, is oxygen itself. Oxygen plays a paradoxical role. There is a parabolic dose response relationship between oxygen and tissue function. At too low a level of oxygen the cells die, and at too high a level of oxygen the cells die. In the middle is the zone of optimal oxygen regulation. The brain is very dependent on oxygen. Obviously, we can go for weeks without eating. We can certainly go for days without drinking fluids, but we can only go for minutes without breathing.

Oxygen is a critically important nutrient to stabilize mitochondrial oxidative phosphorylation and energy production. The paradox is that as oxygen decreases in tissues resulting in ischemia, there are ever-increasing degrees of oxidative stress. That is paradoxical, because it would appear that the time of lowest oxidative stress would be when there is no oxygen. Just as is seen in reprofusion ischemia, where there has been an interruption of the oxygen supply to the heart associated with increased oxidative stress and injury, so it is similarly in the brain in times of low oxygen delivery or any kind of ischemic event.

One can sustain vascular toxic injury to the arteries, creating atheroma that results in lower oxygen to the brain. That is a possible cause of cerebral ischemia leading to increased oxidative injury to the brain and to early-stage dementia or neurodegenerative disease. Oxidative control is very important, and delivery of oxygen is also very important . As I have often mentioned, medicine in every culture, going back to the dawn of early Ayurvedic medicine, has a way of delivering oxygen to tissues through dance, deep breathing, or exercise such as yoga. There are many ways of delivering oxygen non-technologically to try to improve tissue specificity and function.

How do cells endure low oxygen? That is an interesting question that is now being explored. Cells can respond to hypoxia or ischemia, but in so doing, the production of various oxidant species is increased.

As was recently pointed out in a nice review in Science magazine, it is now recognized that cells cannot exactly gasp for breath when they are deprived of oxygen.[12] They must have a way of coping. The method of coping is to turn on a host of genes at low oxygen levels that help the cell survive through times of low oxygen. This is not necessarily the primary way a cell would like to work, however. In turning on those genes, different response elements related to inflammation and oxidative injury are also turned on. The genes controlled by the so-called hypoxia-inducible factors (which are gene response elements), are those that code for such things as red blood cell production and angiogenesis (formation of new blood cells through the angiogenic process), as well as for glycolytic enzymes that produce energy from glucose without the aid of oxygen. This is the pyruvate/lactate shuttle. These hypoxic inducible factors are like master switches that allow cells to respond to falling oxygen. In so doing, it turns on a series of secondary factors related to the production of oxidants—like superoxide and hydroxyl radical—through a series of processes. These are very strong oxidants which can cause injury to tissues. There is a price to be paid when working in an oxygen-deprived environment.

This is seen in a whole series of different types of tissue pathology. Probably most interesting is the one in rheumatoid arthritis and how it relates to the pathogenesis of that condition. A nice review was published on this topic in the journal, Arthritis and Rheumatism, which discusses physiological responses to hypoxia and implications for the hypoxia-inducible factor in the pathogenesis of rheumatoid arthritis.[13] The authors point out that there is close control of oxygen tension in tissues that leads to proper healing and proper immune response. Too low or too high an oxygen level can increase adverse oxidative reactions and lead to conditions that might precipitate or aggravate different types of injurious processes.

In terms of the arthritis process, a wide variety of genes is turned on again by the hypoxia-inducible factor, the gene-response element, that leads to activation of specific types of processes. One of those is angiogenesis, which may be desirable or useful in certain types of protection against low oxygen tension in tissues. The other is the activation of angiogenic-promoting factors that induce oxidative injury. It is, again, how the balance factors play out. In general, increasing activation of processes involved with protection against low oxygen tension will increase the risk to oxidative injury. But, proper delivery of oxygen to the brain is essential.

Why might the brain not be getting adequate oxygen? Is it because of coronary artery atheroma? Is it because of anemia? Is it because of a constriction in some kind of blood supply in a tissue? Is it because of a cardiac abnormality? These are important considerations in assessing proper delivery of oxygen to tissues.

Next, Dr. Willner talked about the excitotoxic relationship to neurodegenerative diseases. The activation of excitotoxicity can occur through various types of receptors on the neuron. These receptor sites may have influence on upregulating the response elements associated with oxidative injury and ultimately apoptosis of the cell.

Dr. Willner alluded to the MPTP work associated with neuroexcitotoxicity and Parkinsonism in young street males taking the Demerol analog. This work suggests that there may be a relationship between toxicity and neuronal excitotoxicity. This may have to do with the activation of specific receptor sites, like the glutamate receptor site that overstimulates the neuronal cell, by upregulating its oxidative function. One of the things that can cause initiation of this process is the lack of control of glutamate/glutamine interconversion in nervous system function. Glutamine production from glutamate is very important. Initiation of excitotoxic reactions could result from poor conversion of glutamate into glutamine due to a defect in glutamine synthetase, the enzyme responsible for glutamine’s production from glutamate.

There is now evidence from the neurology literature showing that the loss of glutamine synthetase activity is associated with epileptogenic effects seen in the hippocampus. One might ask how activation of glutamine synthetase is accomplished and what it is that might lower the activation of the glutamate receptor site. This is the so-called methyl-D-aspartate receptor site, or NMDA. On examination, we find there is a certain family of cofactors that could activate glutamine synthetase and also lower NMDA stimulation. The article that discusses the loss of glutamate synthetase activity in human epileptogenic responses is found in the Lancet.[14] This is another part of the excitotoxic model for neuronal degenerative disease.

The cofactor for the glutamine synthetase enzyme is the pyridoxal phosphate family, which is also involved with the folate cycle. Are there any relationships between inflammation, mitochondrial uncoupling, excitotoxicity, and poor B vitamin nutriture? There is evidence in the literature from animal studies and certain human epidemiological studies that suggests there is an increased incidence of neurodegenerative disease with B vitamin insufficiencies, particularly those B vitamins related to the control and regulation of the steps in neurochemistry. Certain B vitamins play a role in modulating inflammatory response, such as through the modulation of acute phase reactants involved in inflammation and how they interrelate with mitochondrial uncoupling and oxidative stress. Investigators have reported that patients with active IBD are more likely to have low vitamin B6 plasma levels. In this study, a strong correlation between markers of thrombosis risk and alteration in inflammation signaling and low vitamin B6 status was also observed.[15]

Again, we come to the web of these interrelated variables and why the matrix is so important when examining vascular effects, gastrointestinal effects, and effects on neurological tissue. Then we begin to search for Occam’s Razor. What is the central theme that might tie these effects together? Could vitamin B insufficiency be a factor that contributes to the progression or etiology of this condition?

When we talk about B vitamins, inflammation, mitochondrial uncoupling, and the connection between the gut, liver, vasculature, and the brain, we need to ask about homocysteine because it is one of the precursor markers related to the process of CVD . Does homocysteine have any relationship to these inflammatory mediators? The answer that is emerging to that question is yes. However, it does not mean that homocysteine is the be-all-and-end-all for evaluation of the relative risk to inflammation. There are other markers being developed, but homocysteine is certainly one of the variables we want to look at.

Homocysteine engages in neurodegenerative reactions through two mechanisms. One is its oxidation to homocysteic acid, an NMDA receptor activator associated with exocitotoxicity and neuronal apoptosis. The second mechanism, as I mentioned earlier, is that homocysteine may be associated with vasculotoxic injury to the endothelium, which leads to an atheroma that leads to vasculotoxic stress due to oxygen deprivation to the brain. The outcome is cell apoptosis through oxidative injury.

As we look at these two mechanisms, we might ask if homocysteine is connected to B vitamin nutriture. Those of us who have been in this field for a while are well informed of that particular association. What about B6, B12, folic acid, betaine as a methyl donor, and riboflavin as part of the MTHFR reductase complex? Riboflavin stimulates the production of flavin-adenine-dinucleotide, or FAD, the cofactor responsible for the activity of MTHFR. There are cases where individuals have single nucleotide polymorphisms (SNPs) or polymorphisms of MTHFR that require much higher intake of vitamin B2 in order to properly regulate the activity of MTHFR. B vitamin nutrients are responsible for the regulation of homocysteine. Elevated homocysteine can induce oxidative injury, inflammation, and is involved with endothelial injury and NMDA receptor activation and exocitotoxicity. This connects the heart to the brain to the immune system to the liver to the vasculature to the gut. It is a central theme that unites all those organs and resulting pathologies together.

To give you an interesting example from the recent literature, there is a paper published in the Journal of Thrombosis and Haemostasis, titled “Homocysteine and markers of coagulation and endothelial cell activation.”[16] In this paper, the authors discuss the in vitrofindings that have shown a procoagulant effect of homocysteine and present findings from their in vivo study, in which they did not see a relationship between hyperhomocysteinemia and markers of prothrombin activation. However, they used patients with mild homocysteinemia.

I am speculating, but conditions of inflammation and systemic cell stickiness that occur through the activation of adhesion molecules could influence blood/brain barrier permeability in such a way as to increase the uptake of various molecules previously excluded from the brain, initiating increased potential excitotoxicity. Evidence is starting to emerge that indicates this is not just wild speculation, but may have some clinical importance.

That also raises the question about how to maintain proper membrane and endothelial cell activity, which comes back to essential fatty acid nutriture. Is there a potential role in the diet for the proper composition of omega 3 fatty acids such as EPA and DHA, respectively? These fatty acids are known to be important for the proper regulation of the phospholipid composition found in membranes, and in the actual structure/function of membranes. If one is deprived of adequate levels of omega 3 fatty acids, it may have adverse effects on endothelial integrity and on permeability factors that relate to leakiness of those tissues.

One of the things currently being discussed is that within the folate cycle that controls methylation, there are many enzymes dependent upon specific cofactors that are nutrient-derived for their function. Each of those enzymes may be potentially polymorphic, with different SNPs that have differing sensitivities upon specific nutrients. Therefore, we might see a significant variation from individual to individual with regard to how each folate cycle, or methylation cycle, works in different tissues based upon a unique dependency on specific nutrients that is part of that pathway for activation of its function.

This model was recently discussed in a fascinating review paper in the journal, Regulatory Research Perspectives, that talks about the Food & Drug Administration’s ongoing work in the area of methyl deficiency and how that interrelates to environmental exposures and to nutritional imbalances.[17] This came out of a workshop that took place in 2001 and subsequent followup, that talked about the “Trans-HHS Workshop: Diet, DNA Methylation Processes and Health,” held at the National Institutes of Health.

There are many individuals now involved in different laboratories and from different prospective clinical research studies looking at the folate cycle, how it interfaces with homocysteine, and how it interrelates with clinical conditions. Interest in this has increased as a consequence of using disease-modifying agents in rheumatoid arthritis that are anti-folates. I am speaking about low-dose methotrexate that blocks the production of SAM. There is now concern about patients with RA who are on low-dose methotrexate for some period of time. What effects does it have on their folate cycle and ultimately on the tissues, organs, and organ systems that depend upon SAM for their activity (virtually every tissue of the body)?

When we look at that, we look at potential neurological risks, as well as potential cardiovascular risks that could come from things that might interfere with the SAM pathway. There are a variety of exogenous substances that can cause this, other than the use of an anti-folate medication. We can have what is called a “total load effect.” That gets into looking at polynuclear aromatic hydrocarbons and polyhalogenated compounds like DDT and dioxins. All of these have adverse effects upon the production of SAM. We look at toxic metals, including arsenic, lead, and cadmium, which can have adverse effects on the SAM biosynthetic pathways. Even zinc deficiency has an adverse effect on SAM synthesis. B12, folate, B6, betaine, 5-MTHF, zinc, riboflavin, and the absence of exposure to various toxins are all considerations, again coming back to the web-like approach toward reducing relative risk to tissue toxicity.

Last is detoxification. Dr. Rosemary Waring at the Birmingham University Medical School in the Neurology Department, has been studying the relationship of toxicity to neurodegenerative disease for decades. Her work is legendary and has been published about Parkinson’s being associated with certain toxic exposures in the workplace environment—agriculture workers, paint and dye workers. In a recent paper in the Journal of Nutrition and Environmental Medicine, she talks about the plasma cysteine-to-sulphate ratio being a potential marker for individuals undergoing exposure to toxicity and who have endogenous or exogenous toxicity.[18] Low sulphate-to-creatine ratios are associated with poor detoxification. Alterations of the cysteine-to-sulphate ratio may also be an assessment/prognostic indicator of alteration and detoxification that tracks back to potential risk to neurodegeneration.

It is a fascinating story that is emerging and certainly we owe Dr. Willner a tremendous debt of thanks for giving us such a panoramic review to work from in this issue of FMU.

Thank you for being with us. We will see you in July.


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