Parkinson's Disease, the Intestine and Infections
Early in my career, one of my mentors was the eminent scientist and clinician Robert Mahler. He recently passed away at the age of 81, but in the last two years of his life he was an author on two papers (1, 2) about an ailment with which he struggled for many years: Parkinson’s disease.
Despite the best treatment, he was severely incapacitated by the illness, at one stage needing a wheelchair to get from his car to his office. But his fine mind remained undimmed by the illness, and he was intrigued by reports of an association between stomach ulcers and Parkinson’s disease and of dramatic improvements in the symptoms of some people with Parkinson’s disease who were being treated with antibiotics for gastric ulcers. (Last year Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their pioneering work on Helicobacter – a bacterium associated with peptic ulcers.
I mentioned in an earlier post that I have a strong sense that there are more prizes to come on the
interaction between infectious agents, inflammation, genes, the psyche
and the environment.)
Robert was one of the test subjects in a research study and his Parkinsonian symptoms got much better when he was treated with antibiotics. There are now several important pieces of research on the fascinating topic. In some people eradicating Helicobacter may convert rapidly progressive Parkinsonism to a quieter disease, although only a minority of sufferers have evidence of current infection.
There seems to be an interaction between aging, genes and this infectious agent. Clearly not everyone is helped by antibiotic treatment, but this is a whole new line of very promising research.
Genes, Environment and the Brain
We recently looked at the worrying suggestion that environmental toxins could, in susceptible individuals, be contributing to the apparent increase in autism over the last three decades.
There is increasing evidence that there are complex genetic and environmental interactions that contribute to abnormal aging and neurodegenerative disorders like Alzheimer’s, Parkinson’s and Huntington’s diseases.
A new study from Duke University Medical Center in Durham, North Carolina, has done more to dissect this interaction. They collected information on 1136 consecutive patients who presented to the Joseph and Kathleen Bryan Alzheimer Disease Research Center. They showed possible significant contributions of toxic environmental and occupational exposures to pathological aging in 21% of the patients, and interactions of these exposures with common genetic polymorphisms that affect cell injury and inflammation. They found a series of genes that could partially account for differences in the type of cognitive problems that people experience, the age at which they developed them as well as the rate of progression.
The researchers targeted three genes in particular – apolipoprotein E, alpha-1-antitrypsin and the hemochromatosis gene. All three are expressed in the liver and in macrophages: cells that play a critical role in immune responses, inflammation and the body’s response to stress and infections. The first two genes are particularly involved in the metabolism of lipids and the third in the balance of iron and trace minerals. This ties in with another observation. Many chronic illnesses are associated with anemia. It is now thought that this also is a defensive reaction. Not to chronic illness, but to the problem that was far more common during evolution, and that was infection. The liver pulls iron out of the circulation so that bacteria cannot use it for their own growth. This is one of a number of adaptive responses that I discuss in the book and CD series, Healing, Meaning and Purpose.
But it was also clear form this new study that genes were not the only factor. I have spoken before about the small number of strategies that can dramatically reduce our risk of developing Alzheimer’s disease. The authors of this study agree about the importance of factoring in environmental factors including, alcohol use, nutritional deficiencies and sleep and mood disorders, all of which can have an impact on cognition.
This study is yet another step toward clarifying the role of genes, inflammation and cell injury in the development of degenerative changes in the brain.
While pharmacologists can use this information to help devise new ways to protect your brain, you can use it immediately. There is a range of behavioral and dietary strategies that can reduce the burden of inflammation in the body. I shall write about some of them in articles and an eBook in the near future.
We do not know whether these strategies can reduce the risk of Alzheimer’s and Parkinson’s diseases, but there are some intriguing suggestions that they can.
Multiple Sclerosis and Polio
There have been repeated claims that one of the causes of the rising tide of multiple sclerosis (MS) cases is somehow related to polio vaccinations. This idea has been championed by the brilliant Greek homeopath George Vithoulkas. His hypothesis is that the reduction in paralysis from polio appears to parallel a rise in the incidence of MS, and that it is polio vaccine that is to blame. There are many websites repeating the claim that polio vaccinations are the cause of many illnesses.
Is there actually any evidence for this?
I’ve look at several hundred papers in all the languages that I can read, and this is what I think so far.
It is certainly true that people who already have MS may become worse after some types of vaccination.
There have been very occasional reports of children developing an MS type of illness after vaccination, but probably only in children who were genetically predisposed.
There have been a number of studies on polio vaccination and MS. Most with only small numbers of individuals, but the only link seems to be that people with MS tended to have their vaccinations at an older age.
Many of the best epidemiological studies come from Scandinavia, where there are often superb medical records, and little mobility of the population. One study done in Denmark looked not at vaccination, but instead examined data on every person in Copenhagen diagnosed with polio between 1919 and 1954. They found that there was a slightly increased risk of eventually developing MS. This is very difficult research to do well, since the symptoms of the two conditions so often overlap.
There have only been a handful of well-executed independent studies and they have failed to find a link between vaccination and type 1 diabetes, MS or inflammatory bowel disease.
There do seem to be some unusual cases in which autoimmune phenomena have been clearly related to immunization, such as the neurological illness Guillain-Barre syndrome. But they are clearly uncommon. This also provides evidence against some ingredient in the vaccines being the problem.
Another approach has been to look at the poliovirus receptor gene, and again the findings failed to find a role of the gene in the development of MS.
As an aside, there does not seem to be a link between vaccination against hepatitis B and MS, though there have undoubtedly been occasional case in which the illness started after vaccination, and there remains a nagging concern about a possible association. The question always is the extent to which the vaccination could have caused the problem. The fact is that in complex biological systems there is hardly ever one cause for one effect.
On the evidence currently available the polio vaccine/MS hypothesis is not supported.
And I wonder how many readers remember kids with leg braces and iron lungs? Polio can be a nasty illness and I would hate to see it return to countries that have eradicated it.
Industrial Chemicals and Autism
There is an exceedingly important article in this week’s issue of the Lancet, that has not yet received the attention that it deserves.
I have time and again discussed the extraordinary burden of artificial chemicals now born by the human body. None of which was present 100 years ago. It is not rocket science to ask whether this toxic burden may have soething to do with the the rise of many neurological and psychiatric illnesses, given the sensitivity of the growing brain to any kind of environmental insult.
The article, entitled “Developmental Neurotoxicity of Industrial Chemicals,” is written by two senior academics from Denmark who also hold positions at the Department of Environmental Health at Harvard School of Public Health, the Departments of Community Medicine and Pediatrics at Mount Sinai School of Medicine in New York.
What they say is this. The report begins by saying that neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common and can cause lifelong disability. Indeed, 1-in-6 children has a developmental disability, which mostly affect the nervous system. The causes of these problems are largely unknown.
Secondly, the prevention of neurodevelopmental disabilities is hampered by the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof needed for regulation.
Next, the list of potentially damaging chemicals is extremely long. A few industrial chemicals are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction, for instance methylmercury, arsenic and lead. we simply do not know how manyother chemicals may affect the brain. Exposure to these chemicals during early fetal development can cause brain injury at doses that are much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as the gradual elimination of lead additives in petrol. Although these prevention campaigns have been highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. That being the case, since the young brain is so much more sensitiv, we can only assume that many of these chemicals must also be dangerous to the fetus, baby and growing child.
This article is published at the same time as an investigative report in the National Geographic. The magazine paid $15,000 for a reporter to have a full toxicological analysis, and if you have any doubts about toxins, I would urge you to read the article.
As a side bar, many clinical practitioners offer different kinds of toxicological analysis based on hair, skin, blood or electrical testing. Some years ago we looked into many of these methods using confirmatory analyses using a full scale research laboratory at Northwick Park Hospital in London. We found very poor correlations between the results obtained by the laboratory and three labs doing hair and blood analysis. I’m sure that some labs do a good job using hair and other types of analysis for a good deal less than $15,000. But It’s good to be a little cautious before relying too much on some of these unorthox evaluations. Just ask the lab to give you the methods that they use, the standard errors of their testing, their false positive and false negative rates, and how often they get their results checked by an independent laboratory. Then you can be confident that you or your practitioner is using a good one.
The conclusion from all the published literature, some of which is summarized in the Lancet?
Environmental toxins are there, growing and they may be responsible for the catstrophic rise in some neurodevelopmental disorders, in particular autism.
We probably have enough empirical evidence toadvocate some serious cleaning up of the environment, which will likely only happen once people begin to vote with their feet. Governments are taking notice of global warming now that it is being suggested that it may damage national economies.
We need urgently to see whether, if the are present, we have – or can develop – viable methods for clearing these toxins from the human brain
and restoring normal structure and function.
Testosterone and the Death of Brain Cells
I’m sure that you’ve heard the Robin Williams joke, “See, the problem is that God gives men a brain and a penis, and only enough blood to run one at a time.”
Well it may turn out that Robin was right for the wrong reason.
Typically thought of as the “male hormone,” testosterone plays key roles in maintaining health and wellness in both men and women. It is true that most men produce about twenty ties as much testosterone as women, but in both sexes, it is involved in energy, libido, and immune function and helps protect against osteoporosis. It is also essential for the normal development, growth and functioning of the brain. In small amounts it may also be neuroprotective.
However, too much of a good thing can quickly turn bad. Researchers from the Departments of Pharmacology and Cellular and Molecular Physiology at Yale University in New Haven, Connecticut have just published an important study of apoptosis or programmed cell death in neurons exposed to excessive amounts of testosterone. Apoptosis is a process for disposing of un-needed or unwanted cells, but if it gets out of control, it can begin to remove cells that should have been left alone. Apoptosis is thought to pay a role in illnesses including Alzheimer’s disease and schizophrenia.
While too much testosterone destroyed nerve cells, estrogen appeared to be neuroprotective: there was less cell death in the presence of the hormone.
This new finding has a number of important practical implications.
Testosterone is one of the hormones abused by some athletes. It certainly can enable them to pump up their muscles, but it may also make them aggressive. Now we know that the practice may also kill neurons. And loss of brain cells is associated with a loss of brain function. This is yet another reason why people should think long and hard before they try to use testosterone supplements. The concentrations used in the experiments were very close to what we might expect to see in someone supplementing with the hormone.
These effects of testosterone on neurons will likely have long term effects on brain function. Though you do generate new connections and some new neurons throughout life, there is a limit to how many you can put back, once they’ve been tainted by testosterone.
And since this is election year here in the United States, I’m sure that we’re now going to have to have a string of off-color jokes about the esteemed Governor of California….
Aging, Skin and Cancer
There’s a very interesting paper in this month’s issue of the journal Developmental Cell, based on research conducted at the Oregon Health & Science University in Portland, Baylor College of Medicine in Houston and Leiden in the Netherlands.
The investigators have found a pathway through which a gene’s over-expression causes stem cells in the skin to switch from creating hair follicles to creating sebaceous glands. This discovery may not only provide us with new ways of treating hair loss and oily skin, but it may help us to prevent and treat some cancers.
Skin cells turn over very quickly: just think how fast a graze gets covered over. Epidermal stem cells give rise to the outer layer of the skin that serves as a barrier for the body, as well as generating the follicles that produce hairs and sebaceous glands. These glands produce oils to lubricate the skin. In aged skin, a protein called Smad7 is overproduced, which triggers hair loss and sebaceous gland growth.
This is the first study definitively to link Smad7 over-expression and the pathological changes that occur in aged skin.
Here’s the twist: Smad7 shuts down signaling of another group of genes called Wnt. It binds to a Wnt signaling protein known as Beta-catenin and degrades it with an enzyme called Smurf2. (I don’t known why they decided to call it’s call it Smurf: it looks like ponderous chemical humor to me!) Wnt signaling is critical for organ development, but if Wnt signaling is too active, it also causes cancer.
Enhanced Beta-catenin signaling contributes to many types of cancer, including colon, lung and brain. Perhaps inducing over-expression of Smad7 or delivery of Smad7 directly to tumor cells would provide a therapeutic approach because of the boost in Beta-catenin degradation.
And finally, impaired Beta-catenin signaling contributes to neurodegeneration, such as that found in Alzheimer’s and Parkinson’s diseases, retinal degeneration, some bone density defects and aging. For these diseases, blocking Smad7-mediated Beta-catenin degradation may offer a therapeutic approach.
Free Radicals, Aging and Small Hairless Creatures
I’m accused of many things.
Apart from the oft-repeated falsehood that I was the inspiration for Hugh Laurie’s brilliant characterization of the cranky Dr. Gregory House (I definitely was not!), I have been accused of having a fixation with mole rats. Well, that one is partly true: they are fascinating little creatures.
But let me start at the beginning. Over the last three decades, free radicals have entered the national vocabulary. In the 1983 James Bond movie, Never Say Never Again Edward Fox orders Sean Connery to enroll in a health clinic in order to "eliminate all those free radicals."
Free radicals are found in nature: they can be derived from combustion and some other chemical reactions and they are generated in the atmosphere by the action of ultraviolet radiation with chlorofluorocarbons. But most found in the human body don’t come from the environment: they are generated by biological processes. The majority are extremely short lived, but a few special types can hang around for hours.
An excess of free radicals has been linked to an array of illnesses, including:
Some cancers
Diabetic vascular disease
Parkinson’s disease
Schizophrenia
Alzheimer’s disease
Emphysema
Age-related changes in the skin
Macular degeneration
This list just names a few: many other illnesses have been laid at the door of free radicals. You will often see people talking about “oxidative stress,” to describe the damage done by an excess of free radicals. There is a theory that normal aging may be a result of the gradual increase in the production of free radicals in the body
There is something to all this: I did some research on the role of free radicals in diabetic vascular disease in the 1980s, and made some interesting discoveries. It has recently been shown that an excess of free radicals in the wrong place can play a part in generating insulin resistance.
The trouble – as with so many apparently simple ideas – is that many of the popular concepts about free radicals are over-stated or even wrong.
We first have to ask ourselves, “If free radicals are so bad, then why does the body produce them at all?”
The answer is that free radicals play a crucial role in a number of important biological processes, including the killing of bacteria by a group of white cells known as granulocytes. They are also thought to be key cancer killers and prime mediators of normal communication between cells.
Yet they have been pilloried: thought to be the key to so many illnesses when, in fact, they are intimately involved in normal biological processes: if you had no free radicals you would probably die quickly and unpleasantly. We know that because there is a group of rare, fatal illnesses in which children cannot generate free radicals.
Rather than focusing on ways to eliminate free radicals, we should be dealing with ways to balance them.
Our bodies are loaded with sets of enzymes whose task is to mop up excessive numbers of free radicals. The most important of these are superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase.
When you see an advert or article extolling the virtues of some product because it abolishes free radicals or “reactive oxygen,” you know that you are dealing with some nonsensical marketing. Not science.
Fortunately, despite the marketing hype, it’s virtually impossible to obliterate all the free radicals in your body: Some must remain in your system or you will run into all kinds of medical problems.
Let me give you two examples of research that has shown first the good side of a producer of free radicals and second, one of the reasons why we know that there is more to aging than free radicals.
A study from France looked at a dye called mangafodipir that is used in MRI scanning. It was found to increase the cancer-killing ability of some chemotherapy drugs, while at the same time protecting normal cells. Mangafodipir was found to help promote the production of hydrogen peroxide while at the same time, through different biological mechanisms, protecting healthy cells from damage.
The second piece of research concerns my mole rats. I’ve talked about them before. They are extremely long lived: most reach the age of 25-30. And they seem never to get cancer. There are very few species that are spared from cancer: sharks rarely get the disease and there are some simpler organisms that also seem to be spared. So these mole rats have attracted the attention of researchers. What is more, they have very high levels of DNA damaged by oxidation so by rights they should get cancer and age prematurely. The fact that they don’t is leading to a whole new line of thinking about aging and illness.
So the message should be this: oxidative stress may be a factor in illness and aging, but your aim should be to modulate the free radical systems in your body, not to obliterate a key cancer killer.
Eat a diet that is rich in antioxidants
Don’t try and avoid stress: you can’t. Learn to manage it
Take regular physical exercise
Avoid environmental toxins such as smoke, excess sunlight, pesticides and radiation
Psychotropic Medicines and Neurogenesis
One of the genuine breakthroughs of the last few years has been the understanding that the brain is not a static structure, but is instead an organ that grows, refashions and repairs itself to a remarkable degree.
You may be interested in a brief review article looking at the effects of some of the medicines that appear able to stimulate neurogenesis in the adult brain.
It is no longer far-fetched science fiction to say that we are likely soon to be able to regenerate parts of the brain and spinal cord that have been damaged by disease or trauma. And in the meantime, we have an array of stratgeies that you can adopt to keep your brain active throughout life, while dramatically reducing your risk of developing dementia.
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