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.
Memory Molecules
There are still a great many mysteries about memory:
- The molecules in neurons are constantly changing, as are many of the connections between cells. So how can memory be maintained for a lifetime in an environment that is in a constant state of flux?
- Why is it that you can remove large regions of the brain yet memories are not lost? Even in the late stages of Alzheimer’s disease, some long-term memories are maintained even when much of the brain is taken over by plaques and tangles.
- How much memory is there outside the brain and in the body?
- Is some memory maintained not in the brain itself but in fields associated with the body?
Gradually some questions are being answered not just by technology, but by asking new questions and bringing new types of expertise to bear on these problems.
A very interesting new study was published last week in the Journal of Neuroscience. The paper was not by neurologists, but by two mathematicians from the Brain Institute at the University of Utah. Their research suggests that memories are held in our brains because certain proteins serve as anchors, holding other proteins in place to strengthen the connections between nerve cells known as synapses. The anchors keep proteins in place, and these proteins in turn determine how strong a synapse is. And the strength of the synapse is a key to forming and retaining memories.
Synapses function by electrical activity in a neuron releasing a chemical neurotransmitter that affects another neuron or an organ.
One of the primary neurotransmitters involved in learning and memory is called glutamate, that binds to a number of receptors. But the most important for memory are the "AMPA receptors" that are embedded in the receiving ends of neurons. The AMPA receptors are held in place by special scaffolding molecules.
The mathematicians were able to make several predictions about the way in which AMPA receptors stay in place and how repeatedly learning something strengthens the connections between neurons.
The key to learning and remembering is anchoring AMPA receptors on our neurons.
I went into the technical side a bit, because this finding may help us get closer to understanding what goes wrong in Alzheimer’s disease.
It also ties in with some other research out this week in the journal Neuron. A team from the Univesity of Oxford has been trying to work out why adults may find learning more difficult than children. The young learn things more easily, but older brains stiore information more efficiently. They also focused on synapses, and seem to have found the mechanisms involved.
Young brains have many "silent" synapses that don’t do anything unless called upon to learn something. Older brains have to reuse synapses that have already been used, boosting the strength of connections with increased amounts of neurotransmitters.
So as we get older, our brains adopt different strategies for learning new material, and we should get ever better at organizing and integrating information.
That also fits with the strategies that we have used for improving people’s ability to learn and remember. We use connections as in Mind mapping, multiple sensory associations inclusing music, color and smells, and a sophisticated method for asking constant questions to see if new information fits with material that we have already asimilated.
Links, Citations and References
Following my recent article about mystical experiences, I had a charming note which included this question:
"Could you kindly give a reference or link to the above quote from Ramana Maharshi?"
This was my response:
"I am traveling at the moment, so I don’t have access to my library.
Happily I remember exactly where the quote came from. It was from someone who taught me a great deal – the late Paul Brunton. I think that Paul probably did more to introduce Ramana Maharshi to the West than anyone else, and he was also a close friend of Aurobindo. He once commented that it was rather convenient that two of the greatest sages of the 20th century only lived 65 miles apart!
He also mentions Ramana’s comment in Chapter 9, paragraph 23 of Volume 16 of The Notebooks of Paul Brunton.
Here’s the exact quote:
"That these differences of view exist even among illumined mystics is a striking but rarely studied fact. Why did Ramana Maharshi poke gentle fun at Aurobindo’s doctrine of spiritual planes?"I do not know off hand whether there are any websites that specifically discuss their – respectful – differences of opinion.
If that does not give you what you need, please do let me know: I shall be home in a couple of days and I’d be happy to do a bit more digging in my library: I have over 12,000 volumes, and there are quite a lot of lesser known titles in there. Since I raised it, I shall also have a look online when I get home.”
The reason for re-printing this correspondence is this. Regular readers will know that my blog entries are festooned with links, citations and references. That is very deliberate. This blog is a bit different from most of the other medical ones out there in that I try to ensure that you can check everything that I say.
The other day I had the privilege of speaking to the Rotary Club of New York and mentioned that I had written something about five strategies that can dramatically reduce your risk of developing Alzheimer’s disease as well as discussing some of the evidence concerning nutrition and neurogenesis: the production of new neurons. I was asked what they were, and I recommended that people asking the question should check out the article. The reason was simply this: I wanted them to see the evidence for themselves.
I think that we have all had enough of people simply expressing opinions.
Now is the time for people who are writing on line – or anywhere else for that matter – to provide data to support what they are saying.
If you need further reading material on any of the topics that I write about, just let me know: I have access to a great many sources that are not always easy to get at.
A Possible Test for Alzheimer's Disease
I was very pleased for some of my former colleagues from the Institute of Psychiatry at the Maudsely in London.
Years of work by the researchers and unstinting support from pateints and their families seems to be bearing fruit.
Professor Simon Lovestone and his team have published an important paper in this month’s edition of the journal Brain, which is commemorating the centenary of the first description of Alzheimer’s disease. It is very hard to get a paper in to the journal, and the fact that the researchers did, speaks volumes about the quality and importance of their work. The entire article is available online. That was made possible by the Alzheimer’s Research Trust who also funded this work: kudos to them for backing this work and for publicizing the results.
What they have done is to develop a blood test that may be able to pick up signs of Alzheimer’s disease before people start to show symptoms. They used a process called proteomics – the study of proteins – and found levels of two types of protein in the blood that were only present if people had the condition. We do not yet know exactly what the proteins are.
The researchers are quite rightly being cautious at this point. Nobody wants yet again to raise false hopes. There is also the knotty ethical problem of being able to test for people with the earliest stages of the illness. There is the theoretical risk that medical insurers may deny coverage if someone’s test is positive.
But if confirmed, this is of enormous importance: we already know that the earlier that treatment is started the better. And by treatment I certainly do not simply mean medications: controlling blood pressure, glucose and lipids; maintaining optimal nutrition; and taking physical and mental exercise may all slow progression of the illness.
It’s wonderful to have some good news about this often devastating illness.
Alzheimer’s Disease
To commemorate the hundredth anniversary of the first description of Alzheimer’s disease, there’s a very good review article by John Hodges from the University of Cambridge in the November issue of the journal Brain, which was published this morning.
I first met John when we were both teenagers, and even then his writing was a model of clarity. This new article is excellent, and if you have any interest at all in Alzheimer’s disease, I would urge you to read it. The journal has kindly made the entire article available for free through a grant from the British Medical Research Council.
The most important point of the paper is that our understanding of this devastating illness is progressing by leaps and bounds.Yes, there is still a lot that we don’t know, but some ingenious research is opening up a good many new avenues for prevention and treatment.
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.
Dementia
I have written about Alzheimer’s disease in the past, but it is important for everyone to know that not all dementia, and certainly not all memory loss, is Alzheimer’s disease.
There is a brief article on the Psychiatric Resource Forum website that will point you toward some extra resources.
Our biggest interest is always in ensuring that someone who seems to be developing a dementing illness doesn’t actually have one of the large number of remediable causes of cognitive decline, such as depression, an underactive thyroid, vitamin B12 or folate deficiency, or an unusual condition called normal pressure hydrocephalus.
Curry and Cognition
During a visit to Singapore a couple of years ago, I heard about some interesting research that’s just been published in the American Journal of Epidemiology.
The authors did something fairly simple. They took a group of 1,010 people with no evidence of dementia aged 60-93 years, and correlated their consumption of curry with their cognitive performance. Studies like this are not easy: what if more intelligent people like eating curry to begin with? What if sick people can’t get out to the local curry house? And so on.
But the researchers did this all very carefully: they took into account all the known sociodemographic, health, and behavioral determinants of performance on a simple cognitive test. So they controlled for many of the other factors that can accelerate cognitive decline, like depression, smoking, drinking alcohol, high blood pressure, glucose and lipids.
The result was that people who occasionally or often ate curry had significantly better cognitive function than people who "never, or rarely" ate curry.
Is there any logic to this?
Well in fact there is. Curcumin, from the curry spice, turmeric, has been shown to possess potent antioxidant and antiinflammatory properties and to reduce beta-amyloid and plaque burden in experimental studies. There have been serious suggestions about using active constituents of tumeric to try and prevent the development of Alzheimer’s disease.
This research is all very encouraging. The amount of curcumin used in the experimental studies is similar to the amount ingested by having a couple of curries a week, and now the epidemiological study from Singapore suggest that those couple of curries may have a clinically measurable effect. That’s not to say that eating curry three times a day is going to be even better.
All things in moderation: too much curry can play havoc with your digestive processes.
And your relationships….
Parkinson’s Disease, Allergies and Inflammation
The symptoms of Parkinson’s disease have been reported throughout history, but it was first described in the modern era by the great Scottish neurologist James Parkinson in 1817. Even after all these years, we still do not know all that much about what causes it. There’s an interesting study in the August issue of the journal Neurology, which is the official publication of the American Academy of Neurology.
Investigators from the Mayo Clinic used what is known as a case-control design (196 cases and 196 matched controls). What they found was that people who suffered from hay fever or allergic rhinitis, are 2.9 times more likely to develop Parkinson’s disease over a 20-year period.
The researchers did not find any association with autoimmune illnesses such as lupus, rheumatoid arthritis, pernicious anemia or vitiligo. They also did not find any association with asthma.
In addition, people who developed Parkinson’s disease used anti-inflammatory agents less frequently than controls, although this result was not statistically significant. The results may support the hypothesis that there is an inflammatory component in the causation of Parkinson’s disease.
You may ask, “Why on earth would anyone even look at a link like this?” The answer is that there have been previous reports of an association between the use of non-steroidal anti-inflammatories and lower rates of Parkinson’s disease in men but not in women and Alzheimer’s diseases.
This study does not suggest that hay fever causes Parkinson’s disease: it provides evidence for an association between the two. Parkinson’s is probably a group of illnesses with different causes. However, if chronic inflammation around the upper airways could produce inflammation in the brain, we might have a whole new way of preventing a degenerative brain disease.
In a future posting I’ll talk about some natural methods for reducing the burden of inflammation in your body.
