Friday, September 24, 2010

A Natural Response to Alzheimer's Disease

It was only a few years ago that most believed amyloid plaques and protein tangles could not be removed from the nervous system. We now know better and recent findings have important implications for our cerebral health. Over recent years there have been a number of studies highlighting that in contradiction to another once well established opinion, age associated cognitive impairment is not inevitable and there exist a wide range of strategies to ameliorate cognitive decline with aging. Achieving that goal, and in these days that is a realistic goal, is no easy task. It requires a variety of strategies but the long term pay offs are potentially enormous. This possibility first occurred to me on yet another afternoon when I had the energy of a bamboo deprived panda, I was flicking through TV stations and caught a glimpse of an interview with BF Skinner. He related that at his age, 85, he felt he was still going work but he stressed that throughout his life he had been very careful about his health. There is a very important for those who wish to live long and prosper: if that truly is your goal you had better start living towards that goal before you are 35 years old.

This study, you can read the news release here and download the full article here,  highlights one aspect of cerebral health that requires considerable attention because it addresses the very earliest stages of pathological progression and so presents an optimal strategy for preventing cerebral decline at the earliest time points. That is very important because once those protein tangles and plaques reach a certain size various deleterious immunological responses are initiated. Somewhat paradoxically, one of these processes, inflammation, also plays a critical role in preventing the deleterious immunological response. That is more a semantic paradox than a theoretic one. Inflammation is a physiological state where a great many responses are in play and we are only beginning to tease out the good, the bad, and the ugly of those responses. 

The study above relates to how activation of the immune response by Toll Receptor No. 9 leads to the protein tangles being absorbed and degraded. Toll receptors are key mediators of various immunological responses. No we do not fully understand all of this which means we also do not know how much we do not know but need to know ... whoops bit of a Rumsfeld moment there. The last great hope for an immunological based approach was vaccination but as they noted in the news release:
Immunomodulation or vaccination for AD is emerging as an effective means of shifting the equilibrium from Aβ accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages - two forms of toxicity- were shown to occur in previous vaccination studies targeting the adaptive immune system.
I remember the great excitement about the clinical trials for a vaccination. Many predicted disaster if only because an adaptive immune response in the brain is generally rather disastrous, tends to run away and destroy too much tissue, possibly by way of epitope spreading. If you read the Wiki link concerning epitope spreading you will see it is strongly  associated with autoimmunity. (Note also that in that Wiki entry the comment about how low level autoimmunity is very important in preventing cancer.) The CNS expresses a huge array of proteins, it is surmised that the presence of the blood brain barrier is in part to prevent excessive adaptive immunological responses in the CNS. Hence the prevailing view for a long time was that the CNS is "immunologically privileged", the implication being that immune responses were largely absent from the CNS. With respect to the adaptive immune response this is true, but the innate immune response is largely driven by the local tissue environment. Innate immunological responses initiate adaptive immune responses. In the CNS innate immunological responses, including localised but most importantly, transient, inflammatory responses, are essential for maintaining "house keeping" functions but the barrier prevents, hopefully, excessive adaptive arm mediated immunological responses.   

I should add that while the adaptive immune response is limited in the CNS, it is not eliminated. Various  immunological cells will enter the CNS, some even becoming microglia, the resident support and immunological cells in the CNS. Most neuropathologies will demonstrate penetrance of these immunological cells into the CNS, it is my suspicion that once this barrier has been breached inhibiting pathological progression will be near impossible. Hence, as I stressed at the beginning of this post, it is essential to have strategies that stop this pathological progression long before that barrier is breached because with increasing numbers of immunological cells entering the CNS and microglia becoming increasingly activated the result will be a significant leap in inflammation, well beyond that which is beneficial for amyloid clearance. 

 The possible linkage between innate immunological responses and amyloid clearance first came to my attention with a study release only earlier this year. I have addressed that article in this post. To re-iterate, the finding that was inducing gliosis, a word that relates to inflammatory states in the CNS, amyloid clearance became possible. Consider this statement from the abstract of that study:

These results indicate that mIL-6-mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Aβ plaque clearance rather than mediating a neurotoxic feedback loop that exacerbates amyloid pathology.
Note the "early"! To my knowledge this is the first study to highlight how gliosis is an essential process for maintaining cerebral health. I cannot recall another occasion where the word gliosis was associated with something good. So I did a data check. No evidence of gliosis in the abstract  but a very clear suggestion that activation of the innate immune response leads to amyloid clearance. The study is from 2001. That highlights how important it is to be keep on reading, keep on looking. I should add though that the emphasis on the innate immune response only began in 1990's and arose principally because of a major theoretical adjustment to our understanding of immunology. Prior to that the emphasis was very much on the adaptive immune response with the preferred model being the self-nonself model of immunology, a model with such severe limitations it simply didn't allow us the option of seriously considering the implications of immunological responses in the CNS. 

We now have a much better conceptual foundation for understanding the intricate and often bewildering interactions between the CNS and immunological responses. A tight fit, a necessary requirement for innate immune activation to promote house keeping functions thereby preventing amyloid loading but chronic immunological stimulation giving rise to chronic inflammation is extremely undesirable. Future research will elucidate with much greater nuance the precise means by which amyloid clearance can be maintained without "collateral damage" to healthy tissues. 

One reason why exercise may be so beneficial is that it constitutes a type of stressor and perhaps that type of low level stress is sufficient to mobilise innate immunological functions. I do recall studies indicating that both muscle repair post exercise, and neural repair post injury, requires an  inflammatory response. Given the overwhelming evidence that so many factors play a role in cerebral health, from fatty acid balance to psychological stress, it is clear that cerebral health can be modulated by a variety of agents over which we do have some control. These being:

Stress Management

Don't avoid stress manage it. Stress is good, evolution has shaped physiology so that stress is not only a defensive response but a beneficial response. The key variable here is time. Sustained stress can induce too much collateral damage, learning to take time out and crash the stress response is very important. We have all heard about the stress response but how many know about the relaxation response? Yes, it has been postulated and there are even exercises for it. I'm not advocating any formal approach to relaxing, I think most of us probably have a good idea of how to feel relaxed, but it is important to make sure you are not chronically aroused and, more importantly, to acknowledge that we often can be unaware of our state of arousal. As I explored in an earlier post, I suspect a pre-condition for depression is sustained arousal. The regular induction of a relaxation response provides a personal point of reference to help us maintain an awareness of our arousal level. 


 I'm not going into detail on this, it is obvious enough. There are a gazillion suggestions out there with regard to nutrition and cerebral health. I don't buy into the precision of much advice,  possibly put forward to appear scientific, because I think individual variability makes such precision impossible. Fatty acid balance is important, the rest is about good eating. Don't go overboard on the omega 3 stuff, too much omega 3's can induce an inflammatory response and can be dangerous for the retina. The converse though, too much omega 6, and sadly this is true for many people, is much worse. The key is balance. Saturated fats get a bad rap, and incidentally there are studies indicating saturated fats do induce an innate immune response, but saturated fats are not bad, they are essential to our health. Forget the idea that red meat is bad, lean red meat is good but I suggest that we focus on various meat types. Moderation, moderation ... .  Vitamin D supplementation and magnesium supplementation are worth investigating. There is also the suggestion in recent research that maintaining adequate Vitamin B group intake and folate is extremely important. 


Chronic sleep deprivation is a huge problem in our society. There are abundant studies to indicate that chronic sleep deprivation, damn even a couple of days moderate sleep deprivation, initiates a number of undesirable physiological responses. Exercise and eat well all you like but if you are chronically sleep deprived you may as well eat at the local greasy fish shop and live on a couch. 


Exercise but not like you see on all those TV adds. Honestly, if I ever see one more infomercial for Zumba! I'm going to track down that Latin dude who started it all and slowly beat him to death with a soft stick. High intensity exercise is not necessary and too much of it is dangerous. Here's a clue about the adaptive stance of human physiology. Bipedal humans are more energy efficient than quadruple animals. We don't run down prey, we walk down prey. We wear them out with endurance, possibly because our capacity for sustained attention allows us to keep our eyes on the goal. We were made for walking, not running, not Zumba!,  not AB Circle, not Gym by Jake, and I suppose by now you can tell I've been very bored lately and watching too much late night TV! Moderate, light exercise and much more importantly, frequency of exercise. By way of example, a recent Australian study found that even if an individual went to the gym and did their morning run if that individual was sitting down all day there remained an increased their risk for developing Type 2 diabetes. So even those little, intermittent bouts of exercise, like walking an extra distance to the shops, or instead of sitting in the lunch room going for a walk around the local area, is important exercise. 

Toxin Exposure

Be aware of possible toxin exposures. In relation to diabetes, you might to take note of an earlier post. We are swimming in chemical soup of our own making, there is now very strong empirical evidence to implicate pollution in asthma, diabetes, Parkinson's .... oh its a bloody long list. As if CBD air isn't bad enough, and yes it is bad, our own homes often carry more dangerous chemicals than the street air. There is not much we can do about this. If you live or work in the city the simple fact is you are being constantly infiltrated with toxins. This isn't necessarily a problem, the toxin load in most cities is probably manageable by most people, but nonetheless I would consider myself hopelessly optimistic if I asserted that such exposures were without ill health effects. To assert something like that I would have to work for James Hardie or BHP or Shell or Halliburton or join a political party.  Sadly, short of radically changing your lifestyle there is no solution to this problem. My personal view is that the adverse health effects associated with this toxin exposure are generally so low that I don't give a damn. I advise though that I draw this conclusion because in my particular case there are much more important problems and given my personal history and life expectancy toxin exposure fall to the bottom of the list. If, however, if you wish to avail yourself of every chance of a long life, staying away from CBDs and other high air pollution environments should be near the top of the list. 

Job Satisfaction

We spend approximately one third of our conscious time at work so obviously our work environment is very important to our health. Find a job you like because if you have to spend that much time doing something then surely it is worth the effort to work towards doing something you can find satisfaction in doing. Sadly modern economic realities do not make that a possible goal for everyone. Nonetheless as someone who has worked in a very wide variety of employment I can assert that even if you don't like the particulars of your work you can still find enjoyment in being around your work mates and whoever else you encounter in your daily working life. 

Be Happy

If you are unhappy with life change your life or change your attitude. Chronic unhappiness, technically referred to as dysthymia, is an invitation to early cognitive impairment and does substantially increase the risk of dementias and other health conditions. Learn to be happy, make it a goal. It does not just happen, not for everyone, some, perhaps most, have to work at it. In fact given the increasing incidence of depression, the massive use of anti-depressants, the escalating demands of work, the increasingly cold and distant nature of people towards each other, in these days we have to work harder at finding happiness. The ways to happiness are as many as the ways of men(to paraphrase Buddha). You can find your own way but not if you're standing still.

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