Aug 01 2008

Promising Alzheimer’s Treatment

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Comments: 46

Several interesting papers have come out of the recent International Conference on Alzheimer’s Disease, but the one to make headlines was that of Professor Claude Wischik. He has been doing research into tau protein, the protein that forms the neurofibrillary tangles that make up one of the pathological hallmarks of Alzheimer’s disease and is a cause of the death of neurons. He presented data on a new drug, Rember (methylthioninium chloride) that in a phase II trial of several hundred subjects reduced the progression of the disease by 81%.

Alzheimer’s Disease (AD)

AD is a neurodegenerative disease – a category of neurological disorders that involve the death of one or more populations of cells within the nervous system. Their causes are largely unknown, but are likely different among the various degenerative diseases and there is likely multiple mechanisms even within individual syndromes. If the word “disease” is attached to the name of a neudegenerative disorder, that implies that there are specific features (usually pathological) that distinguish it and a specific pathophysiological entity. For example, Parkinsonism is a category of neurological disorders that have the same signs and symptoms. Parkinson’s disease is one such disorder that has specific pathological findings on brain biopsy (although is also has a unique clinical feature – response to dopamine – and so that is how the diagnosis is typically made).

Likewise, AD is a disease (actually it is further divided into two diseases, an inherited form and a sporadic form) – it can only be diagnosed specifically by looking at brain tissue under a microscope. Therefore most people walking around with the diagnosis of Alzheimer’s disease really have a diagnosis of Alzheimer’s type dementia. Dementia is any chronic illness involving global loss of cognitive function, especially memory. Alzheimer’s type means that other causes have been ruled out. That’s it – dementia with a negative workup for a specific treatable cause is Alzheimer’s type dementia, which is often conflated with Alzheimer’s disease, because most of the time they are in fact the same thing. But the diagnosis of AD is usually not confirmed (if at all) until autopsy. Brain biopsies are generally not done because it is an invasive procedure and it will not effect treatment.

By the way – this is why it is very important to insist on an autopsy for any relative who dies with a diagnosis of AD – because they really have a diagnosis of Alzheimer’s type dementia, and autopsy is your one opportunity to get a firm pathological diagnosis, which is important for your family medical history. You owe it to the next generation in your family – do it.

The primary pathological findings in AD are neurofibrillary tangles and plaques. Tangles are, as the name implies, tangle of tau protein. Plaques are more sheet-like in form and are comprised of another protein, beta-amyloid. In the pictures below, the top one shows tangles and the bottom one plaques.

Translational Research

The new study by Wischik is an excellent example of what is called translational research – the application of new basic-science knowledge to clinical treatments.  This may seem obvious – and it is – but because researchers typically focus on either basic-science research or clinical research, specific effort needs to be made to tie the two together in the same research program.

It represents one of the primary strengths of science – all scientific knowledge works together. Our understanding of AD leads directly to our ability to treat it. This is also why to some degree it is useful to allow basic-science researcher to simply research what they find interesting, without a specific tangible goal in mind. In other words, researchers do not have to be looking for a cure for AD, but rather can simply follow their curiosity about the disease, how it works, and what is happening. The knowledge that comes from satisfying the researcher’s curiosity is likely to lead to something tangible, if history is any guide.

AD Treatments 

Current treatments for AD are largely symptomatic. They primarily inhibit the enzymes that break down acetylcholine – the main neurotransmitter involved in memory. Therefore there will be more acetylcholine available in the synapse between two neurons, the strength of the signal will be increased, and memory function will get a little boost. The effects of these drugs are measurable, but modest. They do not restore lost brain cells nor to they alter the course of the disease. I often read discussions of these drugs that report that they delay the progression of the disease, but this is not true. The measured decline of AD patients on these drugs will be less, because they will test better while taking the drug. But as soon as they come off the drug they fall back to their previous curve of progression. Actual progression has not been altered – just temporarily masked by a symptomatic treatment.

This is actually a common mistake in research – a possible confounding factor that can lead to a false conclusion. The academic community, however, is well aware of it. Basically, a drug that has a symptomatic benefit for a disease could give the false impression that it is slowing the progression of the disease if the symptomatic effects are not taken into account. This likely happened in Parkinson’s disease with the drug selegeline.  It was first touted as a drug to slow the progression of Parkinson’s disease but was later found to have symptomatic benefit. When this was taken into account the apparent benefits to delayed progression vanished.

There is one drug for AD, Namenda, which is a glutamate inhibitor. This likely also just has symptomatic benefit, but a small benefit for slowing progression is also possible. Still, while measurable, the benefits are modest.

There is therefore a huge need for a drug that clearly and significantly slows the progression of AD, and this new drug promises to be just that.  The data so far is from a phase II clinical trial, which is a trial in humans with the disease in question, but it is small and preliminary. Such studies are used to justify and help design phase III trials, which are considered definitive clinical trials. This means we are still about 4 years away from Rember hitting the market, at least. This depends upon how quickly a phase III trial can be completed, but of course also on the results. If the results are clearly positive, and no adverse events crop up, it can get through the FDA quickly. But the FDA can be sticklers – they may demand a second trial, or more research to explore possible side effects reported during the study. Drugs can be delayed for years or never make it to market.

If Rember pans out, as everyone hopes it will, it will hopefully be just the beginning of a multi-pronged approach to AD.  This is the direction that clinical research is heading with many neurodegenerative diseases – trying to find a cocktail of many drugs, each of which has a modest benefit but combined has significant benefit. For AD we may eventually have Rember to untangle the tangles, another drug to dissolve the beta-amyloid plaques, another drug to reduce stress on neurons by inhibiting glutamate, and another drug to enhance the action of acetylcholine. There may also be other targets of interest as well.

Because AD tends to strike late in life (although the familial form is younger in onset), and the disease typically progresses over years, slowing down the progression of the disease may allow most people with AD to live a normal lifespan with minimal symptoms – even without a complete cure.

Science Rules

In conclusion I would like to do a completely shameless metaphorical victory dance for science. Science is our most powerful tool for understanding the world and thereby improving our lives. Mysticism, superstition, magical thinking, and all the nonsense that makes up the bulk of alternative medicine does nothing for humanity. Magic isn’t real, science is. This new research is reductionist, materialist, naturalistic science at work. And thank goodness for it.

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46 responses so far

46 Responses to “Promising Alzheimer’s Treatment”

  1. mindmeon 01 Aug 2008 at 11:19 am

    My grandfather had it and pretty much every one of his brothers (he had 3 or 4) had it. I’m thinking I’m at high risk. I do all the active stuff with my mind that’s supposed to keep it at bay (although I sure do enjoy my aluminum moderated cheeze whiz). I’m currently 42 and I’m gambling stuff like this and better will come along in time so any cognition problems I have in my 70s will be of my own making.

  2. superdaveon 01 Aug 2008 at 11:28 am

    Steve, I have heard anecdotally that AD and other neurological deficits are basically inevitable provided one can live long enough to get them. Is there any truth to this?

  3. daedalus2uon 01 Aug 2008 at 11:41 am

    This is interesting. Some of the other readers might not appreciate the extent of the controversy surrounding the physiology behind Alzheimer’s and the various hypotheses of what the “cause” is (which would directly relate to how to stop the progression).

    There is the amyloid hypothesis, where the plaques of amyloid are thought to be the cause. There is also the tau hypothesis where the tangles of tau are thought to be the cause. There are also hypotheses related to energy regulation in the brain and also blood flow.

    Amyloid has received more attention and there have been vaccines which raised antibodies to amyloid which resulted in reductions, but no resolution of Alzheimer’s.

    “The amyloid theory “is in a meltdown,” says Claude Wischik of the University of Aberdeen, Scotland, founder of the biotech TauRx Therapeutics. He argues that the amount of amyloid in patient brains doesn’t correlate much with dementia, and that blocking tau, a second protein that accumulates in the brain cells of demented patients, as his company is doing, is a much better way to go.

    “I could never understand why people were so persuaded by the amyloid theory. It is more about sociology with science,” Wischik says.”

    from

    http://www.forbes.com/2008/07/29/alzheimers-elan-pharmacuticals-biz-healthcare-cz_rl_0729alzheimersresults.html

    My own view is that accumulation of amyloid and tau are both effects and not causes. The fundamental “cause” is reduced metabolism in the brain; reduced ATP production and consumption due to the normal energy regulation operating with a bad setpoint. I think it is ischemic preconditioning that is triggered and then is not un-triggered.

    Ischemic preconditioning is a transient state the brain can enter where it consumes less ATP and where it is much more resistant to ischemic damage. Most of the details of ischemic preconditioning are unknown, but it is triggered by brief periods of ischemia, reduced ATP levels, or by periods of oxidative stress (which are instances of acute low NO). We know that ischemic preconditioning has to be a transient state because if cells could tolerate it long term, they would have evolved to be in that state continuously.

    In Alzheimer’s reductions in brain metabolism are universally observed and are unexplained by either the amyloid or tau hypotheses. The reduction in metabolism is too much to be caused by defects in a single or even a few pathways. Each cell regulates its own metabolism and energy status itself (but in concert with its neighbors). For each cell to have its energy regulation “go bad”, either each cell has “gone bad” independently (very unlikely), or what appears to be a pathological state is actually some type of normal regulatory state but operating in a dysfunctional parameter space. Accumulation of amyloid and tau are completely explained by inappropriately prolonged ischemic preconditioning.

    Amyloid and tau are normally disposed of by ATP consuming pathways, either the proteasome or autophagy. If there isn’t enough ATP, shutting down long term ATP consuming pathways would be a good survival feature. That is exactly what ischemic preconditioning does. Shut off long term ATP consuming pathways to free up ATP for nearer term more time critical pathways. Amyloid and tau accumulations are not doing anything positive, their major detriment is that that they take up space and are perhaps toxic. People can accumulate quite a burden of them, so while they are toxic, they are not acutely toxic. That is, not acutely toxic in the time frame of normal ischemic preconditioning events, a few minutes, a few hours or a few days. The damage due to Alzheimer’s accumulates over years.

    My own view is that accumulation of amyloid and tau are downstream of the true pathology, and I would extend Wischik’s statement about amyloid to tau as well.

    Of course dealing with the sociology of Alzheimer’s research is much more difficult than dealing with the science.

  4. pecon 01 Aug 2008 at 12:00 pm

    “This new research is reductionist, materialist, naturalistic science at work.”

    Yes, and you still have no idea what causes AD. You just love to throw various chemicals into the brain that you think might prevent some of the effect. Your post doesn’t even show any curiosity about what might cause the disease.

    You think nature has done a shoddy job of creating us through evolution, so of course diseases like AD are going to happen. For no special reason, just nature’s shoddy workmanship.

    Well good luck with your new “cocktails” of drugs, I am willing to bet money it doesn’t work. At most it might dull symptoms while causing side effects almost as nasty as the disease.

    Maybe the victory dance should wait until there is a reason to celebrate.

  5. Steven Novellaon 01 Aug 2008 at 12:19 pm

    pec – so predictable. Sure, you bet on magic, I’ll continue to bet on science. So far the score is a million to zero in my favor.

    Of course I and others are interested in the causes of AD – it is an active and very interesting area of research. And as daedalus pointed out, there are various opinions of different researchers who are duking it out with research and evidence – science at work.

    But you again (so predictably) equate not knowing everything about AD with having “no idea”, which is demonstrable nonsense. We have tons of information about what is happening, the tangles and plaques just being the tip of the iceberg. We have lots of clues as well as to what triggers it in some people and not others. But AD, like ALS and other similar diseases, is likely not one simple disease with a simple cause and effect. It seems to be a complex interaction of multiple factors, which may be different in different people, that involve similar effects. The tangles and plaques are probably not purely causative nor purely innocent bystanders, but part of a sequence of events.

    You also create a false dichotomy – yes, evolution is haphazard and that is precisely why there are so many diseases. But that does not mean there isn’t a specific cause for a specific disease. It doesn’t mean we don’t try to figure out why a disease is happening.

    Scientific knowledge is rapidly progressing but will forever be incomplete. It is an endless victory dance. Woo, on the other hand, is worthless and static nonsense.

  6. superdaveon 01 Aug 2008 at 12:41 pm

    That is a nonsensical post even for Pec. The very premise of the post is that research into understanding how AD progresses has led to a potential treatment. It does not even sound like you read the post. Do you honestly believe that there is not significant portion of AD research dedicated to understanding its cause? That is just silly.

  7. superdaveon 01 Aug 2008 at 12:42 pm

    sorry, I used the word post twice in a row, but the firs time i refer to pecs comment and the second time I refer to Dr Novellas blog entry. It was ambiguous as written.

  8. DevilsAdvocateon 01 Aug 2008 at 1:47 pm

    [Time for a MSE on Superdave, ironic given the post subject, lol, j/k]

  9. pecon 01 Aug 2008 at 1:53 pm

    ” evolution is haphazard and that is precisely why there are so many diseases.”

    You are wrong wrong wrong. Most of these diseases are related to the unnatural modern lifestyle. Nature is a great genius and creates machinery that you could not dream of creating even if you had billions of years. Yes, the process is evolutionary, but it is not haphazard, and you have absolutely no rational basis for claiming that it is.

  10. Fifion 01 Aug 2008 at 1:55 pm

    Would it be possible to use the same “pec disclaimer” here as Harriet created for science-based medicine?

  11. pecon 01 Aug 2008 at 1:56 pm

    Yes, nature has programmed us to die, and yes diseases and accidents happen. But decades of dementia would probably not happen very often in individuals with a reasonably natural lifestyle.

    And yes, people live longer now thanks to antibiotics and surgery, so dementia is more likely. But I don’t think that explains the epidemic we have now.

  12. daedalus2uon 01 Aug 2008 at 1:57 pm

    mindme, I am in the same boat as you are. My mother and both her parents died with advanced Alzheimer’s. Since I have been doing research on nitric oxide and have observed the effects that raising my NO/NOx levels have had on me, I am quite sure that I inherited her low NO physiology which I think is what leads to reductions in ATP and mitochondria biogenesis in the brain.

    Amyloid can build up in many other tissue compartments and is not uncommon in many other common degenerative disorders, dilative cardiomyopathy, kidney failure, cirrhosis and even obesity and the metabolic syndrome. I think these all have the same final common pathway, not enough ATP which then triggers ischemic preconditioning (which has different long term effects in each different tissue compartment) which is somewhat different between different individuals.

    Distinguishing causes and effects in physiology is quite difficult because so much of physiology is so tightly coupled.

    I think it is purely related to energy status in the brain or elsewhere. The local control of ATP levels by local NO levels is not appreciated. All cells in a particular tissue compartment need to work “in sync”. They cannot all be controlled individually. There has to be diffusible signals between them that indicate energy status so they can work “in sync”. NO is an important part of keeping everything “in sync”. Maintain ATP at the right level and the damage can be repaired and not accumulate. Damaged proteins can be cleared and not accumulate. The worst things to do are those that compromise energy status of the brain; that would be stimulant drugs of abuse (such as cocaine, amphetamine and PCP). The best things to do are the same things that are good for all the other degenerative diseases, control weight, moderate exercise, etc.

  13. pecon 01 Aug 2008 at 2:51 pm

    Ok daedalus2u, then wouldn’t you agree that the wonderful new drugs Novella is so joyful about are probably not going to be the answer? Since you appreciate that organic systems are complex and interactive, would you say that the reductionist approach has serious limitations?

    ” For AD we may eventually have Rember to untangle the tangles, another drug to dissolve the beta-amyloid plaques, another drug to reduce stress on neurons by inhibiting glutamate, and another drug to enhance the action of acetylcholine.”

    He wants to address each separate aspect of the disease, rather than look at what has thrown the whole system out of whack.

  14. Steven Novellaon 01 Aug 2008 at 3:09 pm

    pec wrote: “He wants to address each separate aspect of the disease, rather than look at what has thrown the whole system out of whack.”

    You are a logical fallacy machine. More false dichotomies.

    You are assuming there is one underlying cause. That assumption may be wrong. AD may have multiple causes conspiring together. Or there may be a single trigger, but until we know what that trigger is we may be able to prevent the negative effects of the disease by blocking multiple downstream effects of that one trigger. Meanwhile we will continue to look for upstream cause(s).

    Your evolutionary claims are unfounded, as is your claim that AD can be prevented by a “natural” lifestyle – whatever that is. Meanwhile biology is full of example of sub-optimal design due to constrained evolutionary history.

  15. mindmeon 01 Aug 2008 at 3:16 pm

    ||He wants to address each separate aspect of the disease, rather than look at what has thrown the whole system out of whack.||

    Pec, and I suppose you know? But thing is, I know too. I know for a fact it’s little blue space men. If your explanation is different from mine, how do we decide who is right, beyond mere assertion?

  16. pecon 01 Aug 2008 at 3:24 pm

    “Meanwhile biology is full of example of sub-optimal design due to constrained evolutionary history.”

    Sub-optimal by your standards.

  17. pecon 01 Aug 2008 at 3:29 pm

    “You are assuming there is one underlying cause. That assumption may be wrong. AD may have multiple causes conspiring together. ”

    Of course. There is seldom a single underlying cause in such a highly complex system, which has so much amazing resilience and so much redundancy. Natural evolution did an amazing job.

    Lifestyle probably contributes greatly to AD and the other modern plagues, because the system is not equipped for decades of almost complete muscular inactivity. It also has trouble with highly processed food and synthetic chemicals, because these never existed until very recently.

  18. pecon 01 Aug 2008 at 3:35 pm

    The American lifestyle attacks the system and eventually it breaks down, although this may take many years. Middle age and old age is when it really catches up with us, although now young kids are also getting sick because the lifestyle has become increasingly lethal.

    You could study how the unnatural lifestyle attacks the system, rather than blaming nature’s poor engineering skills.

    That is why your approach is backwards — you don’t these diseases as the eventual result of repeated attacks on a tough and elegant system. Instead, you see the diseases as something we would expect, regardless of lifestyle, given a shoddy and haphazardly designed system.

  19. Steven Novellaon 01 Aug 2008 at 3:44 pm

    pec – please look up False Dichotomy. It would save us so much time. You seem completely uninterested in improving your ability to think logically and clearly.

    There is no either or between suboptimal design and environmental or lifestyle risk factors. You are making that false distinction – not me.

    There is a ton of research of the epidemiology of AD looking at every conceivable lifestyle risk factor. Just keeping mentally active seems to stave off the disease, probably by promoting neural stem cells. Exercising reduces the risk also.

    But this does not mean a perfectly healthy lifestyle would reduce the risk of getting AD to zero – genetics also play a huge factor, and it seems that some people are just destined to get it. Regardless – when people do get AD it would be nice to be able to treat it. You seem to be against that because it does not accord with your anti-science pro-nature (however you define it) ideology. I, on the other hand, think we should explore every potential avenue.

  20. mat alfordon 01 Aug 2008 at 3:58 pm

    We need to find a more natural environment for pec to live in. May I suggest Afghanistan or Iraq?

  21. daedalus2uon 01 Aug 2008 at 4:11 pm

    pec, neurologists have to look at each symptom separately before it can be determined if they are related or not and by what physiological mechanism(s).

    The process by which researchers are doing this is exactly right. They collect data, generate hypotheses, do experiments to test those hypotheses. Rule out hypotheses that are inconsistent with the data that has been collected. Write up the research and publish it. Eventually this process will be successful or the reasons why it is not successful will be known.

    My disagreement with this particular approach for this particular disorder doesn’t have to do with the process they are using to investigate it. It is researchers exactly like this who have published their research which I have read and which has caused me to rule out both the amyloid and the tau hypotheses based on my own understanding of physiology.

    An integrated holistic conceptualization can only be built up from the details. The details must come first. Until the details are correct a holistic conceptualization cannot possibly be correct. A holistic conceptualization must be correct at each level of detail; from the very small to the very large.

    It is a reductionist approach that generates the details. Without the details being correct there is not a chance of success at generating a correct holistic conceptualization. Once you have a holistic conceptualization that is pretty much correct, a lot of the details fall into place. They “have to be” a certain way if everything is going to fit together in a unified structure.

    Your premise is that the details are fundamentally not understandable. With that approach, the details can never be understood and so a holistic conceptualization can never be realized and can never be correct. Why you have adopted a philosophical approach that predicts failure is not something I understand.

    Your premise that undefined “lifestyle” differences are the cause has no facts or logic to support it.

  22. mindmeon 01 Aug 2008 at 4:24 pm

    Pec nice assertion but consider:

    Little blue spacemen attack the system and eventually it breaks down, although this may take many years. Middle age and old age is when the little blue spacemen really catch up with us, although now young kids are also getting sick because the little blue spacemen have become increasingly lethal.

    You could study how little blue spacemen attack the system, rather than blaming nature’s poor engineering skills.

    That is why your approach Pec is backwards — you don’t get these diseases as the eventual result of repeated attacks by little blue spacemen on a tough and elegant system. Instead, you see the diseases as a result of haphazardly designed lifestyles.

    So, I’m right. You’re wrong. Hope you understand.

  23. pecon 01 Aug 2008 at 4:39 pm

    “when people do get AD it would be nice to be able to treat it. You seem to be against that because it does not accord with your anti-science pro-nature”

    I am not against finding treatments for disease. I am saying that your search would proceed differently if you were more respectful of nature and took a more systemic (non-reductionist) approach.

  24. pecon 01 Aug 2008 at 4:45 pm

    daedalus2u: “Your premise that undefined “lifestyle” differences are the cause has no facts or logic to support it.”

    Novella: “There is a ton of research of the epidemiology of AD looking at every conceivable lifestyle risk factor. Just keeping mentally active seems to stave off the disease, probably by promoting neural stem cells. Exercising reduces the risk also.”

    Looks like you two disagree about this.

    I am saying that extreme inactivity is probably a major contributor, as well as manufactured food and chemicals. Of course you can live a perfectly natural lifestyle and still get sick. But I don’t think we would have this epidemic of dementia if our lifestyle weren’t so crazy.

    And I am not saying we should only consider lifestyle and forget medical treatments. Both are needed. And medical research would be more effective, in my opinion, if the body were seen as an amazing piece of strong, intricate and flexible engineering, rather than as a pile of junk that just happens to work occasionally.

  25. daedalus2uon 01 Aug 2008 at 5:16 pm

    pec, by what basis do you say our lifestyle is “crazy”? Because the lifestyle we have evolved to want to live isn’t good for us?

    Your premises are contradictory. We should credit our evolved physiology as being “an amazing piece of strong, intricate and flexible engineering” but not if it tells us to want to eat double-stuffed Oreos?

    You can’t have it both ways. The lifestyle we now choose to live is the lifestyle our physiology evolved to want to have. Your naturalistic philosophy can’t explain how people can want to do things that are harmful to themselves.

  26. Steven Novellaon 01 Aug 2008 at 6:27 pm

    pec – you confuse risk factors with cause.

  27. Steve Pageon 01 Aug 2008 at 8:06 pm

    Guys, I know it’s fun but I suggest that not feeding the troll here is the best option? Starve it of nourishment and it will stop posting.

    Steve, I saw some dubious research a while back by a Dr Tobinick which involved treating symptoms of AD with a perispinal injection of etanercept (apparently reducing swelling within the brain, thus improving cognitive functioning). However, families of patients of Tobinick’s swear that there is a marked improvement in their loved ones’ symptoms after treatment. Do you think that this is merely confirmation bias, or could there be a genuine benefit to the treatment?

  28. pecon 01 Aug 2008 at 8:52 pm

    “The lifestyle we now choose to live is the lifestyle our physiology evolved to want to have. ”

    We are living with the unforeseen consequences of our attempts to improve on nature. We can’t help being clever but limited and short-sighted, because evolution made us that way. But we are capable of seeing our mistakes once the consequences become obvious. We are capable of improving our lifestyle and giving our bodies what they need.

    This is so well-known I shouldn’t be saying it. Mainstream medical science is unanimous on the subject of lifestyle, with daedalus2u as the sole exception.

  29. DevilsAdvocateon 01 Aug 2008 at 9:10 pm

    Hmmm. Let’s see. I think I’ll pick a profession for which I’ve had zero education, training, or practical experience, and then go harangue its practicing members for doing it all wrong. Of course, these boobs will never listen to me. Closedminded fools.

  30. weingon 01 Aug 2008 at 9:33 pm

    I don’t get this “natural” nonsense. We are part of nature, therefore everything we do is natural for us to do.

  31. daedalus2uon 01 Aug 2008 at 10:07 pm

    Steve, I don’t think that finding is dubious at all. I think it is a powerful confirmation that some of the adverse effects of Alzheimer’s are acute and are due to ischemic preconditioning that has gone on for too long. Terminate the ischemic preconditioned state and some of the acute effects are resolved.

    Etanercept is a TNF-alpha blocker. By blocking activity of TNF-alpha in the peripheral vasculature it has been shown to decrease superoxide formation and increase the activity of NO. In the peripheral vasculature that shows up as increased vasodilation increased vascular reactivity. When injected into the CSF, it would block the effects of TNF-alpha in the brain. One of those effects is to produce superoxide. Superoxide has the effect of acutely lowering NO levels. NO regulates the ATP setpoint via interactions with sGC.

    Generation of superoxide is the mechanism for triggering ischemic preconditioning.

    I think the acute reduction of superoxide causes an acute increase in NO levels and an acute increase in ATP levels. I think this is the same mechanism as how fever sometimes reverses the behavioral symptoms of autism and how fever therapy was used to treat neurosyphilis. Fever therapy was the “standard of care” for neurosyphilis for decades before the advent of antibiotics. I think the chronic inflammation of neurosyphilis was what causes the paralysis.

    http://daedalus2u.blogspot.com/2008/01/resolution-of-asd-symptoms-with-fever.html

    Similarly the positive results the “magic light helmet” for Alzheimer’s which I blogged about (twice) is also consistent with a low NO and low ATP mechanism for Alzheimer’s. I think the magic light helmet may have some serious side effects that could even be fatal (which I discuss on my blog).

    The problem with both of these approaches is that they are transient and physiology will compensate for them. The long term solution is (I think) to raise the basal NO level with a physiological mechanism which is under physiological control. Short of doing that, I don’t think any approach will be successful. As I see it, Alzheimer’s is caused by good regulation around a bad setpoint. That can only be fixed by correcting the setpoint (which can only be done by raising NO levels).

  32. lurchwurmon 02 Aug 2008 at 2:43 am

    pec:

    First off, I’m going to replace “natural lifestyle” with “healthy lifestyle,” as this is the most probable meaning you are trying to give based on the arguments you’ve made.
    Most of us are aware that the average american lifestyle is out of whack, and some of the negative resultant effects can be reasoned through a priori or with little empirical evidence. One example would be the most obvious physiological effect: increased weight puts more pressure on our skeletal frames and less flexibility from that weight increase leads to joint problems. I don’t think most rational people could argue that point, because it seems to follow from the intuitive understanding of the body under increased weight conditions.
    However, I think you are making too big a leap from “medical science is not enamored with the current lifestyle” to “our lifestyles are causing AD.” You also stated that “But I don’t think we would have this epidemic of dementia if our lifestyle weren’t so crazy.” It appears from the wording in some of your statements that you are coming from a position of incredulity of medicine when it conflicts with your desire to lump all diseases under the umbrella of lifestyle woes.
    Another point you made was “Lifestyle probably contributes greatly to AD and the other modern plagues, because the system is not equipped for decades of almost complete muscular inactivity. It also has trouble with highly processed food and synthetic chemicals, because these never existed until very recently.” You didn’t make a strong connecting statement from “decades of almost complete muscular inactivity” to “highly processed foods and chemicals.” Even if you were a trained physician, I would still need to see a compelling sentence connecting those two sentences. It also doesn’t appear that you’re willing to grant a spectrum of health even amongst those who aren’t living a “natural lifestyle.” Everyone who isn’t living a healthy lifestyle has almost no muscular activity? Wouldn’t your assumption limit your hypothetical evidence to a small minority of those who aren’t living a healthy lifestyle? A lot of them are moving around all day and actually have to use more muscle to lug that weight around. Unfortunately, they keep consuming more than they burn off.
    In short, the reason we have science is to blast away conjectures that are the least probable. If we didn’t have science, people could reason a priori truths as facts (and subsequently live in the alternate universe called their imagination!) What if we accepted Berkeley’s idealism that anything we can think of is reality, because reality is only in the mind? What if Hume didn’t offer a rebuttal of skepticism with probable cause and effect explaining reality outside our minds? Pec, we know that a lot of people live unhealthy lifestyles nowadays, but please, bounce your lifestyle claims against the actual AD evidence and stop creating a system in your head that makes the most sense to you regardless of the evidence!

  33. Niels Kjaeron 02 Aug 2008 at 6:11 am

    In my view there is type II-1 and type II-i medicine. When a II-1 doctor discovers a drug which works II-i, the II-1 crowd is allowed a type II-i dance! I compliment the complementary style Steven Novella used in his original post. Cross validation in on its way so I actually look forward to visiting a type II-(1+i) doctor some day.

    Please don’t forget that is difficult to measure things happening inside a electromagnetic pressure cooker.

  34. daedalus2uon 02 Aug 2008 at 10:00 am

    In looking for images that illustrate metabolic changes in the brains of people with Alzheimer’s, I came across this site

    http://www.nia.nih.gov/Alzheimers/Resources/HighRes.htm

    It has a PET scan of a 20 year old brain and an 80 year old brain (I can’t tell the difference, maybe Dr Novella can). The scans of a normal brain and an Alzheimer’s brain are easy for me to tell apart.

    To me, the pretty uniform regulation of energy metabolism over the whole brain looks like good regulation. That regulation is around a good setpoint in the non-Alzheimer’s brains and around a bad setpoint in the Alzheimer’s affected brain. Any type of bad regulation around a good setpoint would show up as asymmetries and fluctuations; increased deviations around the “good” setpoint; deviations that are both positive and negative. Those deviations are absent even in the Alzheimer’s affected brain. I can only conclude there is good regulation around a bad setpoint.

    Alzheimer’s disease was first described over 100 years ago. How much involvement a “modern” lifestyle could have had on that case is unclear. Certainly there couldn’t have been any involvement of antibiotics because that was many years before antibiotics were available. Similarly that was well before the days of manufactured food and synthetic chemicals.

  35. Roy Nileson 02 Aug 2008 at 12:35 pm

    Please don’t forget your next appointment.

  36. eiskrystalon 02 Aug 2008 at 4:12 pm

    Actually, Pec may have a point about diet. Apparently alzheimers is less common in Japan (good fish & veg diet) than in other countries.

    He is however woefully wrong about causes of disease. I’ll give you a clue Pec, there is this little thing called germ theory.

  37. pecon 02 Aug 2008 at 8:37 pm

    “there is this little thing called germ theory.”

    I never said all disease is caused by diet. But a bad lifestyle can weaken the body and make it more vulnerable to all kinds of diseases. Mainstream medicine has finally accepted what alternative medicine had been saying for decades — that lifestyle matters. So it’s kind of silly when you “skeptics” continue denying it.

  38. weingon 02 Aug 2008 at 9:26 pm

    Lifestyle matters allright. Humanity has gone through periods of famine throughout its existence. Just suppose our food supply becomes contaminated and we have a couple months without food. Most of the “bad lifestyle” obese will survive, and the “good lifestyle” thin will starve to death.

  39. pecon 03 Aug 2008 at 8:07 pm

    Good idea weing — encourage your patients to be obese, so they can survive longer without food. But what if the drug supply is also contaminated? How will your obese patients survive without their diabetes, blood pressure and cholesterol drugs?

  40. psamathoson 03 Aug 2008 at 8:35 pm

    I don’t know, a couple months without food would result in the collapse of society and I don’t think belly fat will determine survival in that kind of world. It would probably have more to do with who has the most guns. Guile over gut, if you will.

    However, this is completely irrelevant to the topic at hand. Regarding this (potential) triumph of science, I would like to recall a similar sentiment expressed on xkcd regarding the mapping of the cosmic microwave background, which Steve was perhaps too polite to say:

    Science. It works, bitches.
    http://xkcd.com/54/

  41. eiskrystalon 04 Aug 2008 at 4:05 am

    Mainstream medicine has been messing with diets and stuff for centuries. however there is a big difference between “this magic food will stop disease” (alternative) vs “generally healthy and robust diet is generally good for your whole body” (mainstream)

    Alternative medicine is a collection of poorly thought out ideas usually based on superstition and nonsense. Good diet is not “Alternative”. It is common sense. Something you are clearly lacking.

  42. clgoodon 05 Aug 2008 at 2:16 am

    Dr. Novella:

    Either you’re a saint for putting up with “pec” and actually answering his trolls, or he’s a sock puppet there for didactic purposes. Surely a living, breathing human couldn’t be *that* obtuse!

    Excellent post (as usual). Alzheimer’s is one of my worst fears. I hope this bears fruit, and soon.

  43. More on Rember « Buttle’s Worldon 05 Aug 2008 at 2:20 am

    [...] — buttle @ 22:20 Dr. Novella, writing on the essential Neurologica blog, has more on the hope behind that new Alzheimer’s drug. He includes some good advice: By the way – this is why it is very important to insist on an [...]

  44. Steve Pageon 05 Aug 2008 at 4:44 am

    # daedalus2u on 01 Aug 2008 at 10:07 pm

    Steve, I don’t think that finding is dubious at all. I think it is a powerful confirmation that some of the adverse effects of Alzheimer’s are acute and are due to ischemic preconditioning that has gone on for too long. Terminate the ischemic preconditioned state and some of the acute effects are resolved.

    Sorry, d2u, I’ve only just seen this and I wasn’t very clear in my original post. The reason that I said that the research was dubious was because of question marks about the motives of the author, Dr Edward Tobinick. He made similar claims about the drug (etanercept) before but in relation to treating chronic back pain, whilst failing to disclose that he had stock in Amgen, who produce the drug. There’s an article about it here. http://www.dailymail.co.uk/news/article-562254/Doubts-claims-doctor-reverse-Alzheimers.html (sorry it’s from the Mail, but I don’t have much time and it’s the only link I could find at short notice.)

  45. daedalus2uon 05 Aug 2008 at 8:41 am

    Steve, I was only addressing the physiology of what was reported. I have done no investigation into any COI that those involved might have. People working on other ideas of what might be causing Alzheimer’s have their own COIs. If amyloid or tau is merely associated with Alzheimer’s and not causal, then treatments directed at removing amyloid or tau are dead ends and are doomed to failure. Having many years of research effort turn into a dead end is a COI that all experts working in a field have. The result of acute resolution is incompatible with the hypothesis that the symptoms are caused by too much amyloid or too much tau. But there is no data that incontrovertibly implicates amyloid or tau in a causal manner. That remains an open question which can only be resolved by more data, no matter how many “experts” say otherwise.

    The journal that published one of the reports, also published an account of a senior clinician uninvolved with the research who witnessed some of acute resolutions the treatments produced and interviewed patients and family members before and after treatment.

    http://www.jneuroinflammation.com/content/5/1/3

    It is possible the events were all staged using actors, but I see that as unlikely. The level of acting skill to fool an experienced clinician is pretty high, and would require considerable clinical knowledge on the part of the actors. Apparently there are videos of some of the interviews, I have not looked at any of them.

    Acute improvements of chronic neurological disorders are not unknown or even that rare. I have an extensive blog about fever in the context of autism and some of the history and physiology behind the neurological disorders for which fever therapy was the “standard of care” for decades. These were disorders that we now know are characterized by neuroinflammation. Alzheimer’s is characterized by neuroinflammation. TNF-alpha is one of the cytokines that mediates inflammation. Blocking TNF-alpha acutely would acutely reduce inflammation.

    The result completely fits with my understanding of Alzheimer’s disease as being due to a chronic ATP depletion due to chronic invocation of ischemic preconditioning. Oxidative stress of any kind will invoke ischemic preconditioning. Inflammation does cause oxidative stress. Alzheimer’s is a state of oxidative stress. Any chronic state of oxidative stress is going to cause ATP depletion, and if that ATP depletion is severe enough will cause degeneration. There is nothing surprising or non-physiologic or implausible about that.

    Brain activity can and does change very rapidly. When we think and change our focus of attention, that is what our brains are doing, turning down one part that is doing function X and turning up another part that does the new function Y. Turning off and turning on different parts of the brain occurs continuously during waking hours with time constants of seconds.

    That turning off and turning on of different parts of the brain is observed in fMRI via the BOLD signal, the Blood Oxygen Level Dependent signal where acute changes in the relative amounts of oxyhemoglobin and deoxyhemoglobin change the magnetic susceptibility of that volume element of the brain and produce measurable changes in the MRI signal. These acute changes are due to acute changes in vasodilation that cause the changes in blood flow. These acute changes are due to increased NO causing increased vasodilation. Inflammation and oxidative stress of any type would decrease NO levels (superoxide consumes NO at diffusing limited kinetics). Decreased NO levels would be observed as decreased range and duration of the vasodilation mediated by NO. The volumes observed via fMRI BOLD would get smaller and not persist as long.

    The brain certainly can “turn on” different parts in seconds. If this actually did happen in these Alzheimer’s patients as reported, presumably something akin to the normal “turn on” process occurred. A NO mediated pathway is plausible. I think that is more likely than a direct effect of TNF-alpha receptors. The normal “turn on” of different parts of the brain is not mediated through TNF-alpha receptors. It is hard to imagine how a single dose could administer the proper blockage to TNF-alpha receptors throughout the brain and mediate a controlled resumption of complex functions acutely. A pathway mediated through NO could do that.

    Inflammation is an acute event. TNF-alpha is an acute regulator of that acute event. Regarding back pain, I only looked briefly and only saw the abstract of the article where a single injection of the TNF-alpha blocker didn’t have any residual effects on 1 month follow-up. I certainly don’t think that is the last word on it. Inflammation is under feedback control (as is every other important physiological pathway). The control system for inflammation is complex and has a time constant much shorter than a month. I don’t think I would expect to necessarily see positive effects a month later from a single injection. I have only seen the abstract, but the negative result doesn’t make me think that a positive result is necessarily bogus.

  46. amaon 08 Aug 2008 at 9:25 am

    ># pecon 01 Aug 2008 at 1:53 pm

    >Most of these diseases are related to the unnatural
    >modern lifestyle.

    Yes, that is correct. The unnatural lifestyle makes children survive “children’s diseases”. Very nasty, very nasty. Weeding out at least 20 to 80 percent of the children before the age of 20 is a good idea to clean the gene pool.

    >Nature is a great genius and creates machinery that
    >you could not dream of creating even if you had
    >billions of years.

    Yes, that is correct. To build a virus or bacterium from scratch IS a difficult task.

    >Yes, the process is evolutionary, but it is not
    >haphazard, and you have absolutely no rational basis
    >for claiming that it is.

    Yes, that is correct. All is working as designed in G_D’s plan. Even the extinction of mankind fully applies to the sketchbook.

    ># pecon 01 Aug 2008 at 1:56 pm
    >
    >But decades of dementia would probably not happen
    >very often in individuals with a reasonably natural
    >lifestyle.

    Yes, that is correct. All those people who get all these absolutely unnatural things like appendix-surgery, vaccinations, or antibiotics… Without all this unnatural stuff they never would become dement. They never would become old enough to become dement.

    >And yes, people live longer now thanks to antibiotics
    >and surgery, so dementia is more likely. But I don’t
    >think that explains the epidemic we have now.

    Old people flooding the scene is so unnatural. Yes, right you are!

    ># pecon 01 Aug 2008 at 3:24 pm
    >
    >“Meanwhile biology is full of example of sub-optimal
    >design due to constrained evolutionary history.”

    >Sub-optimal by your standards.

    Yes, that is correct. We all are GENIUSES. So it is clear that we are NOT suboptimal.

    ># pecon 01 Aug 2008 at 3:29 pm

    >Natural evolution did an amazing job.

    Yes, that is correct. Evolution creates a borad range of species, and then weeds out. The latter process is very interesting, and we should not interfere…

    >Lifestyle probably contributes greatly to AD

    Yes, that is correct. Life it all of it forms contributes to AD.

    >because the system is not equipped for decades of
    >almost complete muscular inactivity.

    Yes, that is true. Especially the brain is not equipped for inactivity. It even is not even equipped for activity… Evolution is a great thing…

    >It also has trouble with highly processed food and
    >synthetic chemicals, because these never existed until
    >very recently.

    Yes, that is true. Before bananas were invented we could not eat them.

    ># pecon 01 Aug 2008 at 3:35 pm
    >
    >The American lifestyle attacks the system and
    >eventually it breaks down, although this may take
    >many years.

    Yes, that is correct. Evolution did an impressive job with the human blueprint. even nuts, donuts, and do-nuts need quite a time to crack the body down.

    >Middle age and old age is when it really catches up
    >with us, although now young kids are also getting sick
    >because the lifestyle has become increasingly lethal.

    Yes, that is correct. Living in the savannes is a great thing. Evolution takes only the best.

    >You could study how the unnatural lifestyle attacks the
    >system, rather than blaming nature’s poor engineering
    >skills.

    Yes, that is correct. Nature is absolutely perfect. Mankind withstands all illnesses and lives forever.

    >That is why your approach is backwards — you don’t
    >these diseases as the eventual result of repeated
    >attacks on a tough and elegant system. Instead, you
    >see the diseases as something we would expect,
    >regardless of lifestyle, given a shoddy and
    >haphazardly designed system.

    Yes, that is correct. Our cars are shoddy. They have brakes and windshields. The DNA has repair mechanisms. All work as designed. And as a reset-button we use the defi.

    ># pecon 01 Aug 2008 at 4:39 pm
    >
    >I am saying that your search would proceed differently
    >if you were more respectful of nature and took a more
    >systemic (non-reductionist) approach.

    Yes, that is correct. I am a strong proponent for mankind-free zones.

    ># pecon 01 Aug 2008 at 4:45 pm
    >
    >I am saying that extreme inactivity is probably a major
    >contributor, as well as manufactured food and
    >chemicals.

    Yes, that is correct. More precisely: ALL is a major contributor.

    >Of course you can live a perfectly natural lifestyle and
    >still get sick. But I don’t think we would have this
    >epidemic of dementia if our lifestyle weren’t so crazy.

    Yes, that is correct. Crazyness is an epidemic.

    >And medical research would be more effective, in my
    >opinion, if the body were seen as an amazing piece of
    >strong, intricate and flexible engineering, rather than
    >as a pile of junk that just happens to work occasionally.

    Yes, that is correct. The body is a perfect construction, and what this construction does not handle is a clear sign, that this body is only fullfilling nature’s great plan.

    ># pecon 01 Aug 2008 at 8:52 pm
    >
    >But we are capable of seeing our mistakes once the
    >consequences become obvious. We are capable of
    >improving our lifestyle and giving our bodies what they
    >need.

    Yes, that is correct. We do see that we do a lot of mistakes, so we rewind time and restart again. Anyone with a perfect body can do that.

    ># pecon 02 Aug 2008 at 8:37 pm
    >
    >Mainstream medicine has finally accepted what
    >alternative medicine had been saying for decades —
    >that lifestyle matters.

    Yes, that is correct. Mainstream medicine accepts that alternative medicine says so.

    ># pecon 03 Aug 2008 at 8:07 pm
    >
    >But what if the drug supply is also contaminated? How
    >will your obese patients survive without their diabetes,
    >blood pressure and cholesterol drugs?

    Yes, that is correct. Nature’s plan does not include any artificial drugs.

    What else can I say? I am delighted. pec runs as designed. :-)

    ># Fifion 01 Aug 2008 at 1:55 pm
    >
    >Would it be possible to use the same “pec disclaimer”
    >here as Harriet created for science-based medicine?

    You mean something like this:
    http://www.transgallaxys.com/~kanzlerzwo/showtopic.php?threadid=4030

    The most unearthly tough forum on earth. :-)

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