Test Might Detect Alzheimer's Early

themadchemist

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CNN: Test might detect Alzheimer's early

This article is about a possible diagnostic for Alzheimer's (something that we don't have yet--except post-mortem) developed by the laboratories of Bill Klein and Chad Mirkin. The story reports on a paper published in the Proceedings of the National Academy of Sciences (PNAS).

The really cool thing is that I work in Bill Klein's lab. This article isn't about my project, but it is about a project in which the post-doctoral fellow with whom I work has been highly involved. Actually, the paper is his, Dr. Klein's, and Dr. Mirkin's.

Anyway, this is a preliminary study, but this test might have a lot of potential to help the millions of people who suffer from Alzheimer's.

The amyloid-beta derived diffusible ligands (ADDLs) mentioned in the article were first proposed as the toxins responsible for Alzheimer's by an individual working in our lab. That was 6 or 7 years ago, far before I had any clue what pipetteman was.

I just thought I would share a very interesting news story that also happens to be personally exciting for me.
 

wdlove

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This has potential to be good news, though in the preliminary stage. Being able to detect it early could lead to treatment also. If started early some of the current medications might actually have more efficacy. My mother just died last Spring with Alzheimer's. So this would have personal meaning to me also.
 

mkrishnan

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Jan 9, 2004
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Oooh, fun!!! :)

I work on the same topic, but from a behavioral standpoint -- on finely tuned neuropsychological tests that might have the potential to detect individuals with AD preclinically.

When the article says that the new test has the potential to be several orders of magnitude more sensitive than existing tests, what exactly does it mean? Does it mean for concentrations of BAP / precursors? My impression was that even post-mortem, BAP is strongly correlated with AD but not 100% -- my memory of the Nun Study brains is that there were cases of individuals with a lot of cognitive reserve who had brains with the upper stages of coding for BAP / neurofibrillary tangles, who showed relatively low levels of impairment that would not be characterized behaviorally as dementia.

Nonetheless, this sounds like great work. :)
 

themadchemist

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wdlove said:
This has potential to be good news, though in the preliminary stage. Being able to detect it early could lead to treatment also. If started early some of the current medications might actually have more efficacy. My mother just died last Spring with Alzheimer's. So this would have personal meaning to me also.
I'm sorry to hear about your mother...Neurodegenerative disorders like Alzheimer's are some of the most devastating illnesses out there. I hope that with the one-two punch of better diagnostics and better drugs, we might be able to improve the lot of those with Alzheimer's--or even cure it.

The problem with current drugs is that they don't really target the cause for Alzheimer's, probably because we're not precisely sure what the cause is. Aricept is an acetylcholinesterase inhibitor, if I'm not mistaken. The idea behind it is that acetylcholine receptor expression is reduced dramatically in Alzheimer's patients, so anything you can do to keep acetylcholine in the synapse longer (so that it can bind to whatever receptors *are* left) should help with the symptoms. Therefore, by blocking the enzyme that degrades acetylcholine, that is, acetycholinesterase, one might offset the disease. However, it doesn't matter how much acetylcholine is in the synapse if there are no (or practically no) acetylcholine receptors left. That is why Aricept only staves off the inevitable for a short while--It doesn't attack the cause, but instead tries to offset one of the symptoms.

I think the work with the tau protein and with ADDLs is very interesting because probably, probably, therein lies the answer to the Alzheimer's riddle. We will see. In addition, there is some work now that is challenging the acetylcholine hypothesis for Alzheimer's and suggesting that in addition to acetylcholine receptors, glutamate receptors may play a role in the disease, as well. It's important to figure out how the tau and amyloid-beta aggregates, the likely culprits in this devastating disorder, along with any other causes, bring about negative side effects like acetylcholine receptor loss.
 

themadchemist

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mkrishnan said:
Oooh, fun!!! :)

I work on the same topic, but from a behavioral standpoint -- on finely tuned neuropsychological tests that might have the potential to detect individuals with AD preclinically.

When the article says that the new test has the potential to be several orders of magnitude more sensitive than existing tests, what exactly does it mean? Does it mean for concentrations of BAP / precursors? My impression was that even post-mortem, BAP is strongly correlated with AD but not 100% -- my memory of the Nun Study brains is that there were cases of individuals with a lot of cognitive reserve who had brains with the upper stages of coding for BAP / neurofibrillary tangles, who showed relatively low levels of impairment that would not be characterized behaviorally as dementia.

Nonetheless, this sounds like great work. :)
Sorry for the double post, but let me point something out. You're right, amyloid beta plaques aren't a great correlate for the disease...However, it appears that soluble oligomers of amyloid beta might be...This test is not only sensitive for low concentrations of the target molecule (that's Chad Mirkin's side of the project), but also targets ADDLs (the oligomers), which seem to correlate very well with Alzheimer's.

edit: Sorry all for making this get way too technical way too fast! The article is still worth a read and worthy of discussion here...We can tone down the technical material or have it going simultaneously with a less technical discussion...
 

Drgnhntr

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We started a few studies on Alzheimer's but didn't finish due to lack of funding... So I am not as up on this as I used to. One of the problems a colleague of mine was faced with was to be able to diagnose the disease before death. He is currently working on cognitive tests, but like mkrishnan mentions, the disease effects vary greatly between people. This study is great news.

Another study was aimed at the function of the normal protein. The further the disease progresses, the less normal beta amyloid there is in the brain. We hypothesized that the lack of the normal protein was contributing to the memory problems. Unfortunately we didn't finish this, but it was all very interesting. I would think that if a therapy was developed it would have to be able to remove the the varient form as well as replace the good. Or repair your bodies ability to create the normal form.

I have heard about anti-body, stem cells, and shunts used as possible treatments. Does anyone know anything about how these are going?
 

themadchemist

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Drgnhntr said:
We started a few studies on Alzheimer's but didn't finish due to lack of funding... So I am not as up on this as I used to. One of the problems a colleague of mine was faced with was to be able to diagnose the disease before death. He is currently working on cognitive tests, but like mkrishnan mentions, the disease effects vary greatly between people. This study is great news.
I am personally not from the school of thought that advocates for cognitive tests as the be-all and end-all. Why? Well, Alzheimer's, like any other dysfunction, has to have a molecular, cell biological, biochemical basis...If we are to believe biology at all, we know that all functions, including cognitive and psychological functions, have a basis in the physiological (physiological being used in its broadest sense).

drgnhntr said:
Another study was aimed at the function of the normal protein. The further the disease progresses, the less normal beta amyloid there is in the brain. We hypothesized that the lack of the normal protein was contributing to the memory problems. Unfortunately we didn't finish this, but it was all very interesting.
That IS extremely interesting. I must admit that I had never thought of that...It's an intriguing idea and if you have any more information about it (papers, etc.), I'd love to check that out.

drgnhntr said:
I would think that if a therapy was developed it would have to be able to remove the the varient form as well as replace the good. Or repair your bodies ability to create the normal form.
Perhaps, perhaps, but the evidence I've seen suggests that removing the abnormality is enough to restore cognitive function.

drgnhntr said:
I have heard about anti-body, stem cells, and shunts used as possible treatments. Does anyone know anything about how these are going?
I know about the antibodies, at least. There was an antibody developed against ADDLs (the oligomeric forms of amyloid beta), specifically. Some studies showed that in transgenic mouse models of amyloid beta, which showed congnitive dysfunction, the application of the antibody completely reversed memory loss--within 24 hours!

In Europe, this antibody quickly moved to human clinical trials...While it worked in humans, it created an unacceptable amount of inflammation. Some patients even died. Therefore, the therapy was discontinued. There is, however, promise in searching for an antibody without such negative side effects.

This also demonstrates that ADDLs as drug targets in general might be a smart direction for research. I'm looking at the ability of certain components of ginkgo biloba to block the formation of ADDLs, for example.
 

mkrishnan

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themadchemist said:
I am personally not from the school of thought that advocates for cognitive tests as the be-all and end-all. Why? Well, Alzheimer's, like any other dysfunction, has to have a molecular, cell biological, biochemical basis...If we are to believe biology at all, we know that all functions, including cognitive and psychological functions, have a basis in the physiological (physiological being used in its broadest sense).
I don't think anyone on the cognitive side of dementia research would disagree with that. We just think that a combined approach is better than a purely biological approach, because, while we believe in reductionism, it is not necessarily true that biochemistry is always the most transparent language to discuss mental disorders in. If you push the reductionist thinking all the way to its extreme, then Alzheimer's Dementia is a particle physics problem, isn't it? :)

FWIW our lab looks at biomarkers too. Although we are more interested in process changes and functional measures. I think its fair to say the great range of non-pathological human behavioral / cognitive individual differences are based in functional differences and not structural ones, and that by extension, those functional differences (which may not correlate to the presence of any unique compounds or any compounds in unique locations) are probably also pretty important as a substrate to pathology.

But I'm not aware of anyone who believes AD has no biological basis.... ;)
 

themadchemist

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mkrishnan said:
I don't think anyone on the cognitive side of dementia research would disagree with that. We just think that a combined approach is better than a purely biological approach, because, while we believe in reductionism, it is not necessarily true that biochemistry is always the most transparent language to discuss mental disorders in. If you push the reductionist thinking all the way to its extreme, then Alzheimer's Dementia is a particle physics problem, isn't it? :)
You are, of course, correct...There's a certain point when reductionism, while theoretically accurate, is no longer pragmatically useful as a thought mechanism. And there are times when a macroscopic view, like a cognitive approach, makes sense for treatment or understanding.

The clearest example is psychotherapy. Clearly, psychotherapy is useful, but it does have a molecular and cellular basis. It is sometimes more effective than drugs though, because for reasons we are only beginning to understand, it causes many neural responses that can integrate in a beneficial way. Drugs are chosen to be specific and, without a very large cocktail that would have many side effects, it would be difficult to target all of the various brain regions that talk therapy does.

However, for diagnostics, cognitive studies are a little bit fuzzy. One could diagnose depression in two different people who have the same psychological symptoms. However, we can't be certain that it's the same disease, as far as its causes. The root causes must be physiological changes, and while effective treatments can arise from cognitive approaches, diagnostics are, ideally, physiological in nature.

Alzheimer's is a really good example. By the time you see many cognitive changes, the disease is already far along. There are hypotheses, though, that amyloid beta might be building up for years, even decades, before any serious symptoms are noticeable. Of course, the Nuns study, which noticed that handwriting could be a good predictor for Alzheimer's is very interesting...It's just that handwriting and other cognitive markers are so complex that they can be affected by a million variables--making them poor markers, in general, as far as I know.

However, I'm sure there are some functional measures that might be good correlates. I'm going back and forth on this, but I'm trying to work it out in my mind, as well. If Alzheimer's uniquely and specifically brings about a certain change, then it could be possible to use that change as a marker. I still think that psychological markers are weak, but quantifiable systems-level markers might be more useful.

With Alzheimer's, which seems to be brought on by physiological changes independent of psychological effects and sensory experiences, it would seem treatment by talk therapy or other psychological treatments would not be effective...Who knows, though. There is the cognitive reserve theory, which makes a lot of sense--In other words, crosswords are prophylactic. ;)

mkrishnan said:
FWIW our lab looks at biomarkers too. Although we are more interested in process changes and functional measures. I think its fair to say the great range of non-pathological human behavioral / cognitive individual differences are based in functional differences and not structural ones, and that by extension, those functional differences (which may not correlate to the presence of any unique compounds or any compounds in unique locations) are probably also pretty important as a substrate to pathology.
I dunno...What's there to bring about the functional changes? It has to be something structural. Whether it is a difference in sensory input, wiring, membrane protein expression, etc., something has to cause the change, right?

I guess my problem with functional definitions is that they must, by nature, ignore the cause. Functions are a product of structure, as far as I know, and so it's most useful to focus in on the structure, if you want a clear understanding of what's going on...

If you can dispute this claim of mine, I would greatly appreciate a different perspective.

mkrishnan said:
But I'm not aware of anyone who believes AD has no biological basis.... ;)
Of course not, and you know that I'm not aware of anyone who does so either. :p I was pointing this out for the benefit of those who don't think about Alzheimer's pathology--or other pathologies--on a regular basis, the way that we probably do.
 

Drgnhntr

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themadchemist said:
That IS extremely interesting. I must admit that I had never thought of that...It's an intriguing idea and if you have any more information about it (papers, etc.), I'd love to check that out.
Don't have any publications from our lab on this, yet. We were looking at sAPPalpha in particular. We were also trying to look into copper accumulation and oxidative stress, but that didn't happen... Anyways, here are some abstracts on pubmed (http://www.ncbi.nih.gov/entrez/query.fcgi) that discuss neuroprotective properties of sAPPalpha. Others talk about possible metal binding by beta-amyloid.
These are the pubmed numbers if you are interested:
15605991
14715666
15679114
15565529
15447675
15605992

I just did a quick search. I am having trouble finding hard copies of papers, hope this helps.
 
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