Alzheimer's Disease: A Treatment Strategy

jarice at delphi.com jarice at delphi.com
Mon Jan 23 00:01:23 EST 1995


Regarding my paper on Alzheimer's, Dr. Hatanpaa writes:
 
>I don't think the eye test is worth the trouble until  1) the
>preliminary experiment published in Science has been
>replicated by other groups, and 2) it has been shown that the
>test is specific for Alzheimer's disease (AD) and doesn't give
>false positives in other dementias.
 
>The Science paper was about finding AD patients among
>normal controls. That is not a big challenge as such: a simple
>Mini Mental Test would do as well. The real problem is making
>sure that the dementia is caused by AD. There are many other
>causes of dementia, and for some of those, an effective
>treatment is available once the condition has been correctly
>diagnosed. Pernicious anemia is an example of a condition
>that often causes AD-like symptoms and that can be
>diagnosed by a simple blood test. The diagnosis of AD has to
>be based on careful exclusion of other diseases causing
>dementia. The eye test is of little value until its specificity has
>been proven.
 
Dr. Hatanpaa is incorrect. The eye test group of 58 individuals
included 14 probable Alzheimer's Disease patients, and 4
patients with one of the following non-Alzheimer's type
dementias: Korsakoff's syndrome, multi-infarct dementia,
and dementia with an extrapyramidal syndrome.
 
As figure 1, right hand graph of "A Potential Noninvasive
Neurobiological Test for Alzheimer's Disease" (Science, 266;
1051-1053, 1994) shows, the patients with non-Alzheimer's
type dementia exhibit a pattern of pupil dilation like that of
normal controls.
 
Dr. Hatanpaa is correct that this is a limited sample, and thus
subject to verification by larger-scale studies.
 
>You say the medical literature has proven that effective
>treatment for AD is available. Sorry, but I just can't share your
>enthusiasm in this matter. In my opinion, so far no drug has
>been proven to slow the course of AD. The only possible
>exception to this is acetyl-carnitine, as long as you are willing
>to overlook the fact that the studies showing dramatic effects
>have been done by Italian groups who are sponsored by the
>Italian drug company that makes acetyl-carnitine, while other
>groups tend to get negative results or report very little benefit.
 
I was not aware of the connection between the Italian writers of
papers on ALC and an Italian drug company. None of the papers
hat I have read mention such a connection. What is the source of
your information?
 
In any case, I find it hard to believe that double-blind, placebo-
based, randomized controlled trials of ALC reported by Spagnoli
et al, 1990, are invalid unless you assume fabrication of the
results. In that case, the peer-review process of Neurobiol.
Aging, Neuro-chem. Res., Brain Res., etc. need review. It is true
that Rai et al, 1990, had minimal results in their trial of 36 AD
patients. Positive results were obtained from a UK placebo-
controlled trial (Livingston et al., in press) that substantially
confirmed the beneficial effects of ALC therapy in 71 patients
with AD. There is some indication of negative results. The
majority of studies support some efficacy. Given the fact that
ALC is well tolerated, the risk-possible benefit ratio supports
ALC consumption by AD patients.
 
>In the light of the latest data, Deprenyl has been a
>disappointment considering the initial encouraging findings and
>all the animal data supporting its general neuroprotective and
>antiaging potential. There has been some behavioral
>improvement in some patients, but very little or no cognitive
>improvement. My guess is that all the positive findings are
>caused by Deprenyl's antidepressive effects. It is actually a
>very good antidepressant, possibly as good as any of the
>highly publicized modern antidepressants.  Incidentally, another
>so called smart-drug, Hydergine, is also an antidepressant and
>has shown a similar pattern of slight behavioral changes in AD
>patients. I hope that future Deprenyl studies with larger patient
>numbers will prove me wrong and show that there is a
>subgroup of AD patients whose disease will be actually slowed
>down by Deprenyl.
 
I must say that I generally agree with Dr. Hatanpaa here. The few
long-term studies (> 1 year) do not show any lasting benefit.
Nonetheless, I would still recommend taking it due to "all the
animal data supporting its general neuroprotective and
antiaging potential."
 
>One general remark: in the medical sciences, you shouldn't
>believe any dramatic or revolutionary results until the studies
>have been replicated by at least one other group. Not
>everything you find in Medline is true. One example is a study
>you cite in your paper, the study by a Japanese group that
>claimed that AD could be not only halted but also almost
>reversed by a combination of iron, vitamin B-6, and Coenzyme
>Q10. This was published as a letter to the editor in Lancet in
>1992. Why do you think nothing has been heard of this
>miraculous cure for AD ever since?
 
Good point. I do think that unlikely-sounding therapies are
less likely to find researchers willing to replicate the
study. Nothing HAS been heard. No studies conducted by
western research institutes that either prove or disprove
this therapy have been done, that I'm aware of. One would
expect a more substantial paper to come from Japan at
some point if the results were as represented. Given the
mitochondrial membrane-stabilizing effects of Coenzyme Q-10,
and some evidence that this membrane degradation is
associated with AD, I still recommend it's consumption.
 
>I think the most promising group of drugs for AD is the one
>that you dismiss as ineffective: AchE inhibitors. The problem
>with physostigmine and tacrine is not efficacy, the problem is
>the side effects. However, there are some very promising new
>AchE inhibitors undergoing animal studies. These new drugs
>are specific to the brain type of AchE and therefore shouldn't
>cause systemic side effects.
 
The problem I have with this approach is that it is symptomatic
only: it does nothing to halt the increased lipofuscin deposition
found in AD patients (B-amyloidosis), nor does it affect in any
way the low-grade inflammation response resulting in neuronal
cell death which may be the cause of AD.
 
The brain continues to die; the remaining neurons perform a
little better, though.
 
I disagree strongly that the problem with Tacrine is not efficacy.
A quote from "Development of pharmacologic treatments for
Alzheimer-type dementia, J. Royal Soc. Med. 87:Supp 23, as
included in my paper: "(With Tacrine), the magnitude of the
changes (in patients recieving tacrine) was small, even in
responsive patients, and many patients responded only partially
 or not at all. Furthermore, it appears that treatment response
 is obtained only at higher doses on the margin of patient
tolerability."
 
>By this I don't mean that people with AD shouldn't take the
>drugs that you recommend. If there is even the slightest
>possibility that something might work, why not try it? After all,
>most of the drugs you listed are relatively safe, and AD
>patients couldn't end up much worse anyway.
 
This is a very refreshing attitude, especially by a physician;
unfortunately, I think that it is also a very rare one.
 
A typical comment that I recieved was more like the
following:
 
>Well it was well documented but the actual clinical utility of
>many of the compounds has not been demonstrated.  Medicine
>has a long history of "great ideas" that did not pan out.  I
>think that patients have a right to take whatever they feel is
>justified as long as they are well informed about the
>potential risks and benefits.  I am strongly opposed for others
>to advocate what they should take in the absence of scientific
>proof that it works.
 
>Taking ineffective compounds may produce unwanted side
>effects, certainly wastes money, can build false hope and
>sometimes delays effective diagnosis and treatment.
 
Many thanks to Dr. Hatanpaa for his very thoughtful analysis
of my paper.
 
Jim Rice




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