Re: Question to Russ about Research Article

[Guest guest]

Very interesting articles!

The , et al, article (discussed by Levy in your message below) looked

at anti-muscarinic agents in 120 autopsy confirmed PD patients. It DID NOT

look specifically at Cholinesterase Inhibitors (Aricept, Reminyl, Exelon),

nor did it look at Siminet. The research question was whether to use of

anti-muscarinic agents (which [i believe] are anti-cholinergic), mainly used

for the control of tremor(Benztropine, Orphenadrine, Trihexyohenidyl) and

bladder dysfunction (Oxybutynin, and Tri-cyclic

anti-depressants[Amitriptyline & Imipramine]), was associated with increased

AD-type pathology in post-mortem PD patients... And, yes, it was associated

with greater numbers of plaques and tangles in these PD patients (although

the number of plaques and tangles did not surpass the number commonly seen

in " garden-variety " AD patients).

Keep in mind that the finding was just an ASSOCIATION, and does not imply

causality. Also, remember that these were PD patients, not AD or LBD

patients. Lastly, the sample size was relatively small (Thus, the findings

will have to be replicated by other researchers). Nevertheless, the finding

sparks interest in the cholinergic regulation of plaque and tangle formation

(How the cholinergic/acetycholine system in involved with changing the

disease processes of plaque and tangle formation in dementia). It provides

data that support the possibility of a link between exposure to

anti-cholonergic drugs and AB plaque formation. Also, it's the first study

(in humans) to implicate anti-cholinergic treatments have a relationship to

tangle formation.

This is an important paragraph from the Levy editorial re: the , et al,

article:

" If the relationship between anticholinergics and plaques and tangles is

confirmed by subsequent studies, a major concern will be that long-term

exposure to anti-cholinergics may increase the risk of AD or AD

pathogenesis. It will be important to determine whether or not any

long-term effects of anti-cholinergic drugs are CLINICALLY RELEVANT. If so,

many other questions will arise about the duration of the exposure,

interaction with AD risk factors, and DIFFERENCES among anti-cholinergic

drugs. Because there are FIVE DIFFERENT muscarinic receptor sub-types, each

with DIFFERENT patterns of expression and function in the brain, (only) one

or more of these receptors may be responsible for effects on AB(plaques) and

Tau(tangles), and there may be regionally specific changes. Moreover,

anti-cholinergic drugs have VARYING affinities for receptor subtypes,

suggesting that SOME medications will have more influence on amyloidogenesis

(plaque formation) and tangle formation than others.... Clearly, there are

important heath benefits to many anticholinergic drugs. "

So, you can see that the finding may extend to ONLY SOME anti-cholinergic

drugs. But, the take away message is the same as we've always said here on

this discussion board: Be careful about the use of anti-cholinergic

medication (i.e, some sleep/common-cold over-the-counter medications, some

tricyclic anti-depressants, etc. -- Courage had a list of these medications

brewing somewhere, I think). With your LO's treating physician you have to

weigh the risks/benefits of anti-cholinergic medication carefully, because

they CAN be very helpful for some conditions, but might be harmful in

accelerating the course of dementia (as the , et al, article suggests).

Keep in mind that cholinesterase inhibitors are cholinergic medications (not

anti-cholinergic medications). So, the extended notion from this paper is:

'Well, if anti-cholinergic medications INCREASE plaques and tangles

formation, then maybe cholinergic medications (i.e., Aricept, Reminyl,

Elexon) might DECREASE the formation of plaques and tangles.' However, I

think it's still a reach to think that cholinesterase inhibitors play a role

with plaques and tangles (in the direction of suppressing their

formation)... as of yet. In any event, the notion I just described, is why

the last paragraph (below) seemed contradictory. You really have to read

these articles carefully!

If you have a degree in molecular chemistry, See this links regarding

anti-muscarinic drugs:

http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm

-Russ

Message: 7

Date: Fri, 8 Aug 2003 07:00:56 -0400

Subject: Question to Russ about Research Article

Russ, I know you are busy with exams but when you get a chance could you

translate this article? First off, what are antimuscarinic drugs? Are they

the Aricept, excelon kind? And if so, are they saying here that they may

cause plaques to form in the long-run? ( " Cases treated with antimuscarinic

drugs for more than two years had more than 2.5-fold higher amyloid plaque

density than did untreated cases (P = .005) or cases treated for less than

two years (P = .00005), and they also had the highest density of

neurofibrillary tangles. " )

And then the last paragraph seems to contradict the rest??? Help. Imelda

Antimuscarinic Drugs Linked to Alzheimer Pathology in Parkinson's Disease

> Laurie Barclay, MD

July 25, 2003 — Parkinson's disease (PD) patients taking antimuscarinic

drugs for more than two years have 2.5-fold higher amyloid plaque densities

than untreated patients, according to the results of a small study

published in the August issue of ls of Neurology.

If confirmed, this finding has significant implications. On the one hand,

cholinergics used in Alzheimer's disease may not only have an effect on

symptoms but may be disease-modifying. On the other hand, doctors may need

to be judicious in prescribing or recommending chronic anticholinergics.

" These findings suggest that chronic use of muscarinic antagonist drugs in

the elderly should be avoided, though it has to be said that there would

need to be more clinical evidence from other sources for this to become an

accepted health guideline, " lead author Elaine K. , PhD, from

Newcastle General Hospital, U.K., says in a news release.

Using the Queen Square Brain Bank for Neurological Disorders, the authors

reviewed case records and brain pathology for 120 neuropathologically

confirmed PD cases aged more than 70 years at time of death.

Cases treated with antimuscarinic drugs for more than two years had more

than 2.5-fold higher amyloid plaque density than did untreated cases (P =

..005) or cases treated for less than two years (P = .00005), and they also

had the highest density of neurofibrillary tangles.

According to the authors, physicians have recently reduced their

prescribing of muscarinic antagonists to avoid significant adverse effects

such as delirium.

" This was a very interesting and potentially important study, " says

editorialist Allan Levey, MD, PhD, from Emory University in Atlanta,

Georgia. " The team of researchers in England is outstanding, and the study

capitalizes on a large collection of postmortem brain tissues obtained by

the U.K. Parkinson's disease brain bank over many years. "

He points out that older patients may use several anticholinergic drugs in

combination, such as antidepressants, antihypertensives, antipsychotics,

and antihistamines.

" If future studies provide additional and more direct evidence

demonstrating a more serious effect of anticholinergics on Alzheimer's

disease pathology, and long-lasting clinically significant cognitive and/or

behavioral changes, then common use of anticholinergics will have to be

further questioned, " he says.

On the bright side, this study suggests that cholinergic agents might

protect against plaques and tangles as well as transiently and modestly

improving declines in memory and other cognitive functions in patients with

Alzheimer's disease.

>Ann Neurol. 2003;54:144-146, 235-238

Reviewed by D. Vogin, MD