Parkinson's patients who take medications that block muscarinic cholinergic receptors have increased amyloid plaque and neurofibrillary tangle pathology, according to an article by Elaine Perry of the Newcastle General Hospital in England and colleagues, published in the August edition of the Annals of Neurology.

Beyond the possibility that drugs taken for symptoms of Parkinson's (most commonly for bladder dysfunction) could be contributing to Alzheimer's, this study reveals the wider specter that other common drugs with anticholinergic activity-many antihypertensives, antidepressants, antipsychotics, and even antihistamines-could also spur the formation of AD pathology. Ironically, the data provide good news for patients with AD, for whom it has been suggested that use of AChE inhibitors to boost cholinergic function might slow disease progression (Farlow, 2002).

This study is disturbing and potentially of wide-ranging consequence if confirmed. It grew out of several recent lines of evidence suggesting that boosting cholinergic function in Alzheimer's disease might provide more than temporary symptomatic relief. For example, Christoph Hock, Roger Nitsch, and colleagues at the University of Zurich have shown that selective muscarinic agonists can decrease levels of beta-amyloid (Aβ) in the cerebrospinal fluid of AD patients ( Hock et al., 2000; Nisch et al., 2000; and see related ARF news). There is even more evidence that cholinergic agonists, either muscarinic or nicotinic, can reduce CSF Aβ, brain plaque levels, or tau phosphorylation in animal models of AD. Taken together with the observation of a sixfold increase in dementia among Parkinson's patients, some of which is associated with AD pathology, these bits of data led Perry and colleagues to ask whether interfering with cholinergic function might enhance the formation of Aβ and plaques.

In a sample of 120 pathologically confirmed PD cases, the authors correlated use of antimuscarinc agents with plaque and tangle pathology. They found that long-term use (greater than two years) of the drugs was significantly associated with plaque density-more than 2.5 times higher than untreated or short-term treated cases. Similarly, antimuscarinic drug use was associated with increased tangle density, which suggests that cholinergic enhancement could be a useful strategy in other tauopathies.—Hakon Heimer

Q&As with Elaine Perry and Allan Levey.

In separate email interviews, ARF reporter Hakon Heimer posed questions to study author Elaine Perry and editorial author Allan Levey.

1) What is the background to this report?

Perry: There are numerous lines of evidence that cholinergic transmission is involved in beta amyloidosis. This includes experimental evidence that muscarinic agonists promote the normal processing of the amyloid precursor protein-i.e., they prevent the abnormal processing that leads to deposits of beta-amyloid.

2) What were the most important results of this study and in what respect are they significant?

Perry: That elderly patients with Parkinson's disease treated chronically (>2 years) with muscarinic antagonists develop more plaques and tangles than those not treated with this type of drug, consistent with the above.

Levey: This was a very interesting and potentially important study. The team of researchers in England is outstanding, and the study capitalizes on a large collection of postmortem brain tissues obtained over many years. The study carefully investigated pathological changes in the Parkinson's disease cases, and correlated the findings with exposure to anticholinergic medications. Surprisingly, they found that there were increased numbers of senile plaques and neurofibrillary tangles associated with significant use of anticholinergic medications.

3) What are the immediate clinical consequences of your findings?

Perry: 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 such as we obtained from other sources for this to become an accepted health guideline. And also that many neurologists do not now prescribe this type of drug in Parkinson's disease.

The findings also support the use of muscarinic agonists to prevent age-associated pathologies such as plaques and tangles.

Levey: There are many questions that are unanswered by this study. First, this was an association study and it does not prove cause and effect. Second, since it was a pathological study only, there is no evidence that the findings are of any clinical significance. However, previous research has provided potential mechanisms whereby the use of anticholinergic medications could influence Alzheimer's disease-like pathology. Hence, more research is clearly needed to answer these and other questions raised by the study. At present, there is no immediate reason for clinicians to change their practice. It is already well-established that anticholinergics should be used sparingly in elderly individuals because of the risk of delirium.

Many medications have anticholinergic properties in addition to well-known and commonly used medications for bladder symptoms, tremor, and other symptoms. Thus, clinicians should not be using these medications unless they are indicated, and carefully monitored, to make sure effectiveness outweighs cognitive and other side effects. 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.

4) What further research is called for?

Perry: Further research confirming the finding, either more postmortem studies such as ours, or imaging patients using markers for amyloid which are under development

5) Given that drugs with anticholinergic drugs are used extensively, shouldn't other patient groups be looked at for evidence of plaques and tangles?

Perry: Yes, but mainly in groups who are over 70 years old, since we are seeing the effect in pathology related to brain aging.... Or one could argue that there could be longer-term effects in younger people but that would be pure speculation.

Levey: Yes, other patient groups should be looked at to see if long-term exposure to anticholinergics is associated with increases in plaques and tangles. The major limitation is having a lot of brains to look at, and complete medication records for them.

6) Given the recognition of serious side effects of anticholinergics (e.g., delirium), why are they used at all nowadays?

Levey: Use of anticholinergics for tremor probably has declined with development of more effective antiparkinsonian agents. However, anticholinergics are still widely used for OTHER symptoms in neurological and non-neurological patients. These include bladder symptoms (urinary incontinence is a huge problem in the elderly), dystonia, GI symptoms, and others. More importantly, numerous other medications have anticholinergic properties which are not commonly recognized, including many commonly used medications such as antihypertensives and antidepressants. If the anticholinergics do have an effect on plaques and tangles, one might envision that it is the cumulative anticholinergic effect of multiple medications in any one individual over long periods of time; that is, not just one medication, but it could be a mixture of a bladder medication, an antihypertensive, and an antidepressant, all of which might have contributing anticholinergic effects.

7) How do you approach someone with overlapping symptoms (dementia with Lewy bodies, or advanced Parkinson's with dementia)? Does the clinician ever have to decide on whether to combine apparently contradictory drugs, e.g., anticholinergic and AChE-inhibiting drugs?

Levey: It is not unusual at all, in fact, increasingly common, for a person with Parkinson's disease, memory loss, and urinary incontinence to be on an AChE inhibitor for their memory and an anticholinergic for their bladder. Clinicians are told to believe that the anticholinergic won't affect memory, but show me the data-there isn't much at all.

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  1. An important paper.
    It would be good to have an exhaustive list of anticholinergics listed in order of their atropine equivalent effect.

  2. This is an important finding that adds to the human evidence pointing to a cholinergic-amyloid connection. Our group has contributed by showing that both muscarinic agonists and acetylcholinesterase inhibitors lower CSF and cortical ABeta levels in normal animals and both classes of drug also prevent the ABeta deposition induced experimentally by nucleus basalis lesion. It appears likely that the cortical cholinergic deficit associated with normal aging may be at least partially responsible for age-associated Abeta deposition and that cholinergic agents may be effective at preventing this. It is time for primary prevention trials of cholinergic agents for AD.

    References:

    . Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci Lett. 2000 Mar 31;283(1):9-12. PubMed.

    . The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease. J Neuropathol Exp Neurol. 2000 Apr;59(4):308-13. PubMed.

    . Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res. 2001 Jun 29;905(1-2):220-3. PubMed.

    . Reduction of cortical amyloid beta levels in guinea pig brain after systemic administration of physostigmine. Neurosci Lett. 2001 Sep 7;310(1):21-4. PubMed.

    . Anti-Amyloidogenic Activity of Cholinergic Agents. Drug Dev. Res. 56 (2002) 242-247.

    . Muscarinic agonists as preventative therapy for Alzheimer's disease. Curr Opin Investig Drugs. 2002 Nov;3(11):1633-6. PubMed.

    . Immunotoxin lesion of the cholinergic nucleus basalis causes Abeta deposition: towards a physiologic animal model of Alzheimer's disease. Curr Med Chem 3:57-75, 2003.

References

News Citations

  1. AF102B (Cevimeline or Evoxac) Lowers CSF Aβ in Alzheimer Patients

Paper Citations

  1. . Do cholinesterase inhibitors slow progression of Alzheimer's disease?. Int J Clin Pract Suppl. 2002 Jun;(127):37-44. PubMed.
  2. . Treatment with the selective muscarinic agonist talsaclidine decreases cerebrospinal fluid levels of total amyloid beta-peptide in patients with Alzheimer's disease. Ann N Y Acad Sci. 2000;920:285-91. PubMed.
  3. . The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 2000 Dec;48(6):913-8. PubMed.

Further Reading

Primary Papers

  1. . Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann Neurol. 2003 Aug;54(2):235-8. PubMed.
  2. . Chronically mad as a hatter: Anticholinergics and Alzheimer's disease pathology. Ann Neurol. 2003 Aug;54(2):144-146. PubMed.