2004 overview: Developments in the treatment of dementia

In this overview Professor Serge Gauthier, Canada, discusses some of the issues in dementia that attracted special interest in 2004.

There have been significant breakthroughs in the field of clinical pharmacotherapy of dementia. Of note, as will be highlighted in the following sections, is the maturation of the randomized clinical trial (RCT) designs and outcomes necessary to test treatment hypothesis in Alzheimer's disease (AD) and related dementias, across the different stages of severity.

Lack of efficacy of acetylcholinesterase inhibitors in amnestic Mild Cognitive Impairment

Although there was much hope that acetylcholinesterase inhibitors (AChEI) could offer symptomatic benefit in amnestic Mild Cognitive Impairment (aMCI), or even delay diagnosable dementia, results have been disappointing.

A 6-months study comparing donepezil to placebo failed in terms of primary efficacy outcomes which were the New York University Paragraph Delayed Recall test and the Clinician's Global Impression of Change (ref. 1), whereas preliminary analysis of results from two 2-year studies comparing galantamine to placebo and one 3-year study comparing donepezil to tocopherol and placebo failed to delay conversion to diagnosable dementia.

Results from a 4-year comparing rivastigmine to placebo are still pending. Although disappointing at first look, these studies have given us important knowledge about the natural progression of aMCI, the sensitivity of measurement scales previously used in AD, and the factors that increase the risk of conversion to AD.

Future placebo-controlled studies in this population may be done using enrichment for patients at higher risk of conversion, such as apoE3/4 carriers (ref. 2).

Efficacy of acetylcholinesterase inhibitors and of memantine on behavioral symptoms in AD

Since the observation that donepezil significantly improves behavioral symptoms in moderate to severe AD (ref. 3), there has been interest in behavior as a target for pharmacotherapy for AChEI.

A novel design using randomized washout was used to prove efficacy of donepezil on neuropsychiatric symptoms in mild to moderate AD (ref. 4), and a sub-analysis of a pivotal study of galantamine showed a similar benefit (ref. 5).

A sub-analysis of pivotal studies comparing memantine to placebo in moderate to severe AD showed an effect on agitation unseen with AChEI (ref. 6). This may translate into a "neuroleptic sparing effect" which would be important considering the risk of cerebrovascular events associated with some of the atypical neuroleptics.

Partially positive results from Alzheimer 2000

There was much interest in a "pragmatic study design" as a proof of clinical and pharmaco-economic benefit for AChEI in patients treated outside of specialty clinics. Alzheimer 2000 (ref. 7) gave us partial answers to these questions.

Despite a small number of subjects, there was a statistically significant difference in favor of donepezil compared to placebo for the first two years of this 3-year study, for the Mini Mental State Examination and basic activities of daily living.

These effects were lost in the third year partly because of the few patients left (51 out of 566) and the repeated wash-out from active medication. No delay in institutionalization was found at three years.

It is hoped that better designed and properly powered pragmatic studies will look at the benefit of combination of AChEI and control of vascular risk factors and/or cognitive training.

Brain imaging as supportive evidence for disease modification

There has been a report on the potential value of imaging brain amyloid in AD with the Pittsburgh compound (ref. 8), and there is hope that this dynamic scan could be used in RCT aiming at reducing the amyloid load using gag-mimetics such as Alzhemed or other amyloid-acting treatments.

Anatomical imaging using magnetic resonance imaging is already commonly used in RCT aiming at modifying AD progression, using substraction of serial pictures a year apart and looking for a reduction of rate of atrophy.

Such "surrogate outcome" could play a determining role in convincing regulatory bodies, clinicians, patients and caregivers of a true "disease-modifying effect".

Efficacy of acetylcholinesterase inhibitors in non-AD dementias

Reports have been published on the symptomatic benefit of donepezil in cognitive dysfunction associated with multiple sclerosis (MS) (ref. 9) and of rivastigmine for dementia associated with Parkinson's disease (PDD) (ref. 10).

Of note, the efficacy measures have been selected based on the profile of the cognitive deficits found in these conditions, including the selective reminding test for patients with MS and the Cognitive Drug Research power of attention tests for PDD.

Conclusions

The field of dementia treatment offers much hope and challenges. New RCT looking at symptomatic benefit and disease modification can be performed right across the spectrum of dementia, from prodromal to severe stages. The study results from 2004 must now be translated into guidelines for clinical practice.