AChE Inhibitor Gets Fly Boys' Attention

In a small, preliminary study, researchers have found that the Alzheimer's drug donepezil (Aricept) can slightly improve the performance of older airline pilots on a flight simulator, particularly in tasks emphasizing attention. The authors hasten to caution cognitively normal people against using the drug to improve performance—the improvement is slight and there has been no research on the side-effects of the long-term use of such drugs in normal populations.

The "cholinergic hypothesis" postulates that loss of cholinergic function in the cerebral cortex underlies age-related cognitive decline. Indeed, previous experiments in older adults had suggested that boosting acetylcholine (ACh) levels (with drugs like such as donepezil that inhibit a synaptic ACh scavenging esterase) can improve performance on memory and recognition tasks.

Jerome Yesavage and colleagues at the Palo Alto (Calif.) Veterans Affairs Health Care System and several other institutions noted that pressure is beginning to mount on clinicians to prescribe AChE inhibitors to older adults (without AD or even mild cognitive impairment) for whom age-related cognitive decline can interfere with normal living. A controversial case in point is that of pilots, who are currently forced to stop flying regular passenger routes at the age of 60.

As the authors point out, the flight simulator tests required for commercial pilots are ideal for studying the effects of any number of drugs. The tests allow for the collection of reliable, highly quantifiable data, and also can be designed to focus on particular cognitive areas, such as sustained attention, working memory, or psychomotor speed.

In the double-blind, parallel study, the pilots (n = 18; avg. age 52) first practiced a series of complex piloting tasks on a simulator. Half the subjects then took donepezil 5 mg/day for thirty days, while the other half took placebos. After 30 days, the pilots who had taken donepezil showed little loss of performance on the tests learned at baseline, while the placebo group showed a significant decrement in performance. The strongest effects were on emergency tasks and approach to landing, both of which require dividing attention between a series of stimuli.

"The association of cholinergic drugs with better attention has led investigators to suggest that part of the benefit of cholinergic drugs on memory performance may be mediated through attentional components involved in working memory," write the authors, noting that their own results support this suggestion.—Hakon Heimer

Comments

  1. This paper documents an effect that probably has been known for some time, i.e. that inhibition of acetylcholinesterase may improve memory in nondemented individuals. The effect size is, however, a major issue. This is a function not only of drug, dosage, target population, but also of the sensitivity of measurement. In this study the measurement is highly quantified and has been sensitive to a number of drug effects (alcohol, marijuana, nicotine). So one is left with the question of about how large is the effect. Our collaborator Martin Mumenthaler has been comparing effect sizes across studies and feels this effect is about the same size (though in the opposite direction) of alcohol hangover. This is not to say this should be a treatment for hangover! But, it is one attempt to get a handle on the size of a subtle drug effect. ‑ Jerome Yesavage

    Food for further thought: "Although the results of this study do not suggest that current cholinergic drugs are useful for nondemented adults, it is hard to predict what drugs will be developed in the future. In their conclusion, the authors raise much thornier questions that ought to be discussed in public forums sooner rather than later: "Even though our results need to be replicated in larger samples, if cognitive enhancement becomes possible in intellectually intact individuals, significant legal, regulatory, and ethical questions will emerge. To date, cholinesterase inhibitors have been used primarily for the treatment of AD. Recently, they have been considered as palliative approaches for individuals at risk for AD, such as those with mild cognitive impairment. However, many older adults, who will never have AD, have cognitive impairments that impact their day-to-day functioning, and there is an increasing demand for therapeutic interventions to remediate such deficits. How should one pay for such interventions? Will we further worsen the divisions between the "have" and "have-nots" when the rich are cognitively enhanced not only through better education but also through drugs or other technologies? Finally, how should one regulate the use of such agents in settings and populations beyond aviation and normal aging, such as chess matches or test taking among college students?" (From Yesavage et al. 2002)

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Primary Papers

  1. Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O'Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ. Donepezil and flight simulator performance: effects on retention of complex skills. Neurology. 2002 Jul 9;59(1):123-5. PubMed.

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