This study is the first combined longitudinal and cross-sectional investigation of how ChEI treatment might impact cognitive domains critical to driving safely in AD patients. Specifically, we investigated changes in performance across a set of computerized tests designed to assess simulated driving, attention, and executive processes with ChEI treatment; these tests were administered first separately (i.e., single-task condition) and then in combination (i.e., dual-task condition) in order to simulate typical situations encountered in on-road driving that demand effective use of sustained, selective, and divided attention.
In the present study, ChEI treatment was found to affect cognitive function consistently across the longitudinal and cross-sectional comparisons on the primary outcome measures. First, ChEI treatment was associated with better tracking accuracy within the simulated driving task, with this improvement observed as a main effect of treatment in the Pre/Post treatment comparison and as an effect of ChEI user status under single-task conditions in the Users/Non-Users comparison. The failure to also observe a significant effect of ChEI status under dual-task conditions in the cross-sectional comparison may be due in part to group differences in their prioritization in performing the two simultaneous tasks, since only the ChEI Users displayed a significant decrement in tracking under dual-task conditions. That is, the ChEI Non-Users may have weighted accurate performance of the tracking task more heavily under dual-task conditions than did the ChEI Users, which may in turn have compensated for any effect of ChEI treatment status. Second, ChEI treatment was associated both with better target detection accuracy and with decreased search response times within the visual search task for both the Pre/Post treatment and the Users/Non-Users comparisons. Finally, ChEI treatment significantly improved overall time to complete the mazes while not affecting accuracy of completion.
Taken together, the demonstration of similar effects of ChEI across these two comparison studies provides converging evidence for the impact of ChEI therapy on driving-related attentional abilities in AD patients. The vital role that acetylcholine plays in normal attention and executive function has been well documented; these cognitive processes are mediated through cortical projections arising from the basal forebrain cholinergic system.20, 21
Disruption of cholinergic pathways is thought to underlie the very early appearance of attentional deficits in AD, which often precede decrements in other domains such as language and visuospatial functioning. ChEIs increase the availability of acetylcholine at pre-synaptic cholinergic nerve terminals which may mitigate the pathological effects of AD on the cholinergic system in the mild to moderate stages of the illness.
Relatively little is known about the therapeutic effects of this class of drugs on cognitive domains in AD other than memory as the ChEI pivotal trials did not include measures of attention. However, positive treatment effects of ChEI on various aspects of attention (divided, sustained, and selective attention) and executive function have been demonstrated in animal models22, 23
and in a limited number of investigations in subjects with mild cognitive impairment (MCI), AD, and cognitive normals.5, 24–29
The results of these exploratory cross-sectional studies in patients with MCI or AD indicated that improvement in either attentional processes or executive control was associated with ChEI treatment.24–26
The present study confirmed these conclusions within a casecontrol cross sectional study, and also provided the first longitudinal investigation of the effects of ChEI treatment on these cognitive processes within the same individual.
Do substantive differences exist between the individual ChEIs in respect to their effects on attention? Of the four ChEI approved for the treatment of AD in the United States, galantamine is distinguished by its ability to modulate nicotinic acetylcholine receptors via allosteric potentiation, in addition to inhibiting acetylcholinesterase.30
While differences in efficacy on cognitive and functional outcomes in AD clinical trials have not been demonstrated for galantamine compared to the other CHEIs,31
it is possible that nicotinic receptor modulation might have additional therapeutic effects on attention in AD. Both muscarinic and nicotinic acetylcholine systems contribute to attentional task performance; the complimentary roles of muscarinic and nicotinic cholinergic receptors in visual processing have been demonstrated in a small group of healthy elderly subjects using physostigmine and scopolamine probes and positron emission tomography (PET) imaging.32
Although some researchers have theorized that the contribution of nicotinic cholinergic transmission to attentional functioning may be of even greater importance with increasing cognitive impairment, very little is known about the differences between galantamine and the other ChEIs on attention in AD.28
In one report, both donepezil and galantamine improved some aspects of attention in subjects with mild-moderate AD, but those treated with galantamine improved more quickly relative to baseline than those treated with donepezil.28
We were unable to evaluate potential pharmacological differences between ChEIs on test performance in our study. The majority of participants in the longitudinal and cross-sectional studies were prescribed donepezil, so the extent to which our findings can be generalized to AD patients treated with other CHEIs is unknown.
Although provocative, these results of this study cannot be directly extrapolated to predict the effects of ChEI on actual on-road driving performance in AD. While computerized maze and visual search tasks have been shown to correlate with road test performance in drivers with AD in previous studies8–11, 33
, this study lacks a direct measure of on-road driving performance. Another limitation of this study is the lack of an untreated comparison group. The case-control comparison made between the ChEI users and ChEI non-users, however, suggests that the improvements seen in the simulated driving, attention and executive control measures post-ChEI treatment in the prospective study are not due simply to practice effects.
Despite the limitations, these preliminary findings warrant further investigation. Although many early stage patients with AD continue to drive safely for some period after diagnosis, the eventual suspension of driving privileges is an inevitable milestone for all. Attentionally demanding, complicated situations occur frequently while driving, so it is not surprising that impairments in visual attention have been linked to increased crash risk in older adults. 34–36
Individuals with AD have greater difficulty performing adequately in complex visual environments compared with cognitively normal elders and are at higher risk of driving unsafely.33
Potential compensatory strategies (including the use of cognitive enhancing medications) aimed at improving driver safety and decreasing motor vehicle crashes in drivers with AD have not been a research focus to date, but should be studied according to a recent review.37
In the absence of a cure for AD, these types of studies are of critical importance as the prevalence of cognitively impaired drivers will continue to rise as the population ages.