Detecting an Early Response to Donepezil With Measures of Visual Attention

Overview

Acetylcholinesterase inhibitors (AChE-I) comprise a class of drugs used to treat Alzheimer's disease (AD), but controversy about their usefulness remains. Modest response rates of treated versus placebo groups, small effect sizes with respect to efficacy, drug costs, and clinical relevance of the effects are problematic. Standard efficacy measures of efficacy are not sufficiently sensitive, and trying to assess cognitive change after 4-6 months of therapy confounds the drug effect and the natural progression of the disease. Surprisingly, attention has never been included in the assessment of AChE-I drugs. The rationale for using attentional measures are that (1) Attentional deficits are recognized as a critical cognitive change in the earliest phases of AD; (2) Attentional function is directly mediated by the cholinergic system, and responds rapidly to cholinergic augmentation, particularly on tasks that tax available attentional capacity are dose dependent; and (3) Acetylcholine is depleted in AD. However, the link between attention and cholinergic depletion in AD has not been fully explored, especially with regard to response to cholinergic treatment. The study tests if attentional performance can be a more sensitive marker of response. In a longitudinal study we measure attentional, as well as cognitive and behavioral performance in de novo AD patients undergoing donepezil treatment. The investigators develop visual attentional measures and contrast them to global and domain-specific cognitive scores on three occasions (T1) baseline pre-treatment, (T2) after approximately 6 weeks, and (T3) after 6 months treatment. The T1-to-T2 arm is a double-blind placebo control period, after which members of the placebo group start open-label treatment. The assessment at 6 months allows us to determine whether the changes seen earlier at T2 can predict patients who respond, or determine which measures best predict response. We hypothesize that attention measures are more sensitive than standard global measures or other cognitive domains and that the change of attentional function can be detected after only after approximately 6 weeks treatment. Knowledge from this project will facilitate and inform our decisions about individual patients undergoing pharmacological treatment.

Acetylcholinesterase inhibitors (AChE-I) comprise the major class of drugs used to treat Alzheimer's disease (AD). Despite widespread use, there is controversy about the usefulness of these medications. Concerns have been modest response rates of treated versus placebo groups, relatively small effect sizes with respect to efficacy, drug costs, and clinical relevance of the effects. One problem is that measures of efficacy used may not be sufficiently sensitive to detect a true drug effect. Another problem is that changes noted after 4-6 months of therapy confound the drug effect and the natural progression of the disease. Lastly, patient heterogeneity may contribute to the wide range of degree of response, further decreasing overall effect sizes. The investigators address three important issues to improve the clinical usefulness of cholinergic therapy. First, outcome measures are needed that are sensitive to the effects of cholinergic treatment. Second, outcome measures should be sensitive to the drug effect early in the course of treatment before a measurable decline of the disease progression occurs. Third, improved treatment would be attained if specific patient characteristics or performance measures were identified, which contributed to, or even predicted who will likely benefit. The premise of the current proposal is that measures of higher-order attention - currently omitted from standard assessments of treatment outcome - can provide insight into early efficacy of cholinergic treatment. The investigators are conducting a preliminary study that supports our hypotheses by testing the value of such attentional measures. The rationale for using attentional measures is as follows: (1) Attentional deficits are recognized as a critical cognitive change in the earliest phases of AD; (2) Attentional function, particularly tasks that tax available attentional capacity, is mediated by the cholinergic system; and (3) Acetylcholine is depleted in AD. However, the link between attention and cholinergic depletion in AD has not been fully explored, particularly with regard to response to cholinergic treatment. Surprisingly, attentional measures have not been included in the evaluation of AChE-I in the treatment of AD. The investigators propose that attentional performance could serve as a highly sensitive outcome measure and a marker of response. Study aims and hypotheses 1\. To determine that higher-order attentional measures are sensitive to the effect of cholinergic change early in the course of treatment. The investigators predict that performance on attentional tasks will improve in AChE-I treated patients compared to placebo controls after 7±1 weeks of treatment. 2\. 2a. To examine the effect of cholinergic treatment on attentional measures as compared with global measures or measures of other cognitive domains. The investigators predict that the performance on tasks of attention is more sensitive than traditional global measures of performance. 2b. To examine whether cholinergic treatment changes the relationships among measures of attention and measures of other cognitive function. The prediction is that that the relationships among attention and cognitive domain measures will change with treatment. 3\. To determine whether performance at 7±1 weeks can predict response at 6 months 3a. Patient response to AChE-I may be influenced by demographic variables, or influence performance in one or more cognitive domains. The aim is to determine which cognitive domain or demographic characteristic best predicts treatment response at six months. It is hypothesized that attention and memory (both mediated by cholinergic mechanisms) will best predict treatment response seen at six months. 3b. To determine whether an attentional change seen in patients early in the treatment course predicts drug response. It is hypothesized that change in attention measured between baseline and 7±1 weeks will predict overall improvement in those patients who show positive treatment response at six months. Knowledge gained from this project will facilitate and inform our decisions about individual patients undergoing pharmacological treatment. The application of these goals can apply to current AChE-I treatment as well as other treatments, such as those now involving combined cholinergic and glutaminergic agents. BACKGROUND AND SIGNIFICANCE Attention and Alzheimer's disease (AD): The vulnerability of higher-order attention tasks in AD occurs in tasks such as selective attention, and covert orienting. Attentional deficits are documented in patients with prodromal AD who later develop the disease, suggesting potential sensitivity of attention to disease onset. Mechanisms of attention are mediated via anterior executive control (required in conjunctive search and inhibitory control) and via posterior disengagement. The deficits in AD may be explained by regional frontal or posterior dysfunction, or by a disconnection between the frontal and posterior attentional networks that disrupt the feedback system. Acetylcholine and attention: A primary modulator of attention is acetylcholine (ACh). Decreased ACh impairs attentional function in animals and humans including vigilance in rat, covert orienting in primate and AD, and complex attention in human airplane pilots. ACh functions in a dose related manner, with increased task load of higher background noise correlating with increased ACh release. Cholinergic antagonists (e.g., scopolamine) slow reaction time (RT) and increase omission errors on visual search, and increase omission and commission errors on signal detection. Higher scopolamine doses slow RT in covert orienting in primates involving inferior parietal regions. AD, attention and cholinesterase inhibitors: The relationship between attention and acetylcholine has not been well demonstrated in the assessment of AChE-I. Efficacy studies of donepezil, galantamine or rivastigmine show modest effect sizes ranging from 1.8-4.1 points on the 70 point Alzheimer Disease Assessment Scale - Cognitive section (ADAS-Cog) scale. These small effect sizes may partially be a function of using this outcome measure, which obscures the sensitivity to attention and memory with a global score. Targeted cognitive domains may be better response indicators. In a post-mortem analysis of AD patients, regions of low cholinergic activity correlated to memory and attention. Moreover, after 12 weeks of galantamine treatment, AD patients who reached therapeutic dose showed faster RT, better choice reaction time and in memory, recognition of faces. Also, on functional imaging, early response to AChE-I appears to affect regions that mediate directed attention. In summary, if attentional function is intrinsically linked to the level of cholinergic activity, it should used be an outcome measure of AChE-I treatment in AD to improve treatment sensitivity.