Detecting an Early Response to Donepezil With Measures of Visual Attention
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Donepezil Hydrochloride; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 5mg of Donepezil Hydrochloride by mouth; prepared placebo looking exactly the same as drug. Participants took placebo by mouth for approximately 6 weeks, and after unblinding, they took donepezil hydrochloride for 6 months.
Other intervention name(s): Aricept; Placebo pill
Intervention MeSH terms: Donepezil
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Double Blind Placebo Control
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Other
Keywords: Alzheimer Disease; Attention; Donepezil hydrochloride