Detecting an Early Response to Donepezil With Measures of Visual Attention
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Alzheimer Disease |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 50 - 95 |
| Updated: | 1/13/2019 |
| Start Date: | December 1, 2005 |
| End Date: | July 31, 2019 |
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.
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.
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.
Inclusion Criteria:
- Clinical diagnosis of Alzheimer's Disease
- Mini Mental State Examination score >15 / 30
- Can swallow pills
Exclusion Criteria:
- No other dementia due to Parkinson's disease, Lewy Body dementia, Normal Pressure
Hydrocephalus, Fronto-temporal dementia, or prominent cerebral vascular accident
- No prior or concurrent use of cholinesterase inhibitors
- No prior or concurrent use of memantine hydrochloride
- No other concurrent anticholinergic treatments
We found this trial at
1
site
Winthrop University Hospital Founded in 1896 by a group of local physicians and concerned citizens,...
Click here to add this to my saved trials
