Clinical trial NCT03073876
Conditions: Alzheimer Disease
Keywords: Alzheimer Disease Attention Donepezil hydrochloride
Sponsor: NYU Langone Health
Start date: 2005-12-01; Completion date: 2021-01-13
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Participants in the Drug group received oral 5mg of Donepezil Hydrochloride daily for 6 months. The Drug group was assessed at baseline, after approximately 6 weeks and after 6 months of treatment. The baseline to 6 weeks phase was part of the double-blind, placebo controlled portion of the trial. arm 2: Participants in the placebo group first received oral administration of a placebo pill for approximately 6 weeks. After that initial interval, the study was unblinded and participants in the placebo group then received 5mg of donepezil hydrochloride treatment for 6 months.

The Placebo group was evaluated at baseline, after 6 weeks of placebo, after 6 weeks of donepezil hydrochloride drug treatment, and 6 months of donepezil hydrochloride treatment.
Interventions: intervention 1: Donepezil Hydrochloride intervention 2: Placebo
Intervention descriptions: intervention 1: 5mg of Donepezil Hydrochloride by mouth intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
Project Title: Detecting an early response to donepezil with measures of visual attention
NCT03073876
Date: 9/7/2006


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention   
To be used only by the Alzheimer’s Association, 
KR and Associates, and their agents that evaluate this application. 
DO NOT DUPLICATE
Page 1 
PROBLEM STATMENT 
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 medications1,2. 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 effect3. Another problem is that changes noted after 4-6 months 
of therapy represent a confound of 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.  
We must address three important issues to improve the clinical usefulness of cholinergic therapy. First, 
we need outcome measures 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 we knew which patient characteristics or 
performance measures contribute to, or even predict, who will likely benefit. The premise of the current 
proposal is that measures of higher-order attention, which are currently omitted from standard assessments of 
treatment outcome, could provide necessary insight into early efficacy of cholinergic treatment. We are 
conducting a preliminary study that supports our hypotheses 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. We 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. We 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. We 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. We predict 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 glutamanergic agents. 


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
WORKPLAN 
 
Background and significance 
Attention and Alzheimer’s disease (AD): The vulnerability of higher-order attention tasks in AD occurs in 
tasks such as selective attention4,5, and covert orienting6. Attentional deficits are documented in patients with 
prodromal AD who later develop the disease7, suggesting potential sensitivity of attention to disease onset. 
Mechanisms of attention are mediated via anterior executive control (required in conjunctive search8,9 and  
inhibitory control9) and via posterior disengagement10. The deficits in AD may be explained by regional frontal 
or posterior dysfunction, or by a disconnection11 between the frontal and posterior attentional networks12 that  
disrupt the feedback system13.  
Acetylcholine and attention: A primary modulator of attention is acetylcholine (ACh)14. Decreased ACh 
impairs attentional function in animals and humans including vigilance in rat15, covert orienting in primate16 and 
AD17, and complex attention in human pilots18. ACh functions in a dose related manner, with increased task 
load of higher background noise19 correlating with increased ACh release20. Cholinergic antagonists (e.g., 
scopolamine) slow reaction time (RT) and increase omission errors on visual search21,22, and increase omission 
and commission errors on signal detection23. Higher scopolamine doses slow RT in covert orienting in primates 
involving inferoparietal regions16.  
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 donepezil24, galantamine25 or 
rivastigmine26 show modest effect sizes3 ranging from 1.8–4.1 points on the 70 point 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 attention27. 
Moreover, after 12 weeks of galantamine treatment28, 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 regions29 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. 
Methods 
I. EXPERIMENTAL DESIGN  
The proposed study is a 6-month longitudinal design assessing 40 newly diagnosed patients with AD as they 
start donepezil treatment (see Figure 1). The brief first arm (between T1-T2) is randomized, double-blind, 
placebo controlled, after which all patients are treated open label. Visual attentional measures will be contrasted 
with global and cognitive domain measures. The baseline assessment is before treatment, T1, after which 
patients will be randomized into treatment and placebo groups. The T2 assessment occurs at 7±1 weeks, after 
approximately 2 weeks of optimum treatment dose in the treated group. After the T2 assessment, the treatment 
assignment will be unblinded, and placebo patients will begin treatment. In order to include all participants in 
the final 6 month analyses, participants initially treated with placebo will undergo an additional testing (T2-
pA). At T3 all participants will have been treated for a full 6 month period.  
Drug choice and placebo: Donepezil has been chosen for this protocol: We have preliminary data with this 
agent; effective dose can be achieved early in the course of treatment; it requires only once-daily 
administration; it requires single dose titration step from 5mg to max. dose of 10 mg. Randomization, 
preparation, and treatment with drug vs. placebo will be managed by the pharmacy director of the hospital site 
Rationale for double-blind placebo design: Our preliminary data (see below) is based on a repeated measures, 
longitudinal design without a placebo group. Inclusion of the placebo arm, T1-T2, would allow us improve our 
ability to test our hypotheses and determine the validity of an early treatment effect. We are cognizant of the 
Figure 1. 


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
short delay of treatment for 50% of the participants; however, given the current controversy of the efficacy of  
the drug1, we feel that being able to answer whether effects are detectable early, and whether those effects occur 
in responders, outweighs this minimal risk.  
INSTRUMENTS – MEASURES 
Experimental tasks (‡) were developed and/or programmed in our laboratory. Task selection was based on: 
avoidance of floor or ceiling effects assuring that patients with a range from mild to moderate AD can perform 
tasks; availability of alternate forms. Patients with no computer experience are allowed and sufficient practice. 
Global measures: 1.ADAS-Cog (70-point scale); standard pharmacological rating tool; 2. DRS (Dementia Rating 
Scale) total score and subtest profiles; 3. MMSE (MiniMental Status examination); standard cognitive measure; 
4. CDR (Clinical Dementia Rating scale) including standard and sum of box-scores to measure function. 
Cognitive Domains 
Attention Focused and sustained attention: A. Digits Forward - WAIS III;  
B. ‡ Simple Reaction Time: RT to a single stimulus presented on a computer screen at randomized intervals.  
C. ‡Visual Selective Attention: This is a computer version of a paper and pencil cancellation task, developed by 
the PI for patients with AD. Participants indicate presence or absence of a target among an array of distractors, 
which vary in density (number of items on screen). Outcome measures include RT, hits, and false alarms. 
D. ‡Visual covert orienting: Posner’s paradigm assesses covert orienting by comparing response to a target 
preceded by a valid or an invalid cue. Outcome measure is RT to target detection. In valid conditions, the target 
(i.e., ‘X’) follows a cue in the ipsilateral visual field and in invalid conditions the contralateral field. Valid and 
invalid tasks are equally frequent (50%) and presented randomly. On 80% of the trials, the cue to target interval 
(Stimulus Onset Asynchrony, SOA) is 150 msec; the remaining 20% of the trials are catch trials (SOA=700 
msec), which are included in the task, but excluded from analyses.  
E. ‡Choice Reaction Time: a computer task examines RT on a same/different choice response of two stimuli. 
The task demonstrates participants’ ability to discriminate shapes in a non-search condition. 
Memory: 1) Hopkins Verbal Learning Test (measures of total learning, delay, intrusions, serial position).  
Language: 1) Fluency: Letter cue (FAS); 2) Semantic cue; 3) Boston Naming Test-15 item (multiple forms). 
Visuospatial function 1) Clock drawing; 2) Benton - Visual Form Discrimination30. 
Frontal-executive function: 1) D-KEFS Trails31 (measures of set-switch; speed; contrast) 
Psychiatric Status: 1) Geriatric Depression Scale32 (GDS); 2) Neuropsychiatric inventory33. 
II. PARTICIPANTS:  Recruitment: Patients will be recruited through the Memory and Cognitive Disorders 
Center at Winthrop-University Hospital. The PI has a 12 year established network of geriatricians, psychiatrists 
and neurologists throughout the Long Island, NY area who refer patients for diagnostic determination. 
Additional resources will allow the current average of 5-8 weekly referrals to be screened.  


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
Patient characteristics: This is a particularly difficult patient population to access, as many patients entering 
primary research centers have already initiated medication prescribed by community physicians. A major 
strength of this proposal is access to patients who are being newly diagnosed, and are undergoing de novo 
treatment with AChE-I. Neuropsychological tests used for diagnosis will not overlap with tests used as study 
dependent measures. Inclusion criteria: Study inclusion criteria include satisfying NINDS-ADRDA criteria for 
AD, with ruled out vascular, mixed or other etiology of dementia. Diagnosis will be reached by consensus of 
neuropsychology (NSF), geriatrics (JB and LO), neurology (LSH), and neuroradiology (LSH, OO). Stable 
concurrent therapy with non-cholinesterase inhibitors will be allowed including NSAIDS, Vitamin E, or SSRI 
antidepressants. Patients must be able to perform attention tasks (MMSE >15) and have corrected vision. If a 
patient meets criteria both patient and kin provide written consent Exclusion criteria: any prior AChE-I use, or 
concurrent anticholinergic treatment (e.g., incontinence medication) or use of memantine. 
Sample size: 50 patients will be recruited. Power analysis tests the null hypothesis that an average yearly 
decline in unmedicated AD patients is 3 MMSE points. With criterion for significance (alpha) of 0.05, and a 2-
tailed test, a proposed sample size of 40 (drug = 20; placebo = 20), will have power exceeding 80% to yield a 
statistically significant result on Covert orienting task (most stringent attention task). Current attrition rate of 
22% requires recruitment of additional 10 participants.  
IRB: A preliminary longitudinal study using only treated AD patients has been approved by both University 
and Hospital IRBs (#01-06-05-03) through 5/1/05. All patients and a responsible kin (or legal guardian) will 
give written consent in compliance with risk to vulnerable populations. IRB application for the proposed design 
(using treated and placebo groups) is pending. All data will be managed in compliance with HIPAA and IRB 
regulations, including secure electronic transfer via encrypted SSL protocols.  
III. PROCEDURES Neuropsychological and computer testing will be administered by the PI or GRA at 
Winthrop-University Hospital, lasting 2½ hours with appropriate breaks. Patients will be paid $30 for each 
session at that visit. Compliance for multiple visits will be insured via phone and mail contacts with families.  
IV. DATA MANAGEMENT Raw data and analyses will be managed with SPSS and S-PLUS. The heterogeneity of 
AD can result in wide variation, particularly on RT data. Data will be reviewed and undergo necessary 
transformation to insure normal distribution of error variance, reduced skew, and minimized effects of extreme 
values. When indicated, RT data will be treated in a two step procedure omitting individual trials of extreme 
outliers (-3 < z > +3) and a logarithmic (log10) transformation. All analyses will be evaluated with and without 
transformations and be reported if discrepancies arise. 
PRELIMINARY DATA 
Preliminary data from our laboratory support our hypothesis that attentional measures can detect effects of 
AChE-I treatment. 1) Effect of load: We first confirmed8 that higher load levels in selective cancellation 
affected 18 AD patients more than 18 age-matched controls, with higher commission errors and longer RTs as 
load increased. At high-load, the task was very sensitive in capturing attentional deficits even in high 
functioning patients. 2) Effect of drug: In subsequent analyses34, subgroups of these patients (on donepezil, 
n=8; off donepezil, n=9) were matched on demographic variables of age, duration, or severity of illness. The 
ability to discriminate targets from distractors, d-prime p=.058, and the likelihood of endorsing a target 
correctly was better in treated compared to non-treated patients, beta p=.029. Treated patients were better at 
discriminating targets and rejecting non-salient stimuli correctly, implicating an attentional benefit of treatment. 
3) Preliminary results of longitudinal study: 13 patients with AD (CDR 0.5-1.0) treated with open-label 
donepezil have been evaluated on all tests pretreatment (T1) and after a mean of 7.75 weeks (T2). Global 
measures fail to capture significant T1–T2 change (ADAS-Cog, DRS, CDR, CDR-Box score: p>.10). However, 
our experimental attentional tasks are detecting change. On selective attention, accuracy of target detection is 
faster (p<.001) at low density, while maintaining accuracy (p=.19). On the more dense arrays, there is a small 
but significant drop in accuracy, but slower detection (p<.01) suggesting a speed-accuracy tradeoff. On covert 
orienting, validity effect changed over time (p=.031; effect size=0.33). The degree of load interacts with 


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
response. These data suggest that attentional functions (e.g., search, speed/accuracy tradeoff, disengagement) 
detect early cholinergic effects, while global measures do not. The study with increased power and inclusion of 
a placebo group will permit more general conclusions. 
ANALYSES 
Aim 1. To document that higher-order attentional measures are sensitive to the effect of cholinergic change 
early in the course of treatment, Ancovas on Group (treated, placebo) will be performed with measures of 
attention (e.g., simple RT, Covert orienting, Choice RT and Selective Attention) at T2 as the dependent 
variables and measures of attention at T1 as covariates. 
Aim 2a. To determine the relative sensitivity of attention compared with other measures. The effect size of each 
attentional measure will be compared with the effect sizes of global and cognitive domain measures35.   
Aim 2b. To determine whether change of certain measures covary, change data from placebo and drug groups 
will be pooled, and Pearson correlations of the reliable change36 among measures T2-T3 will be compared. To 
determine whether the relationships among measures differ between drug and placebo groups, measures at T2 
will be correlated with one another within each group, and individual differences multidimensional scaling will 
be applied to each of the two matrices.  
Aim 3a. To document which cognitive domains or demographic variables best account for treatment response at 
six months, a hierarchical, multiple regression will be performed. Reliable change scores of each cognitive 
domain (T2–drug group; T2-pA–placebo group) will be predictor variables, and ADAS-cog T3-T1 difference 
scores serve as the dependent variable. DRS will be entered first into the regression to control for disease 
severity, followed by attention and memory, with frontal-executive, visuo-spatial and language variables 
following. The incremental-F tests will evaluate the unique variances contributed by attention or memory to 
ADAS-cog without the contribution of the remaining domains. We will conduct additional analyses using a 
dichotomous responder/non-responder dependent variable (defined by >4 point improvement on ADAS-Cog). 
Aim3b. To determine whether the change on the experimental attentional measures seen in patients early in the 
treatment course predicts treatment change at 6 months, a hierarchical regression analyses will be conducted 
with attention score change T2-T1 (T2 for drug group; T2-pA for placebo group) used as the predictor 
variables, and ADAS-cog score (difference T3-T1)  used as the dependent variable. Group membership 
(drug/placebo), DRS, and demographic variables will be entered into the regression to control for age, 
education, initial dementia severity. 
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3.Rockwood K.2004. Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease. J Neurol Neurosurg 
Psychiatry;75:677-85. 
4.Foldi NS, Horn-Levinson L, Vedrody S et al.2004. Early detection of treatment change of acetylcholinesterase inhibitor in 
Alzheimer disease using measures of visual attention. Neurobiol Aging 25; S192. 
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6.Parasuraman R, Greenwood P, Haxby JV et al.1992. Visuospatial attention in dementia of the Alzheimer type. Brain;115:711-33. 
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13.Wolfe JM.2003. Moving towards solutions to some enduring controversies in visual search. Trends Cog Sci;7:70-6. 


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
14.Burk JA, Sarter M.2001. Dissociation between the attentional functions mediated via basal forebrain cholinergic and GABAergic 
neurons. Neuroscience;105:899-909. 
15.Himmelheber AM, Sarter M, Bruno J.2000. Increases in cortical acetylcholine release during sustained attention performance in 
rats. Cog Brain Res;313-25. 
16.Davidson MC, Marrocco RT.2000. Local infusion of scopolamine into intraparietal cortex slows covert orienting in rhesus 
monkeys. J Neurophysiol;83:1536-49. 
17.Levy JA, Parasuraman R, Greenwood P et al.2000. Acetylcholine affects the spatial scale of attention: Evidence from Alzheimer's 
disease. Neuropsychology;14:288-98. 
18.Yesavage JA, Mumenthaler MS, Taylor JL et al.2002. Donepezil and flight simulator performance: effects on retention of complex 
skills. Neurology;59:123-5. 
19.Himmelheber AM, Fadel J, Sarter M et al.1998. Effects of local cholinesterase inhibition on acetylcholine release assessed 
simultaneously in prefrontal and frontoparietal cortex. Neuroscience;86:949-57. 
20.Sarter M, Bruno JP.1997. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Rev;23:28-46. 
21.Mirza RN, Stolerman PI.2000. The role of nicotinic and muscarinic acetylcholine receptors in attention. 
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final analysis of a US multicentre open-label study. Eur Neuropsychopharm;10:195-203. 
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KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
ABSTRACTS 
3000 character abstract for general public.  
Although the majority of patients with Alzheimer’s disease (AD) are receiving acetylcholinesterase inhibitor 
treatment, there are no objective measures to determine whether the drug is working. This has frustrated 
families and physicians, and resulted in more scrutiny about the medications’ efficacy, cost, and clinical utility. 
These medications still remain part of standard treatment regimens, but we are remiss by not developing ways 
to assess if the drug is effective, and by not determining efficacy early in the course of treatment.  
 
Surprisingly, important measures that should be used to assess cholinergic change are lacking: the measures 
omitted involve attention. Attention is very sensitive to levels of acetylcholine. Research shows that 
acetylcholine directly mediates attention, and that attention is one of the earliest cognitive changes that occurs 
in the course of the disease, even during the pre-clinical, MCI phase. Animal models show that attention 
improves with increased acetylcholine, and deteriorates when acetylcholine levels are lowered. Yet, the link 
between attention and acetylcholine depletion in AD has never been fully explored, especially with regard to 
response to cholinergic treatment. To date, no study has investigated how acetylcholinesterase inhibitors affect 
attentional function in AD. We have preliminary data that now shows that measures of attention do change even 
after a few weeks of treatment, where traditional global measures do not show significant change. We predict 
that attentional measures will be excellent, more sensitive measures of response.  
 
We propose a 6-month longitudinal study, testing patients with standard measures and new experimental visual 
attention tasks. A first testing occurs before treatment, after which patients are randomized with half the patients 
treated with donepezil and half with placebo. A brief double-blind control period follows, during which treated 
patients will be titrated to optimal medication dose. After a second testing compares the subgroups, all patients 
receive open-label medication. The third testing occurs after 6 months, to determine the degree of response as 
measured by the traditional global scale (ADAS-Cog), and to determine whether the change at  the second 
testing can predict the performance at 6 months. 
 
We predict 1) that measures of attention are more sensitive than standard global measures; 2) that 
acetylcholinesterase inhibitor treatment affects attentional function early in the course of treatment; 3) that 
attentional measures can serve as important outcome measures to differentiate and predict good versus poor 
responders. 
 
This project provides tools to help us decide whether cholinergic treatment is effective. Our findings are 
generalizable and apply to other cholinergic treatments, and treatments now involving combined cholinergic 
and glutamanergic agents. 


KRS:  APPLICATION FORM FOR INDIVIDUAL RESEARCH PROJECT©  
Applicant Name (Foldi, Nancy S.):  
Project Title: Detecting an early response to donepezil with measures of visual attention    
To be used only by the Alzheimer’s Association, 
 
 
KR and Associates, and their agents that evaluate this application.  
DO NOT DUPLICATE 
Page 1  
3000 character abstract for technical audience  
Acetylcholinesterase inhibitors (AChE-I) comprise the major class of drugs used to treat Alzheimer’s disease 
(AD), but controversy about the usefulness of these medications1,2  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 cognitive 
change after 4-6 months of therapy represent a confound of the drug effect and the natural progression of the 
disease. Patient heterogeneity that may contribute to the wide range of response may also be further decreasing 
overall effect sizes. 
Surprisingly, attention has never been included in the assessment of AChE-I drugs. The rationale for 
using attentional measures is obvious: (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. We 
propose that attentional performance could serve as a highly sensitive outcome measure and a marker of 
response 
The proposed 6-month longitudinal study examines attentional, cognitive and behavioral performance in 
40 de novo AD patients undergoing donepezil treatment. New visual attentional measures will be contrasted 
with global cognitive measures and cognitive domain scores on three occasions (T1: pre-treatment; T2: 7 weeks 
(plus or minus 1 week); T3: post 6 months treatment). The T1-to-T2 arm of the design includes a double-blind 
placebo control period, after which all patients undergo open-label treatment. The assessment at 6 months will 
allow us to determine whether the changes seen earlier at T2 can predict patients who respond, or determine 
which measures best predict response.  
We present our preliminary data that support our rationale. Attentional measures are showing significant 
change after 7 weeks, while global measures are not. 
The proposed study predicts: 1) that measures of attention are more sensitive than standard global 
measures; 2) that AChE-I treatment affects attentional function early in the course of treatment. It is critical to 
determine efficacy before disease progresses. 
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 glutamanergic agents.