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Table 13.5

Clinical Dementia Rating (CDR)

Impairment Level and CDR Score (0, 0.5, 1, 2, 3)

Cognitive-Function

Category

None

Questionable

0.5

Mild

Moderate

Severe

Memory No memory loss or slight

inconsistent

forgetfulness

Consistent slight forgetful-

ness; partial recollection

of events; “benign” forget-

fulness

Moderate memory loss;

more marked for recent

events; defect interferes

with everyday activities

Severe memory loss; only

highly learned material

retained; new material

rapidly lost

Severe memory loss; only

fragments remain

Orientation Fully oriented Fully oriented except for

slight difficulty with time

relationships

Moderate difficulty with

time relationships; oriented

for place at examination;

may have geographic dis-

orientation elsewhere

Severe difficulty with time

relationships; usually dis-

oriented to time, often to

place

Oriented to person only

Judgment and

problem solving

Solves everyday problems

and handles business and

financial affairs well; judg-

ment good in relation to

past performance

Slight impairment in solving

problems, similarities, and

differences

Moderate difficulty in han-

dling problems, similari-

ties, and differences;

social judgment usually

maintained

Severely impaired in han-

dling problems, similari-

ties, and differences;

social judgment usually

impaired

Unable to make judgments

or solve problems

Community affairs Independent function at

usual level in job, shop-

ping, volunteer, and social

groups

Slight impairment in these

activities

Unable to function indepen-

dently at these activities

although may still be

engaged in some; appears

normal to casual inspection

No pretense of indepen-

dent function outside

home

Appears well enough to

be taken to functions out-

side a family home

No pretense of independent

function outside home

Appears too ill to be taken

to functions outside a fam-

ily home

Home and hobbies Life at home, hobbies, and

intellectual interests well

maintained

Life at home, hobbies, and

intellectual interests

slightly impaired

Mild but definite impair-

ment of function at home;

more difficult chores aban-

doned; more complicated

hobbies and interests

abandoned

Only simple chores pre-

served; very restricted

interests, poorly main-

tained

No significant function in

home

Personal care Fully capable of self-care Needs prompting

Requires assistance in

dressing, hygiene, keeping

of personal effects

Requires much help with

personal care; frequent

incontinence

Source:

“A New Clinical Scale for the Staging of Dementia,” by C. P. Hughes, L. Berg, W. L. Danziger, L. A. Coben, and R. L. Martin, 1982,

British Journal of Psychiatry, 140,

pp. 566–572. Reprinted with permission.

346

Confusional): moderate cognitive decline, clear-cut deficit on careful clinical inter-

view; Stage 5 (Early Dementia): moderately severe cognitive decline; Stage 6 (Mid-

dle Dementia): Severe cognitive decline; Stage 7 (Late Dementia): very severe

cognitive decline. Reliability of the FAST has been demonstrated with intraclass

correlations of above .85. Concurrent validity has been assessed against the Global

Deterioration Scale and a number of neuropsychological tests (Reisberg, Sclan,

Franssen, Kluger, & Ferris, 1994). The sensitivity of the FAST to the entire course of

AD, even in its most severe stages, may be indicative of the potential value of this

instrument for further investigation of the temporal longitudinal course of AD.

LINICAL

EMENTIA

ATING

The Clinical Dementia Rating (CDR; Hughes, Berg, Danziger, Coben, & Martin,

1982) scale is the most widely used in clinical practice as well as research to assess

the severity of disease progression. The CDR is helpful as a guide in the clinical

management of AD as well as other dementias. A trained physician, nurse, psy-

chologist, or other health professional administers the CDR to both the patient and

a reliable informant or collateral source such as a family member as a semistruc-

tured interview. The CDR is shown in Table 13.5.

Impairment levels are determined for six cognitive function categories: (1)

Memory, (2) Orientation, (3) Judgment, (4) Community Affairs, (5) Home and

Hobbies, and (6) Personal Care. A 5-point scale is used to rate the function in each

category: 0 = Normal (no significant problem); 0.5 = Questionable impairment

(more than just normal aging); 1 = Mild impairment (mildly impaired relative to

peers); 2 = Moderate impairment; 3 = Severe impairment. The scores for each cat-

egory are then analyzed using scoring rules to determine an overall CDR score.

The CDR table provides descriptive anchors that guide the rater in making appro-

priate ratings based on interview data and clinical judgment. Subjects who re-

ceive a score of 1 or greater show clear signs of dementia. The reliability of the

CDR has been further established (Berg et al., 1992). Longitudinal data are avail-

able on its use (Berg et al., 1988; Galasko et al., 1995), and it has been validated

against neuropathological information (Morris, McKeel, Fulling, Torack, & Berg,

1988; Morris et al., 1991).

COGNITIVE ASSESSMENT

INI

-M

ENTAL

TATE

XAMINATION

The Mini-Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975;

Folstein, Robins, & Helzer, 1983) is a quantitative measure of cognitive status in

adults. It is a brief questionnaire and can be used to screen for cognitive impair-

ment, to estimate the severity of cognitive impairment at a given point in time, to

follow the course of cognitive changes in an individual over time, and to docu-

ment an individual’s response to treatment. The MMSE has shown validity and

reliability in psychiatric, neurologic, geriatric, and other medical populations. It

has also been used as a research tool to screen for cognitive disorders in epidemi-

ological studies and to follow cognitive changes in clinical trials. It is presented in

Table 13.6.

Alzheimer’s Disease 347

348

Table 13.6

The Mini-Mental State Exam (MMSE)

Patient Examiner

Date

Maximum

Score

Orientation

5 ( ) What is the (year) (season) (date) (day) (month)?

5 ( ) Where are we (state) (country) (town) (hospital) (floor)?

Registration

3 ( ) Name 3 objects: 1 second to say each. Then ask the patient all 3 after you

have said them. Give 1 point for each correct answer. Then repeat them until

he/she learns all 3. Count trials and record.

Trials

Attention and Calculation

5()

Serial 7s. 1 point for each correct answer. Stop after 5 answers. Alternatively

spell “world” backward.

Recall

3 ( ) Ask for the 3 objects repeated above. Give 1 point for each correct answer.

Language

2 ( ) Name a pencil and watch.

1 ( ) Repeat the following “No ifs, ands, or buts”

3 ( ) Follow a 3-stage command:

“Take a paper in your hand, fold it in half, and put it on the floor.”

1 ( ) Read and obey the following: CLOSE YOUR EYES

1 ( ) Write a sentence.

1 ( ) Copy the design shown.

Total Score

Source:

“Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician,”

by M. F. Folstein, S. E. Folstein, and P. R. McHugh, 1975,

Journal of Psychiatric Research, 12,

pp. 189–198. Reprinted with permission.

Alzheimer’s Disease 349

Although the MMSE has limited specificity with respect to individual clini-

cal syndromes, it represents a brief, standardized method for grading cognitive

mental status. It assesses orientation, attention, immediate and short-term

recall, language, and the ability to follow simple verbal and written com-

mands. Furthermore, it provides a total score that places the individual on a

scale of cognitive function. Details of extensive subsequent validity and relia-

bility studies are described by Tombaugh and McIntyre (1992). Loewenstein

and colleagues (2000) tested the utility of an additional delayed recall of the 3

items as a screening test for mild cognitive impairment. Extended delayed re-

call of the 3 items was at 5-minute intervals. Sensitivity of 83.3% and speci-

ficity of 90% was achieved in differentiating cases with mild cognitive

impairment from individuals with normal cognition.

7-M

INUTE

CREEN

To recognize AD, which tends to be missed in primary care, the 7-Minute Screen

(Solomon & Pendlebury, 1998) was developed as a brief neurocognitive screening

battery. It covers multiple cognitive domains of orientation, memory, visuospatial

function, and verbal fluency and takes approximately 7 to 11 minutes, includ-

ing scoring. It can be rapidly administered by allied health professionals with-

out authentic training. No clinical judgment is needed. The portion assessing

the orientation is the Benton Temporal Orientation Test, which assesses the

ability to identify the month, date, year, day, and time of day (Benton, 1983).

The portion assessing the memory is an abbreviated version of the Enhanced

Cued Recall Test, which uses 16 items presented pictorially (Grober, Buschke,

Crystal, Bang, & Dresner, 1988). The subject is instructed to encode the items

and recall them with cues, and then recall again without cues. When the sub-

ject cannot recall any additional items, the examiner provides appropriate cues

for the remaining items. The score for this portion is the total number of items

remembered in both the uncued and cued recall. The portion assessing the vi-

suospatial function is a clock-drawing test with a simple scoring system

(Freedman et al., 1994). The examiner says to the subject, “I want you to draw

a clock with all the numbers on it. Make it large.” The subject is then asked to

draw the clock hands set at 20 minutes before 4 o’clock. A score is determined

using the scoring system. The portion that focuses on expressive language is a

test of verbal fluency (Monsch et al., 1992; Risen, 1980). The examiner asks the

subject to name as many members of the category “animals” as possible during

a 1-minute period. The score is the total number of items named. It was re-

ported that the 7-Minute Screen gave more accurate results than the MMSE for

patients with mild or very mild AD.

NFORMANT

UESTIONNAIRE ON

OGNITIVE

ECLINE IN THE

LDERLY

The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE;

Jorm & Jacomb, 1989) is a questionnaire administered to an informant about

changes in the subject’s cognitive function in everyday life (see Table 13.7). It

evaluates cognitive decline independent of premorbid ability. There are long and

short versions of the IQCODE.

350 E

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RACTICE

The examiner asks the informant to recall what the subject was like 10 years

ago and to compare that with what the subject is like now. The examiner then

asks the informant to indicate whether each of the situations shown in the table

of the IQCODE has improved, stayed the same, or gotten worse during the past

10 years. The short version of the IQCODE includes 16 situations. The judg-

ment is chosen from five evaluations: “Much improved,” “A bit improved,”

“Not much change,” “A bit worse,” and “Much worse.” It is important to com-

pare the subject’s present performance with 10 years ago. For instance, if 10

years ago the subject always forgot where he or she had left things, and he or

she still does, then this would be considered “Not much change.” The internal

consistency of the IQCODE was .93; the validity, measured against MMSE,

showed a correlation of .78. Further studies have shown that the IQCODE is as

good as the MMSE in the diagnosis of dementia (Jorm et al., 1991, 1996). A 16-

item version has been found to perform as well as the long version (Jorm,

1994). Validity has been affirmed by showing that subjects rated as having

moderate or severe decline were found to have greater change on the cognitive

tests (Jorm et al., 1996).

EVERE

MPAIRMENT

ATTERY

The cognitive function of very impaired patients cannot be measured with standard

neuropsychological tests. To assess these severely demented patients, the Severe Im-

paired Battery (SIB; Panisset, Roudier, Saxton, & Boller, 1994; Schmitt et al., 1997)

was developed. The SIB takes into account the specific behavioral and cognitive

deficits associated with severe dementia. It takes approximately 20 minutes to ad-

minister. It is composed of very simple one-step commands that are presented in

conjunction with gesture cues. The six major subscales are Attention, Orientation,

Table 13.7

Items from Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)

Remembering things about family and friends, e.g., occupations, birthdays, addresses

2. Remembering things that have happened recently

3. Recalling conversations a few days later

4. Remembering his/her address and telephone number

5. Remembering what day and month it is

6. Remembering where things are usually kept

7. Remembering where to find things that have been put in a different place from usual

8. Knowing how to work familiar machines around the house

9. Learning to use a new gadget or machine around the house

10. Learning new things in general

11. Following a story in a book or on TV

12. Making decisions on everyday matters

13. Handling money for shopping

14. Handling financial matters, e.g., the pension, dealing with the bank

15.

Handling other every day arithmetic problems, for example, knowing how much food

to buy, knowing how long between visits from family or friends

16.

Using his/her intelligence to understand what’s going on and to reason things through

Source:

“The Informant Questionnarie on Cognitive Decline in the Elderly (IQCODE): Socio-

Demographic Correlates, Reliability, Validity and Some Norms,” by A. F. Jorm and P. A. Jacomb,

1989,

Psychological Medicine, 19

(4), pp. 1015–1022. Reprinted with permission.

Alzheimer’s Disease 351

Language, Memory, Visuospatial Ability, and Construction. There are also brief

evaluations of praxis and the patient’s ability to respond appropriately when his or

her name is called. In addition, there is an assessment of social interaction skills ab-

stracted from the Communicative Activities in Daily Living Scale (Holland, 1980).

FUNCTIONAL ASSESSMENT

LZHEIMER

’

ISEASE

OOPERATIVE

TUDY

—A

CTIVITIES OF

AILY

IVING

The Alzheimer’s Disease Cooperative Study—Activities of Daily Living (ADCS-

ADL; Galasko, Schmitt, Thomas, Jin, & Bennett, 2005) inventory consists of a com-

prehensive battery of activities of daily living questions used to assess the

functional capabilities of patients. Although ADL includes a wide range of activi-

ties, ADL scores should have broad applicability and reflect the severity of ADL

impairment. A set of informant-based items describing the performance of ADL

was developed to identify which ADL domains are useful for assessment of pa-

tients in clinical research on AD. A total of 45 ADL items selected on the basis of

a literature review and clinical experience were tested. They were then narrowed

to 27 items that were widely applicable, showed good test-retest reliability be-

tween repeated estimations, and correlated with the severity of dementia. The

modified ADCS-ADL inventory was thus established (Galasko et al., 1997). Each

ADL item is rated from the highest level of independent performance to complete

loss. The investigator applies the inventory by interviewing a caregiver who is fa-

miliar with the behavior of the patient.

Patients with AD who have reached a stage of moderate to severe dementia are

still capable of performing a limited range of ADL. From a large pool of ADL data

in a cohort, 19 items were chosen in consideration of their applicability, reliability,

good scaling, concordant validity, and sensitivity in detecting changes in perfor-

mance over a period of months. The subset of items, including ratings of the pa-

tient’s ability to eat, dress, bathe, telephone, travel, shop, and perform other

household chores, has been validated for the assessment of patients with moder-

ate to severe dementia. This is the modified ADCS-ADL—severe inventory

(Galasko et al., 2005), which has a scoring range of 0 to 54, with the lower scores

indicating greater functional impairment.

ISABILITY

SSESSMENT FOR

EMENTIA

The Disability Assessment for Dementia (DAD; Gelinas, Gauthier, McIntyre, &

Gauthier, 1999) is an assessment tool for functional disability, designed to meet

the specific needs of community-dwelling elderly patients who have AD. Func-

tional disability is measured with the DAD by evaluating the basic, instrumen-

tal, and leisure activities of daily life. The basic ADL are related to self-care

and include dressing, hygiene, continence, and eating. The instrumental ADL

are related to maintenance in a specific environment and include meal prepara-

tion, telephoning, housework, taking care of finances and correspondence,

going on an outing, taking medication, and the ability to stay safely at home.

The leisure activities go beyond self-maintenance and are for the purpose of

recreation. To understand the cognitive dimensions of disabilities in ADL, the

activities have been subdivided into initiation, planning and organization, and

effective performance.

352 E

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Table 13.8

Symptoms of Behavioral Pathology in Alzheimer’s

Disease (BEHAVE-AD) Rating Scale

Category Example

Paranoid and delusional ideation “People are stealing things” delusion

“One’s house is not one’s house” delusion

“Spouse (or other caregiver) is an imposter ” delusion

Delusion of abandonment (e.g., to an institution)

Delusion of infidelity

Other suspiciousness or paranoia

Other delusions

Hallucinations Visual

Auditory

Olfactory

Haptic

Other

Activity disturbances Wandering

Purposeless activity

Inappropriate activity

Aggressiveness Verbal outbursts

Physical threats and violence

Agitation

Diurnal rhythm disturbances Day-night disturbances

Affective disturbances Tearfulness

Depressed mood

Anxieties and phobias Anxiety about upcoming events

Other anxieties

Fear of being left alone

Other phobias

Source:

“Behavioral Pathology in Alzheimer ’s Disease (BEHAVE-AD) Rating Scale,” by B. Reisberg,

S. R. Auer, and I. M. Monteiro, 1996,

International Psychogeriatrics, 8

(Suppl. 3), pp. 301–308.

Reprinted with permission.

BEHAVIORAL ASSESSMENT

EHAVIOR

ATHOLOGY IN

LZHEIMER

’

ISEASE

ATING

CALE

Before development of the Behavior Pathology in Alzheimer’s Disease (BEHAVE-

AD; Reisberg, Auer, & Monteiro, 1996) rating scale, several scales, including the

Symptoms of Psychosis in Alzheimer’s Disease (Reisberg & Ferris, 1985), were

available for measuring behavioral disturbances and psychiatric disorders in pa-

tients with AD. However, such scales generally mixed cognitive disturbances

with behavioral symptoms or included functional impairment. The BEHAVE-AD

scale was developed to measure behavioral disturbances related to dementia sep-

arately from the cognitive and functional disturbances. Separate assessment of

each symptomatic domain is particularly important because behavioral distur-

bances of dementia might be amenable to treatment.

The items of BEHAVE-AD are shown in Table 13.8. The rating scale consists of

seven categories, including 25 items of behavioral disturbances. Each symptom is

Alzheimer’s Disease 353

scored on a 4-point scale of severity: 0 = Not present; 1 = Present; 2 = Present, gener-

ally with an emotional component; and 3 = Present, generally with an emotional and

physical component. The rating scale also contains a 4-point global assessment of the

overall magnitude of the behavioral symptoms in terms of disturbance to the care-

giver or danger to the patient. Sclan and colleagues (1996) determined interrater reli-

ability of the scale transculturally, including patients from France. Interrater

reliability was excellent, with agreement coefficients ranging from .65 to .91. Patter-

son and colleagues (1990) reported very good reliability rating (kappa value = .62 to

1.00 on 20 of the 25 items, with percentage agreement of between 82% and 100%).

OHEN

-M

ANSFIELD

GITATION

NVENTORY

Agitation can be operationally defined as inappropriate verbal, vocal, or motor

activity that is not judged by an observer to result directly from the needs or

confusion of the agitated individual (Cohen-Mansfield & Billig, 1986). Agitation

is not a diagnostic term but a term describing a group of symptoms. Agitated

behavior is socially inappropriate and may be manifested in three ways: abusive

or aggressive behavior toward self or others; appropriate behavior performed

with inappropriate frequency, such as repeatedly asking questions; and inap-

propriate behavior according to the social standards for a given situation, such

as taking off one’s clothes in the activity room of a nursing home (Cohen-Mans-

field, Marx, & Rosenthal, 1989).

The purpose of the Cohen-Mansfield Agitation Inventory (CMAI; Cohen-

Mansfield, 1996) is to assess the frequency of manifestation of agitated behavior

in elderly persons. The CMAI was developed for use in nursing homes. Although

originally developed for research purposes, it has recently also been used for

clinical purposes. It has thus been used by family caregivers, social workers, ac-

tivity directors of senior day care centers, and other clinical staff members, as

well as researchers. The items of the CMAI are presented in Table 13.9. The CMAI

Table 13.9

Cohen-Mansfield Agitation Inventory (CMAI)

1. Pace, aimless wandering

2. Inappropriate dress or disrobing

3. Spitting (including at meals)

4. Cursing or verbal aggression

5. Constant unwarranted request for attention or help

6. Repetitive sentences or questions

7. Hitting (including self)

8. Kicking

9. Grabbing onto people

10. Pushing

11. Throwing things

12. Strange noises (weird laughter or crying)

13. Screaming

14. Biting

Source:

“Conceptualization of Agitation: Results Based on the Cohen-

Mansfield Agitation Inventory and the Agitation Behavior Mapping Instru-

ment,” by J. Cohen-Mansfield, 1996,

International Psychogeriatrics,

(Suppl. 3), pp. 309–315. Reprinted with permission.

354 E

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consists of 29 items, each rated on a 7-point scale of frequency: 1 = Never; 2 = Less

than once a week; 3 = Once or twice a week; 4 = Several times a week; 5 = Once or

twice a day; 6 = Several times a day; 7 = Several times an hour. The CMAI ques-

tions pertain to the prior 2 weeks.

CURRENT STATUS AND FUTURE OUTLOOK FOR DRUG

TREATMENT: A MECHANISM-BASED APPROACH

HOLINESTERASE

NHIBITORS FOR

YMPTOMATIC

REATMENT

It is possible to prescribe any of four cholinesterase inhibitors (ChEls), that is,

tacrin, donepezil, rivastigmine, and galantamine, as well as the N-methyl-D-

asparate antagonist, memantine, to treat AD. The efficacy and safety of these

drugs have already been established. They are used for so-called symptomatic

treatment, and the purpose of administering these drugs is to delay progression

of the symptoms associated with AD. Many institutes and pharmaceutical com-

panies are vigorously pursuing development of immunotherapy using vaccines

and other drugs as disease modifiers as well as basic therapeutic drugs such

as secretase, but none of the potential products has reached the stage of clinical

application.

Recently, there have been reports describing the efficacy of ChEIs. Assess-

ments of the efficacies of donepezil, rivastigmine, galantamine, and memantine

were published by the AD2000 Collaborative Study Group (Courtney et al., 2004)

and by Kaduszkiewicz, Zimmermann, Beck-Bornholdt, and van den Bussche

(2005). Here, we would like to discuss the efficacy of ChEIs, focusing mainly on

the findings of these two studies cited. With respect to the future outlook for AD

drugs, we summarize and briefly comment on the results of studies that used

ChEIs to treat mild cognitive impairment.

Current Status of Cholinesterase Inhibitors for Treating Alzheimer’s Disease A

meta-analysis of the efficacy of three ChEI drugs (donepezil, galantamine,

and rivastigmine) was performed based on 121 original articles and 34 review

papers, which were selected from 2,285 reports on AD published between 1992

and 2002 (Ritchie, Ames, Clayton, & Lai, 2004). The results of 10 donepezil, six

galantamine, and five revastigmine studies were compared using regression

analysis in terms of the dose-dependence effect and the dropout rate. All

three drugs were confirmed to be superior to the placebo with respect to the

results of cognitive test batteries. However, whereas donepezil and rivastig-

mine exhibited a greater effect at high doses, a significant dose-dependent ef-

fect was not observed for galantamine. For the global clinical assessment,

the treated groups were superior to the placebo, but a definite correlation

between the dose and effect was not observed for donepezil and galantamine.

For the dropout rates, there were not significant differences among the three

drugs, other than the high dose of donepezil. In other words, even though

the mechanisms of action of the three drugs are somewhat different—

the Acetyleholinesterase (AChE) inhibitory action of donepezil is more potent

than its Y Butirilcolinesterasa (BuCE) inhibitory action, the potentiating ac-

tion of galantamine on nicotine receptors is potent, and rivastigmine has both

AChE and BuChE inhibitory actions—there were no substantial differences

Alzheimer’s Disease 355

in the clinical usefulness of the drugs when evaluating them using the cogni-

tive test batteries and the global clinical assessment. More recently, the review

of 26 randomized controlled trials confirmed that the results for ChEIs were

similar to the results just cited (Takeda et al., 2006). The authors of the review

attempted to draw conclusions concerning the effects on quality of life and

to compare the drugs, but they were unable to come to any conclusions due to

the limited number of reports. Adverse drug effects due to ChEIs were re-

viewed in the report of Kaduszkiewicz and colleagues (2005). The incidence

of adverse drug effects with each of the three drugs increased as the adminis-

tered dose was increased, but it is difficult to compare the three drugs be-

cause little was reported about the dose or time of onset of the adverse effects.

It may be possible to state that the typical nongastrointestinal adverse effects

of the drugs were insomnia for donepezil and dizziness for galantamine and

rivastigmine.

Kaduszkiewicz and colleagues (2005) reviewed 22 randomized, double-

blind, placebo-controlled studies conducted on ChEIs between 1989 and 2004.

The reports were selected based on specific criteria. The criteria in their

analysis included methodological parameters: the inclusion and exclusion cri-

teria for the subjects; the method of randomization; methods and criteria for

stratification, blinding, outcome measures, and method of analysis; signifi-

cant level; power of the tests; whether or not both groups that participated in

the study received the same treatment; aspects relating to the results such as

baseline data, adverse drug effects, intention-to-treat analysis, number of sub-

jects included in the analysis, outcome of assessment end points, and con-

formity of the results; and overall interpretation of the research, such as

whether the name of the sponsor was clearly stated, the study methods, and

clinical significance. In their review, Kaduszkiewicz and colleagues did not

examine the characteristics of the clinical efficacy among ChEIs, but rather

determined the efficacy of ChEIs overall from the point of view of the study

design. They concluded, as in past evidence-based reviews, that the efficacy of

ChEIs was confirmed in several clinical trials. On the other hand, the efficacy

measured using the assessment scales used in the clinical trials was modest,

and they pointed out that there were many methodological deficiencies in the

studies themselves. Furthermore, they pointed out that it was impossible to

conclude whether donepezil was effective or not based on the results in the

AD2000 study because the study period was not established beforehand and

because the results for the 5 mg and 10 mg groups were not shown separately.

Kaduszkiewicz and colleagues stated that although the three ChEIs were ef-

fective, their overall efficacy in the treatment of AD was not really that high.

However, we believe this was not an appropriate statement, because they did

not consider such aspects as the health insurance systems of the different

countries or the degree of recognition of AD by family physicians. Finally, it

should be emphasized that consistent results were obtained in the studies that

used the three ChEIs.

N-methyl-D-asparate Antagonist Memantine is the only agent other than the

cholinesterase inhibitors that has been approved for treatment of AD. It is a

moderate-affinity, noncompetitive N-methyl-D-aspartate receptor antagonist