Donepezil Slows Neurodegeneration

8/8/2019 Donepezil Slows Neurodegeneration

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Article

676 Am J Psychiatry 162:4, April 2005http://ajp.psychiatryonline.org

Does Donepezil Treatment Slow the Progression

of Hippocampal Atrophy in Patients

With Alzheimers Disease?

Mamoru Hashimoto, M.D., Ph.D.

Hiroaki Kazui, M.D., Ph.D.

Keiji Matsumoto, M.D.

Yoko Nakano, M.D., Ph.D.

Minoru Yasuda, M.D., Ph.D.

Etsuro Mori, M.D., Ph.D.

Objective: The only approved pharmaco-

logical approach for the symptomatic

treatment of Alzheimers disease in Japan

is the use of a cholinesterase inhibitor,

donepezil hydrochloride. Recent in vivo

and in vitro studies raise the possibility

that cholinesterase inhibitors can slow the

progression of Alzheimers disease. The

purpose of the present study was to deter-

mine whether donepezil has a neuropro-

tective effect in Alzheimers disease by us-

ing the rate of hippocampal atrophy as a

surrogate marker of disease progression.

Method: In a prospective cohort study,54 patients with Alzheimers disease who

received donepezil treatment and 93 con-

trol patients with Alzheimers disease who

never received anti-Alzheimer drugs un-

derwent magnetic resonance imaging

(MRI) twice at a 1-year interval. The an-

nual rate of hippocampal atrophy of each

subject was determined by using an MRI-

based volumetric technique. Background

characteristics, age, sex, disease duration,

education, MRI interval, apolipoprotein E

(APOE) genotype, and baseline Alzheimers

Disease Assessment Scale score were com-

parable between the treated and control

groups.

Results: The mean annual rate of hippo-

campal volume loss among the treated pa-

tients (mean=3.82%, SD=2.84%) was signif-

icantly smaller than that among the

control patients (mean=5.04%, SD=2.54%).

Upon analysis of covariance, where those

confounding variables (age, sex, disease

duration, education, MRI interval, APOEgenotype, and baseline Alzheimers Dis-

ease Assessment Scale score) were entered

into the model as covariates, the effect of

donepezil treatment on hippocampal at-

rophy remained significant.

Conclusions: Donepezil treatment slows

the progression of hippocampal atrophy,

suggesting a neuroprotective effect of

donepezil in Alzheimers disease.

(Am J Psychiatry 2005; 162:676682)

At present, the only approved pharmacological ap-proach for the symptomatic treatment of Alzheimers

disease in Japan is the use of cholinesterase inhibitors.

Donepezil hydrochloride has been demonstrated to have

significant effects in slowing symptomatic progression in

24-week placebo-controlled trials (1), and some long-term

studies have shown that there is no less benefit after 1 year

of treatment (2, 3). One observational study (4) showed

that cholinesterase inhibitor treatment alters the natural

history of Alzheimers disease, as indicated by the delay in

admission to nursing homes. Furthermore, a longitudinal

neuroimaging study using single photon emission com-puted tomography (SPECT) demonstrated that treatment

of patients with Alzheimers disease with donepezil for 1

year reduced the decline in regional cerebral blood flow

(rCBF) (5), suggesting the preservation of functional brain

activity in donepezil-treated patients. Although these

studies appear to have demonstrated the efficacy of done-

pezil in slowing down clinical disease progression, it is not

clear whether donepezil treatment slows disease progres-

sion in Alzheimers disease.

Neuropathologically, Alzheimers disease is characterized

by the presence of neurofibrillary tangles and senile

plaques, impaired synaptic function, and cell loss ( 6).

Although these histological features cannot be examined

noninvasively, the cell loss that accompanies them can be

seen in vivo as atrophy with magnetic resonance imaging

(MRI). Among the characteristic neuropathological changes

in Alzheimers disease, the most prominent structural

changes at the initial stage occur in the hippocampal for-

mation (7, 8). MRI-based volumetry of the medial tempo-

ral lobe structures has been proposed as a useful tool for

the clinical diagnosis of Alzheimers disease (8). Serial MRI

studies permit calculation of rates of atrophy over time. It

has been proposed that measurement of the rate of atro-

phy could be used to monitor the effectiveness of antide-

mentia drugs for Alzheimers disease (9, 10). If an anti-Alz-

heimer drug can slow down the anatomic progression of

Alzheimers disease pathology, this should be detectable

as a decrease in the rate of hippocampal atrophy in treated

patients.


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Am J Psychiatry 162:4, April 2005 677

HASHIMOTO, KAZUI, MATSUMOTO, ET AL.

http://ajp.psychiatryonline.org

The purpose of the present study was to determine

whether a cholinesterase inhibitor, donepezil hydrochlo-

ride, has a neuroprotective effect on Alzheimers disease.

Using an MRI-based volumetric technique, we examined

the rates of hippocampal atrophy in donepezil-treated

Alzheimers disease patients and compared the results

with those in control patients.

Method

Subjects and Study Design

In the present study, a prospective cohort was compared with a

historical control cohort. All procedures followed the clinical

study guidelines of the ethics committee of Hyogo Institute for

Aging Brain and Cognitive Disorders, a research-oriented hospital,

and were approved by the institutional review board. Written in-

formed consent was obtained from the patients or their families.

The control group was selected among those who participated

in the annual follow-up program before donepezil was intro-

duced. Patients with Alzheimers disease who were examined at

the Hyogo Institute for Aging Brain and Cognitive Disorders were

invited to the Hyogo Institutes Alzheimers disease annual follow-

up program starting in July 1993. The consent and availability of a

reliable caregiver and the absence of severe behavioral problems

impelling institutionalization were the requirements for partici-

pating in the program. At baseline, the patients were examined

comprehensively by both neurologists and psychiatrists under a

short-term admission to the infirmary and were given routine

laboratory tests, EEGs, and standardized neuropsychological ex-

aminations. The patients medical history was systematically col-

lected from reliable family members by using a database format.

Other imaging studies, such as MRIs of the brain, magnetic reso-

nance angiograms of the head and neck, and cerebral perfusion

or metabolism studies with positron emission tomography or

SPECT were performed at baseline. Neuropsychological tests and

MRIs were repeated at 1-year intervals. The clinical and investiga-

tive data collected prospectively in a standardized fashion were

all added to the database (11).After donepezil hydrochloride was licensed and marketed in

November 1999 in Japan, the annual follow-up program was re-

vised to the donepezil follow-up program because most patients

with Alzheimers disease were treated with donepezil. The treated

group consisted of consecutive patients with mild to moderate

Alzheimers disease who received donepezil treatment and were

enrolled in a prospective longitudinal cohort study between No-

vember 1999 and June 2003. Treatment with donepezil was a pre-

requisite for participating in the revised program. After the same

baseline assessments as the annual follow-up program were eval-

uated, the patients received 3 mg/day of donepezil for 1 or 2 weeks

and then 5 mg/day (the approved maximum dose in Japan). Do-

nepezil hydrochloride was prescribed for the entire year after the

initial MRI, and compliance was monitored at every visit (every 3

months). Neuropsychological tests and MRIs were repeated at 1-year intervals. The treated patients satisfied six inclusion criteria:

1. Meeting criteria of the National Institute of Neurological

Disease and Stroke/Alzheimers Disease and Related Disor-

ders Association for probable Alzheimers disease (12)

2. Having minimal to moderate functional severity (a score of 15

or more on the Mini-Mental State Examination (MMSE) (13)

3. Having no lifetime history of other neurological or mental

disorders

4. Taking no established and documented antidementia drugs

other than donepezil (agents with possible antidementia

properties, such as nonsteroidal antiinflammatory drugs,

vitamins E, ginkgo biloba, and lecithin were allowed)

5. Having no evidence of focal brain lesions on a MRI

6. There being informed consent from patients and their rela-

tives for determination of their apolipoprotein E (APOE)

genotype

The control group was selected among those who participated

in the annual follow-up program between July 1993 and October

1999. Requirements for inclusion in the present study were thesame as those for the donepezil follow-up participants except for

the use of donepezil. Those who received anti-Alzheimer drugs

other than donepezil were not included in the present study. In

this study, only baseline and 1-year follow-up data were used.

Cognitive Functions

The status of global cognitive function was assessed with the

MMSE and the Alzheimers Disease Assessment Scale (14). The Alz-

heimers Disease Assessment Scale was administrated by neuro-

psychologists (along with the MRI examination) who were not in-

volved in managing the patients at a 1-year interval (1014 months).

MRI Volumetry

We directly measured the volume of the hippocampal forma-

tion on high spatial resolution three-dimensional spoiled-gradi-ent echo images (15). The images were generated perpendicular to

the anterior-posterior commissure plane that covers the whole

calvaria with a 1.5-T MRI unit (Sign Advantage 5.x, General Elec-

tric Medical Systems, Milwaukee). The operating parameters were

as follows: field of view=220 mm, matrix=256256, 1241.5 mm

contiguous sections, TR=14 msec, TE=3 msec, and flip angle=20.

The detailed hippocampal MRI volumetric procedure is de-

scribed elsewhere (15). In brief, the MRI data set was transmitted

to a computer from the MRI unit, and after an appropriate data

conversion, it was analyzed by using the public domain Image

version 1.62 program (developed at the National Institutes of

Health and available on the Internet at http://rsb.info.nih.gov/

nih-image/) with residential macro programs developed in our

institute. Hippocampal formation volume in all subjects was

measured by a single investigator (M.H.) who was blinded to 1) allclinical information, 2) the order (initial and follow-up) of MRIs,

and 3) the time of enrollment. Before starting the measurement,

the rater inspected the suitability of MRIs for hippocampal volu-

metry. If either one of the two MRIs obtained for a subject was un-

suitable for volumetry because of motion artifacts or for any other

technical reason, the subject was excluded from the study.

For volumetry, we used a combination of semiautomatic seg-

mentation-through-density thresholding and manual tracing,

thereby lowering partial voluming and the observers bias. The re-

liability and validity of volumetry have been established and de-

scribed elsewhere (9, 15). The hippocampal formation was de-

fined to include the pes hippocampi, digitationes hippocampi,

alveus hippocampi, dentate gyrus, and subiculum (1618). The

boundary of the hippocampal formation was defined from the

entire head of the hippocampus to the slice where the crus of the

fornix was seen in full profile. The outline of the hippocampal for-

mation together with the surrounding white matter and CSF was

first traced with a manually guided mouse cursor, and subse-

quently, the gray matter of each structure was extracted by den-

sity thresholding set at a range between minimum and maximum

pixel values. The maximum value was defined as the largest value

for any pixel of the gray matter (represented by the caudate head).

The minimum value was defined as one-half the sum of the mean

pixel value of the gray matter and the mean value of CSF (repre-

sented by the lateral ventricle) (16). The slice volume of the hip-

pocampal formation was obtained by automatically counting the

number of pixels within the segmented regions and then multi-


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age, sex, disease duration, education, MRI interval, APOE

genotype, and baseline Alzheimers Disease Assessment

Scale score were entered into the model as covariates, the

effect of donepezil on hippocampal atrophy remained sig-

nificant (F=10.34, df=138, p=0.002).

Even if the two patients who did not receive the full 1-

year dosage of donepezil were excluded from the analyses,

the results remained unchanged; donepezil treatment had

significant effects on Alzheimers Disease Assessment

Scale score (F=4.37, df=141, p


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680 Am J Psychiatry 162:4, April 2005

DONEPEZIL AND HIPPOCAMPAL ATROPHY


cholinesterase inhibitors was postponed reminds us of a

potential disease-modifying effect.

A recent long-term randomized, double-blind trial (26)

showed that no significant benefits were seen with done-

pezil compared with placebo in the institutionalization

and progression of disability. In the study, there were no

significant differences in behavioral symptoms, caregiver

well-being, and caregiver time costs. On the other hand,

statistically significant cognitive and functional effects

were maintained over at least 2 years. Because many of the

outcomes are influenced by the interaction of complex bi-

ological, social, and environmental factors, they might be

inappropriate for assessing the neuroprotective effects of

donepezil.

To explain the neuroprotective effect of cholinesterase

inhibitors, mechanisms based on beta-amyloid metabo-

lism have been postulated. Accumulation of amyloid is

one of the earliest changes in Alzheimers disease pathol-

ogy (27, 28) and may cause neuronal death in the CNS (29,

30). In vitro studies have demonstrated a link between

cholinergic activation and beta-amyloid precursor proteinmetabolism. Wallace et al. (31) found evidence that lesions

of the cholinergic nucleus basalis of Meynert increased

the synthesis of beta-amyloid precursor protein in the ce-

rebral cortex of rats. Wolf et al. (32), using human CNS

neurons, found increased amyloid precursor protein se-

cretion and decreased beta-amyloid protein production

with carbachol stimulation of muscarinic receptors (32).

These studies support a beneficial alteration in amyloid

processing associated with cholinergic stimulation. Ki-

hara et al. (33) examined the effects of nicotinic receptor

agonists on amyloid beta cytotoxicity in cultured rat corti-

cal neurons and found that nicotinic receptor stimulation

may be able to protect neurons from degeneration in-duced by amyloid beta. Svensson and Nordberg (34) dem-

onstrated that tacrine and donepezil at clinically relevant

concentrations attenuated amyloid beta (25-35)-induced

toxicity in rat pheochromocytoma PC12 cells. The neuro-

protective effect was blocked by the presence of the nico-

tinic antagonists mecamylamine and tubocurarine, sug-

gesting an intervention through nicotinic receptors.

Our study has some limitations. First, because it was a

comparative study with a historical control group rather

than a randomized study, it suffers from several sources of

bias. The groups are not comparable because of the selec-

tion of subjects who received the intervention (selection

bias), the cointerventions and other medical management

being received by the two groups were different (perfor-

mance bias), and the methods of outcome measurement

being used in the two groups were different (detection

bias). Although there was no intention to select subjects

for the control and treatment groups, patients who could

not tolerate the initial doses of donepezil were not in-

cluded in the donepezil follow-up program. This could

have been a source of selection bias. However, we are un-

aware of any evidence that donepezil tolerance predicts

disease progression. Because the control group in the

present study was not concurrent but historical, there was

a generation difference of several years between the

groups. Although the generation difference was a possible

source of selection and performance bias, the difference

in the patients generation was not likely to affect the vol-

umetric results, and the cointerventions and other medi-

cal management did not change throughout the first and

second halves of the study period. Second, it has been rec-

ognized that open-label studies are not optimal. The fact

that the investigators were not blinded to treatment might

increase the donepezil effect. However, neither hippo-

campal volume nor the Alzheimers Disease Assessment

Scale score was a subjective outcome measure. Further-

more, in the present study, the Alzheimers Disease Assess-

ment Scale was administered by neuropsychologists who

were unblinded but not involved in managing the pa-

tients, and MRI volumetry was made by an investigator

who was blinded to all clinical information. Therefore, it

was unlikely that detection bias affected the results of the

rate of hippocampal atrophy or the Alzheimers DiseaseAssessment Scale score in favor of the donepezil-treated

group. Third, dropouts are a problem for this type of de-

sign and a possible source of exclusion bias. Simply ignor-

ing everyone who has withdrawn from a clinical trial may

bias the results, usually in favor of the intervention. There-

fore, it is standard practice to analyze the results of com-

parative studies on an intention-to-treat basis. In the

present study, two patients who did not take the full 1-year

dosage of donepezil because of adverse events or poor

compliance were included in the primary analyses.

As a result, the patients background characteristics,

such as age, sex, education, disease duration, disease se-

verity, and MRI interval, were comparable between thetwo groups, and even after we controlled for these vari-

ables, the effect of donepezil on hippocampal atrophy re-

mained unchanged. In any case, the significant difference

of the rate of hippocampal atrophy was likely to be due to

the intervention with donepezil. Although our findings

should be confirmed by a randomized, controlled long-

term trial in patients with Alzheimers disease, it would be

unethical to conduct such a study to extend the knowl-

edge of donepezil.

The present results suggest that donepezil has not only

a symptomatic effect but also a neuroprotective effect. If

donepezil does, in fact, influence disease progression, we

need to modify our treatment strategies; donepezil is not

an optional but rather a mandatory treatment for Alzhe-

imers disease and should be started in the prodromal or

very early stage of the disease. Mild cognitive impairment

is a condition that frequently progresses to Alzheimers

disease, which requires early diagnostic and therapeutic

interventions. Donepezil, through its neuroprotective ef-

fect, could possibly inhibit progression from mild cognitive

impairment to Alzheimers disease. Further studies are

needed to determine whether donepezil slows the progres-


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sion from mild cognitive impairment to Alzheimers dis-

ease. Hippocampal atrophy could be used as a surrogate

marker of disease progression in such studies. Further-

more, the potential neuroprotective mechanism should be

refined and exploited to enhance the drugs effectiveness in

treating Alzheimers disease. A better understanding of this

mechanism may suggest strategies for designing improved

drugs.

Received June 11, 2004; revision received Sept. 1, 2004; accepted

Sept. 10, 2004. From the Hyogo Institute for Aging Brain and Cogni-

tive Disorders, Hyogo, Japan; Sawa Hospital at Toyonaka; the Depart-

ment of Psychiatry and Behavior Science, Osaka University Graduate

School of Medicine, Osaka, Japan; the Department of Psychiatry and

Neurology, Kobe Graduate University School of Medicine, Hyogo, Ja-

pan; and the Department of Behavioral Neurology and Cognitive

Neuroscience, Tohoku University Graduate School of Medicine, Sen-

dai, Japan. Address correspondence and reprint requests to Dr. Ha-

shimoto, Sawa Hospital, 1-9-1 Shiroyamacho, Toyonaka, Osaka, 561-

8691, Japan; [email protected] (e-mail).

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Donepezil Slows Neurodegeneration