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Does Donepezil Treatment Slow the Progression of Hippocampal Atrophy in Patients With Alzheimer’s 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 pharmacological approach for the symptomatic treatment of Alzheimer’s 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 Alzheimer’s disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer’s disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. Method: In a prospective cohort study, 54 patients with Alzheimer’s disease who received donepezil treatment and 93 control patients with Alzheimer’s disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRIbased volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer’s Disease Assessment Scale score were comparable between the treated and control groups. Results: The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly 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, APOE genotype, and baseline Alzheimer’s Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant. Conclusions: Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer’s disease. (Am J Psychiatry 2005; 162:676–682)
t present, the only approved pharmacological approach for the symptomatic treatment of Alzheimer’s 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 Alzheimer’s disease, as indicated by the delay in admission to nursing homes. Furthermore, a longitudinal neuroimaging study using single photon emission computed tomography (SPECT) demonstrated that treatment of patients with Alzheimer’s 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 donepezil in slowing down clinical disease progression, it is not clear whether donepezil treatment slows disease progression in Alzheimer’s disease.
Neuropathologically, Alzheimer’s 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 Alzheimer’s disease, the most prominent structural changes at the initial stage occur in the hippocampal formation (7, 8). MRI-based volumetry of the medial temporal lobe structures has been proposed as a useful tool for the clinical diagnosis of Alzheimer’s disease (8). Serial MRI studies permit calculation of rates of atrophy over time. It has been proposed that measurement of the rate of atrophy could be used to monitor the effectiveness of antidementia drugs for Alzheimer’s disease (9, 10). If an anti-Alzheimer drug can slow down the anatomic progression of Alzheimer’s disease pathology, this should be detectable as a decrease in the rate of hippocampal atrophy in treated patients.
Am J Psychiatry 162:4, April 2005
the rater inspected the suitability of MRIs for hippocampal volumetry. 15). The images were generated perpendicular to the anterior-posterior commissure plane that covers the whole calvaria with a 1. thereby lowering partial voluming and the observer’s bias. TE=3 msec. ET AL. the gray matter of each structure was extracted by density thresholding set at a range between minimum and maximum pixel values. Taking no established and documented antidementia drugs other than donepezil (agents with possible antidementia Am J Psychiatry 162:4. we examined the rates of hippocampal atrophy in donepezil-treated Alzheimer’s disease patients and compared the results with those in control patients. The detailed hippocampal MRI volumetric procedure is described elsewhere (15).psychiatryonline. properties. Hippocampal formation volume in all subjects was measured by a single investigator (M. 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. donepezil hydrochloride. Treatment with donepezil was a prerequisite for participating in the revised program. magnetic resonance angiograms of the head and neck. The consent and availability of a reliable caregiver and the absence of severe behavioral problems impelling institutionalization were the requirements for participating in the program. All procedures followed the clinical study guidelines of the ethics committee of Hyogo Institute for Aging Brain and Cognitive Disorders. The patients’ medical history was systematically collected from reliable family members by using a database format. MRI Volumetry We directly measured the volume of the hippocampal formation on high spatial resolution three-dimensional spoiled-gradient echo images (15). ginkgo biloba. Patients with Alzheimer’s disease who were examined at the Hyogo Institute for Aging Brain and Cognitive Disorders were invited to the Hyogo Institute’s Alzheimer’s disease annual followup program starting in July 1993. Milwaukee).gov/ nih-image/) with residential macro programs developed in our institute. the annual follow-up program was revised to the donepezil follow-up program because most patients with Alzheimer’s disease were treated with donepezil. 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 (represented by the lateral ventricle) (16). the patients received 3 mg/day of donepezil for 1 or 2 weeks and then 5 mg/day (the approved maximum dose in Japan). Written informed consent was obtained from the patients or their families. and 3) the time of enrollment. Having no lifetime history of other neurological or mental disorders 4. Before starting the measurement. the MRI data set was transmitted to a computer from the MRI unit. Using an MRI-based volumetric technique. and standardized neuropsychological examinations. April 2005 Cognitive Functions The status of global cognitive function was assessed with the MMSE and the Alzheimer’s Disease Assessment Scale (14).5 mm contiguous sections. has a neuroprotective effect on Alzheimer’s disease. dentate gyrus. The treated group consisted of consecutive patients with mild to moderate Alzheimer’s disease who received donepezil treatment and were enrolled in a prospective longitudinal cohort study between November 1999 and June 2003. a prospective cohort was compared with a historical control cohort. The hippocampal formation was defined to include the pes hippocampi.info. only baseline and 1-year follow-up data were used.) who was blinded to 1) all clinical information. For volumetry. a research-oriented hospital. Neuropsychological tests and MRIs were repeated at 1year intervals. Having no evidence of focal brain lesions on a MRI 6.org 677 . Requirements for inclusion in the present study were the same as those for the donepezil follow-up participants except for the use of donepezil. alveus hippocampi. and after an appropriate data conversion. After donepezil hydrochloride was licensed and marketed in November 1999 in Japan. The reliability and validity of volumetry have been established and described elsewhere (9. In this study. such as nonsteroidal antiinflammatory drugs. The outline of the hippocampal formation together with the surrounding white matter and CSF was first traced with a manually guided mouse cursor. If either one of the two MRIs obtained for a subject was unsuitable for volumetry because of motion artifacts or for any other technical reason. Having minimal to moderate functional severity (a score of 15 or more on the Mini-Mental State Examination (MMSE) (13) 3.x. MATSUMOTO. The operating parameters were as follows: field of view=220 mm. TR=14 msec. we used a combination of semiautomatic segmentation-through-density thresholding and manual tracing. 2) the order (initial and follow-up) of MRIs. There being informed consent from patients and their relatives 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. 124×1.5-T MRI unit (Sign Advantage 5. and compliance was monitored at every visit (every 3 months). The Alzheimer’s Disease Assessment Scale was administrated by neuropsychologists (along with the MRI examination) who were not involved in managing the patients at a 1-year interval (10–14 months).62 program (developed at the National Institutes of Health and available on the Internet at http://rsb. and subiculum (16–18). EEGs. Neuropsychological tests and MRIs were repeated at 1-year intervals. and cerebral perfusion or metabolism studies with positron emission tomography or SPECT were performed at baseline. matrix=256×256. The clinical and investigative data collected prospectively in a standardized fashion were all added to the database (11). such as MRIs of the brain. it was analyzed by using the public domain Image version 1. the subject was excluded from the study. The purpose of the present study was to determine whether a cholinesterase inhibitor. KAZUI. The control group was selected among those who participated in the annual follow-up program before donepezil was introduced. and lecithin were allowed) 5. General Electric Medical Systems. Other imaging studies. the patients were examined comprehensively by both neurologists and psychiatrists under a short-term admission to the infirmary and were given routine laboratory tests. and subsequently. The treated patients satisfied six inclusion criteria: 1. The slice volume of the hippocampal formation was obtained by automatically counting the number of pixels within the segmented regions and then multihttp://ajp. and flip angle=20°. In brief. After the same baseline assessments as the annual follow-up program were evaluated. Method Subjects and Study Design In the present study. Those who received anti-Alzheimer drugs other than donepezil were not included in the present study. At baseline.H. The maximum value was defined as the largest value for any pixel of the gray matter (represented by the caudate head). and were approved by the institutional review board. Donepezil hydrochloride was prescribed for the entire year after the initial MRI.nih.HASHIMOTO. digitationes hippocampi. Meeting criteria of the National Institute of Neurological Disease and Stroke/Alzheimer’s Disease and Related Disorders Association for probable Alzheimer’s disease (12) 2. vitamins E.
6 SD 10. genomic DNA was extracted from peripheral blood with a Genomix DNA extraction kit (Talent Corp.. 1-year dosage of donepezil. Seven withdrew their consent.8 plying the number by the voxel size: 9([220/256]2 × [1. we used two-way analysis of variance. respectively). 15 patients were excluded because their MRIs were of poor quality. Of the 108 patients who completed the entire procedure of the annual follow-up study.8 31. Of the 65 patients who completed the entire procedure of the study. respectively. these patients were included in the primary analyses. The change in cognitive decline was expressed as the difference (points) between the baseline and 1-year Alzheimer’s Disease Assessment Scale scores.57) was significant. The background characteristics of both groups are summarized in Table 1. p=0.55.3 19. p<0. In a further analysis.03.005. 93 patients remained in the control group.7 SD 10.1 2.5 3. Thus.3 9. SD=2. The APOE genotype was determined by using polymerase chain reaction restriction fragment length polymorphism. df= 143.98) was measured as an intraclass correlation coefficient derived from three repeated measurements by a single rater under blinded conditions in 10 randomly selected subjects. and the remaining three withdrew for other reasons.2 One or Two APOE ε4 Allele(s) Present (N=50) N 13 37 SD 9. intervals between the first and second MRI.0 395 21. The treated and control groups were not significantly different in age.0 23. df=143. and F=5.7 27.8 9. The effect of donepezil treatment on the change in Alzheimer’s Disease Assessment Scale scores was significant (F=5.02).5 2. When the interaction term was not significant.84%) was significantly lower than in the control group (mean=5.2 35.2 18.9 36. Results Twelve of 77 patients who were initially enrolled in the donepezil follow-up program were dropped from the study.. Hippocampal volumes and Alzheimer’s Disease Assessment Scale scores are summarized in Table 2.04%. The average volume of the right and left hippocampal formations was used for the analysis.64.32.54%) (t=–2.5 9. However. they were further examined with analysis of covariance (ANCOVA) in which age. treated and untreated).3 35 2. df=143. In brief. p<0. APOE genotype. the effect of donepezil on hippocampal atrophy is possibly influenced by the APOE genotype. Statistical Analysis The annual rate of hippocampal atrophy was defined as the percentage change.7 392 21.8 389 21.7 APOE ε4 Allele Absent (N=43) N 5 38 Mean 69. In a one-way ANCOVA. p=0. p=0. which was computed as baseline hippocampal formation volume minus 1-year hippocampal formation volume divided by baseline hippocampal formation volume (×100).e. disease duration.0 19. The test-retest reliability (kappa=0. Italy) according to the manufacturer’s protocol.6 SD 9.. two were institutionalized.08.e. or baseline MMSE scores. 678 http://ajp.3 388 21. sex. but the interaction term was not significant (F=0.psychiatryonline. education. April 2005 Determination of APOE Genotype The detailed method for APOE genotyping is described elsewhere (19).78% for the right and left hippocampal formations. education. and their interaction.9 Characteristic Sex Male Female Total (N=54) N 12 42 Mean 69.5 9. which included the effects of donepezil treatment (i. 21).1078 mm 3]).82%.9 2. APOE type (i.0 2.8 Control Group APOE ε4 Allele Absent (N=19) N 6 13 Mean 69.1 386 21. interval between the two MRI studies (days).2 9.9 9. The level of significance was set at p<0. Trieste.6 35 2.1 21. where standard deviation indicates square root value of the arithmetic mean of 10 variance estimates) were 2. the effects of the donepezil treatment were examined with a t test.5=1.4 29 3. sex. Two patients did not receive the full. df=143.06) nor the interaction term (F=0.19.8 35 4. but neither the effect of the APOE ε4 allele (F=3.05 for all statistical analyses. SD=2. One patient discontinued donepezil after 3 weeks because of adverse effects. where Am J Psychiatry 162:4. p<0.008).29. df=143. df=145.8 35 2. Coefficients of variation (standard deviation/mean.org . according to the procedure described by Wenham and colleagues (20). disease duration.5 SD 7.9 SD 9. 54 patients remained in the treated group.78).5 2. Because the APOE ε4 allele is known to be specifically related to hippocampal atrophy in Alzheimer’s disease (9.5 19. Thus. the mean annual rate of hippocampal atrophy in the treated group (mean=3. p=0.8 389 21. presence and absence of the APOE ε4 allele).9 Mean 71. and baseline MMSE score were entered into the model as covariates. Therefore.5 31. and the other took the drug irregularly (receiving about 60% of the full dose).8 Total (N=93) N 18 75 Mean 70.7.8 33. df=143. 11 were excluded because the quality of one of their two MRIs was unsuitable for volumetry. Demographic and Clinical Characteristics of Patients With Alzheimer’s Disease Donepezil-Treated Group One or Two Apolipoprotein E (APOE) ε4 Allele(s) Present (N=35) N 6 29 Mean Age (years) Education (years) Duration of disease (months) Magnetic resonance imaging interval (days) Baseline score on Mini-Mental State Examination 69.3 25 3. The effects of donepezil treatment and the APOE ε4 allele on the rate of hippocampal atrophy were significant (F=8. When significant effects were found.DONEPEZIL AND HIPPOCAMPAL ATROPHY TABLE 1.84% and 2.
84 15. and the APOE ε4 allele had a significant effect on the rate of hippocampal atrophy (F=4.02). In one study (24).54 effect of treatment. have raised the possibility that cholinesterase inhibitors have slowing effects on both symptomatic and disease progression in Alzheimer’s disease patients. followed by 26 weeks of rivastigmine treatment. placebo-controlled extension studies. both open-label.6 435 2.9 3.93%.14. for Am J Psychiatry 162:4. sex. Furthermore. ET AL.002). donepezil seemingly slows the rate of hippocampal atrophy. and reduce the decline in rCBF (5).HASHIMOTO.54%) (t=–2. df=138.76%) was significantly lower than in the control group (mean=5. df=142. Our data are consistent with this observation. and baseline Alzheimer’s Disease Assessment Scale score were entered into the model as covariates. April 2005 679 . p<0.59 4. one randomized.6 4. MRI interval. In a previous study. the effect of donepezil on hippocampal atrophy remained significant (F=10.05). was lower than in patients who were treated with donepezil for all 15 months. df=143. long-term donepezil treatment has been demonstrated to slow the decline in cognition and functional activities (2. effect of APOE ε4 allele. KAZUI.3 2.37. Moreover.4 449 2. The mean annual rate of hippocampal atrophy in the treated group (mean=3.9 496 3.0 2391 5. df=141. p<0. the level of cognitive function in patients who were treated with placebo for 3 months. placebo-controlled pilot study in patients with Alzheimer’s disease demonstrated that donepezil-treated patients had significantly smaller mean decreases in total hippocampal volumes compared with placebo-treated patients. p<0. replicating our previous observation that the APOE ε4 allele is specifically related to accelerated hippocampal pathology in Alzheimer’s disease (9).9 6. the results remained unchanged.82%) was about 24% less than in the control patients (5.82 5. APOE genotype. SD=2. no significant interaction was noted between donepezil treatment and the APOE genotype. which leaves the underlying disease process unaltered.8 428 2.15 4.8 3. The mean annual rate of hippocampal atrophy was significantly higher in the patients with the APOE ε4 allele than in those without the APOE ε4 allele.8 2502 3. However.4 3.04%). In the other study (25). Although that study had limitations in that it included a relatively small number of patients and the period of drug treatment was short. our data are consistent with the results (23). delay the admission to a nursing home (4). p<0.4 461 2.9 7. or to neuroprotection modifying the disease process. two clinical trials.60 14. Thus.04 4. the level of cognitive function of the patients who were treated with placebo for 26 weeks. age. was lower than that in patients who were treated with rivastigmine for all 52 weeks.2 2496 4. Recently.0 –0. MATSUMOTO.40 5.0 457 2. 3). The present results suggest that donepezil has both symptomatic and disease-progression slowing effects.02).psychiatryonline. disease duration.21 5.org Discussion In the present study. these studies do not answer the question of whether the beneficial effects of donepezil are due to symptomatic suppression. the mean annual decline in the Alzheimer’s Disease Assessment Scale score in the control group (3. p=0.9 4.53.15 16. 3). donepezil treatment had significant effects on Alzheimer’s Disease Assessment Scale score (F=4. double-blind.b a Significant b Significant Control Group APOE ε4 Allele Absent (N=19) Mean SD One or Two APOE ε4 Allele(s) Present (N=50) Mean SD APOE ε4 Allele Absent (N=43) Mean SD Total (N=54) Mean SD Total (N=93) Mean SD Mean SD 14. SD=2.04) and the rate of hippocampal atrophy (F=6. Annual Change in Alzheimer’s Disease Assessment Scale Score and Rate of Hippocampal Atrophy Among Patients With Alzheimer’s Disease Donepezil-Treated Group One or Two Apolipoprotein E (APOE) ε4 Allele(s) Present (N=35) Variable Baseline Alzheimer’s Disease Assessment Scale score Annual change in Alzheimer’s Disease Assessment Scalea Baseline hippocampal formation volume (mm3) Annual hippocampal atrophy rate (%)a.8 points). education.6 points) was significantly larger than in the treated group (0. df=141. the rate of hippocampal atrophy and for the change in Alzheimer’s Disease Assessment Scale. these results are consistent with the results of previous long-term studies of donepezil (2. Even if the two patients who did not receive the full 1year dosage of donepezil were excluded from the analyses.4 2585 4.2 4.8 0. followed by 12 months of donepezil treatment. the effect of donepezil treatment did not appear to be affected by the APOE genotype (22).34. On the other hand. In recent studies.04%.5 2514 3.4. The inability to catch up in those in whom the treatment with http://ajp. and suggest that treatment with donepezil for 1 year was associated with a cognitive benefit.6 2481 5.0 7. The decrease in hippocampal volume in the treated patients (3. TABLE 2.81 16.32 16.
were comparable between the two groups. the effect of donepezil on hippocampal atrophy remained unchanged. in fact. Accumulation of amyloid is one of the earliest changes in Alzheimer’s disease pathology (27. and the cointerventions and other medical management did not change throughout the first and second halves of the study period. (32). statistically significant cognitive and functional effects were maintained over at least 2 years. Mild cognitive impairment is a condition that frequently progresses to Alzheimer’s disease. If donepezil does. the significant difference of the rate of hippocampal atrophy was likely to be due to the intervention with donepezil. A recent long-term randomized. The groups are not comparable because of the selection of subjects who received the intervention (selection bias). usually in favor of the intervention. and MRI interval. the Alzheimer’s Disease Assessment Scale was administered by neuropsychologists who were unblinded but not involved in managing the patients. social. patients who could not tolerate the initial doses of donepezil were not included in the donepezil follow-up program. Further studies are needed to determine whether donepezil slows the progresAm J Psychiatry 162:4. it was unlikely that detection bias affected the results of the rate of hippocampal atrophy or the Alzheimer’s Disease Assessment Scale score in favor of the donepezil-treated group. they might be inappropriate for assessing the neuroprotective effects of donepezil. Kihara et al. suggesting an intervention through nicotinic receptors. (33) examined the effects of nicotinic receptor agonists on amyloid beta cytotoxicity in cultured rat cortical neurons and found that nicotinic receptor stimulation may be able to protect neurons from degeneration induced by amyloid beta. In the present study. the difference in the patients’ generation was not likely to affect the volumetric results. found increased amyloid precursor protein secretion and decreased beta-amyloid protein production with carbachol stimulation of muscarinic receptors (32). controlled longterm trial in patients with Alzheimer’s disease. In vitro studies have demonstrated a link between cholinergic activation and beta-amyloid precursor protein metabolism. First. which requires early diagnostic and therapeutic interventions. The neuroprotective effect was blocked by the presence of the nicotinic antagonists mecamylamine and tubocurarine. Second. because it was a comparative study with a historical control group rather than a randomized study. Because many of the outcomes are influenced by the interaction of complex biological. Although the generation difference was a possible source of selection and performance bias. through its neuroprotective effect. In the study. On the other hand. (31) found evidence that lesions of the cholinergic nucleus basalis of Meynert increased the synthesis of beta-amyloid precursor protein in the cerebral cortex of rats. it suffers from several sources of bias. However. In any case. it is standard practice to analyze the results of comparative studies on an intention-to-treat basis. influence disease progression. Our study has some limitations. it has been recognized that open-label studies are not optimal. mechanisms based on beta-amyloid metabolism have been postulated. such as age. Therefore. we are unaware of any evidence that donepezil tolerance predicts disease progression. the patients’ background characteristics. Furthermore. Wolf et al. and MRI volumetry was made by an investigator who was blinded to all clinical information. Because the control group in the present study was not concurrent but historical. there was a generation difference of several years between the groups. Simply ignoring everyone who has withdrawn from a clinical trial may bias the results. 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. Wallace et al. These studies support a beneficial alteration in amyloid processing associated with cholinergic stimulation. April 2005 680 http://ajp. caregiver well-being. The fact that the investigators were not blinded to treatment might increase the donepezil effect. The present results suggest that donepezil has not only a symptomatic effect but also a neuroprotective effect. double-blind trial (26) showed that no significant benefits were seen with donepezil compared with placebo in the institutionalization and progression of disability. and environmental factors.DONEPEZIL AND HIPPOCAMPAL ATROPHY cholinesterase inhibitors was postponed reminds us of a potential disease-modifying effect. dropouts are a problem for this type of design and a possible source of exclusion bias. Third. could possibly inhibit progression from mild cognitive impairment to Alzheimer’s disease.psychiatryonline. 28) and may cause neuronal death in the CNS (29. However. Therefore.org . and even after we controlled for these variables. in the present study. the cointerventions and other medical management being received by the two groups were different (performance bias). we need to modify our treatment strategies. This could have been a source of selection bias. donepezil is not an optional but rather a mandatory treatment for Alzheimer’s disease and should be started in the prodromal or very early stage of the disease. it would be unethical to conduct such a study to extend the knowledge of donepezil. using human CNS neurons. sex. Svensson and Nordberg (34) demonstrated that tacrine and donepezil at clinically relevant concentrations attenuated amyloid beta (25-35)-induced toxicity in rat pheochromocytoma PC12 cells. disease duration. neither hippocampal volume nor the Alzheimer’s Disease Assessment Scale score was a subjective outcome measure. disease severity. 30). Although our findings should be confirmed by a randomized. To explain the neuroprotective effect of cholinesterase inhibitors. Donepezil. Although there was no intention to select subjects for the control and treatment groups. education. As a result. and caregiver time costs. and the methods of outcome measurement being used in the two groups were different (detection bias). there were no significant differences in behavioral symptoms.
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