Differential Effects of Acetylcholinesterase Inhibitors on Clinical ...

45 downloads 0 Views 1MB Size Report
Apr 10, 2015 - Acetylcholinesterase inhibitors · Donepezil · Rivastigmine · Galantamine · Regional cerebral blood flow · Single-photon emission computed ...
E X T R A

Dement Geriatr Cogn Disord Extra 2015;5:135–146 DOI: 10.1159/000375527 Published online: April 10, 2015

© 2015 S. Karger AG, Basel 1664–5464/15/0051–0135$39.50/0 www.karger.com/dee

This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.

Original Research Article

Differential Effects of Acetylcholinesterase Inhibitors on Clinical Responses and Cerebral Blood Flow Changes in Patients with Alzheimer’s Disease: A 12-Month, Randomized, and Open-Label Trial Soichiro Shimizu Haruo Hanyu

Hidekazu Kanetaka

Daisuke Hirose

Hirohumi Sakurai

Department of Geriatric Medicine, Tokyo Medical University, Tokyo, Japan

Key Words Acetylcholinesterase inhibitors · Donepezil · Rivastigmine · Galantamine · Regional cerebral blood flow · Single-photon emission computed tomography · Alzheimer’s disease Abstract Background/Aims: The present study evaluated the differences in treatment outcomes and brain perfusion changes among 3 types of acetylcholinesterase inhibitors (AchEIs, i.e. donepezil, rivastigmine, and galantamine). Methods: This was a prospective, longitudinal, randomized, open-label, 3-arm (donepezil, rivastigmine, or galantamine), parallel-group, 12-month clinical trial carried out in 55 patients with AD. Results: At 6 months, the results of the MiniMental State Examination (MMSE) and the Trail Making Test (TMT)-Part A showed an improvement versus baseline in the donepezil treatment group. All groups showed a significant increase in regional cerebral blood flow (rCBF), mainly in the frontal lobe. Significant rCBF reduction was observed in the temporal lobe and cingulate gyrus in all 3 groups. Conclusion: AchEI treatment prevents the progression of cognitive impairment and increases the relative © 2015 S. Karger AG, Basel rCBF in the frontal lobe.

Introduction

Currently, there are 4 types of pharmacological treatments for Alzheimer’s disease (AD) available in Japan, namely the acetylcholinesterase inhibitors (AchEIs) donepezil, rivastigmine, and galantamine, and the NMDA receptor antagonist memantine. AchEIs are the standard treatment for patients with mild-to-moderate AD [1, 2]. Soichiro Shimizu, MD Department of Geriatric Medicine, Tokyo Medical University 6-7-1 Nishishinjuku Shinjuku-ku, Tokyo 160-0023 (Japan) E-Mail soichiro_s @ hotmail.com

E X T R A

Dement Geriatr Cogn Disord Extra 2015;5:125–146 DOI: 10.1159/000375527

© 2015 S. Karger AG, Basel www.karger.com/dee

Shimizu et al.: Differential Effects of Acetylcholinesterase Inhibitors on Clinical Responses and Cerebral Blood Flow Changes in Patients with Alzheimer’s Disease

AchEIs each work via characteristic mechanisms [3–7]. From reports of various metaanalyses on the efficacy of individual AchEIs, it is generally accepted that AChEIs have significant favorable effects on cognition [8–10]. On the other hand, one open-label randomized study reported a statistically significant improvement in behavioral and psychological symptoms of dementia (BPSD) in patients treated with memantine, donepezil, and rivastigmine, but not in those treated with galantamine [11]. Therefore, whether the various AchEIs exert differential effects on AD patients remains largely unknown. Functional neuroimaging methods, such as positron emission tomography and singlephoton emission computed tomography (SPECT), are widely used in the diagnosis and understanding of the pathophysiology of patients with AD. Past studies have shown changes in the regional cerebral blood flow (rCBF) and regional cerebral glucose metabolism (rCBMglc) of patients with AD receiving AchEI therapy [12–19]. Most studies showed that AchEI therapy in patients with AD is associated with rCBF and rCBMglc changes, mainly in the frontal lobe. However, there was little difference in the effects of each AChEI on rCBF and rCBMglc. The present study aimed to evaluate the differences in treatment outcomes and rCBF changes among the 3 types of AchEIs. To our knowledge, this is the first study in Japan to evaluate the differences in the effects of 3 types of AchEIs on AD patients. In an attempt to address the question about the differential effects of AchEIs on AD patients, a randomized, 3-arm, parallel-group, 12-month clinical trial was designed to evaluate the effects of 3 AchEIs (donepezil, rivastigmine, and galantamine) that are currently available for the symptomatic treatment of AD. Materials and Methods

Patients Patients were eligible to enter the trial if they met all of the following criteria at baseline. The diagnosis of AD was based on the NINCDS-ADRDA criteria [20]. All patients had MiniMental State Examination (MMSE) scores [21] of 10–24 at baseline and a dementia severity of 1 (mild) or 2 (moderate) based on the Clinical Dementia Rating [22]. Patients were excluded if they had the following: evidence of other neurologic or psychiatric disorders (i.e., stroke, Parkinson’s disease, or depression); any medication with central nervous system activity; coexisting severe medical conditions or terminal diseases that would compromise the patient’s ability to safely complete the trial, and abnormal results of biochemical analysis that may affect cognition (i.e., vitamin B12 deficiency, hypothyroidism, hyperammonemia, etc.). None of the patients had the following: concomitant treatment with cholinomimetics, tricyclic antidepressants, or neuroleptics; concomitant treatment with any other psychotropic medication at the time of the first visit and during the study; evidence of bradyarrhythmia in the baseline electrocardiogram, and a history of alcohol abuse. The patients were permitted to continue receiving a fixed dose of other medications classified as antihypertensives, anticoagulants, antiplatelets, diuretics, lipid-reducing agents, and antidiabetic drugs. They underwent neuropsychological battery testing at baseline, and after 6 and 12 months of treatment, and SPECT at baseline and after 12 months of treatment. Study Design This was a prospective, longitudinal, randomized, open-label, 3-arm, parallel-group, 12-month clinical trial comparing donepezil, rivastigmine, and galantamine. We recruited 75 first-visit outpatients with AD, who fulfilled the conditions described in the Patients section above, from the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University. For treatment-group allocation, we prepared 25 sheets

136

E X T R A

Dement Geriatr Cogn Disord Extra 2015;5:125–146 DOI: 10.1159/000375527

© 2015 S. Karger AG, Basel www.karger.com/dee

Shimizu et al.: Differential Effects of Acetylcholinesterase Inhibitors on Clinical Responses and Cerebral Blood Flow Changes in Patients with Alzheimer’s Disease

of paper (12 sheets for men, 13 sheets for women) with the name of each of the 3 AchEIs and put them in an envelope. The patients were asked to choose one of these envelopes. Patients were hence randomized to receive treatment with 1 of the 3 AchEIs for 12 months. The dosages of all AchEIs in this study were set to those approved for mild-to-moderate AD by the Ministry of Health, Labour and Welfare of Japan. Oral donepezil was administered at a dose of 5 mg per day, transdermal rivastigmine at 18 mg per day, and oral galantamine at 24 mg per day. According to the results of a pivotal clinical trial, donepezil has been judged to be effective for mild-to-moderate AD at a dosage of 5 mg per day in Japan [23]. We assessed adverse events by medical examination, laboratory tests, and electrocardiogram 30 days after the start of AChEI treatment. Twenty-eight similarly aged healthy control subjects (12 men and 16 women), ranging from 51 to 85 years old (mean age 74.3 ± 8.5 years), were also included for the SPECT analysis. This study was approved by the Ethics Committee of Tokyo Medical University. Informed consent for the SPECT studies was obtained from all control subjects. For the patients, consent was obtained before entry, following a detailed explanation of the study’s aim. It was obtained from either the patients themselves or their closest relative. All procedures were in accordance with ethical standards on human investigation and with the principles of the declaration of Helsinki. Assessment Treatment effects were evaluated at baseline, and after 6 and 12 months of treatment using the following 5 multidimensional rating scales: MMSE [21], Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) [24], Trail Making Test (TMT)-Part A [25], Neuropsychiatric Inventory (NPI) [26], and Functional Activities Questionnaire (FAQ) [27]. MMSE and ADAS-cog were regarded as evaluating cognitive function. Furthermore, among the subitems of the ADAS-cog, we regarded items 1, 9, 10, and 11 as measures of memory, items 2, 3, 4, 5, and 6 as measures of language, and 7 and 8 as measures of praxis. TMT-Part A was regarded as assessment of the frontal lobe function, and NPI and FAQ were regarded as BPSD assessment by the caregiver. Assessments were performed by an experienced clinical psychologist who was blind to the patients’ clinical data. SPECT Imaging All subjects were imaged using a triple-head rotating gamma camera (PRISM 3000 XP, Picker) with a fan-beam collimator that permits a spatial resolution of 6.8-mm full width at half maximum. Imaging was started 15 min after intravenous injection with 222 MBq of N-isopropyl-p-[123I]iodoamphetamine. In practice, full width at half maximum would be higher (approximately 10–12 mm) when scanning subjects because of the increase in source to collimator distances together with the effects of scattering within subjects, both of which degrade spatial resolution. Prior to the injection, the subjects sat in quiet and relaxed surroundings with their eyes open for 10 min. After the injection, the subjects lay down with their eyes closed during the imaging. SPECT images were acquired in 24 steps (72 projections), each of which collected counts for 40 s. Reconstruction of the images was performed by filtered back-projection using Butterworth and Ramp filters (order 8; cutoff 0.40/cm) with attenuation correction (Chang method, 0.09/cm). The matrix size and slice thickness of the SPECT images were 128 × 128 mm and 4.3 mm, respectively. 3-Dimensional Stereotactic Surface Projection Analysis A 3-dimensional stereotactic surface projection (3D-SSP) created with the Neurological Statistical Image Analysis Software (NEUROSTAT), developed by Minoshima et al. [28], was used to evaluate the spatial distribution of abnormal CBF. Image analysis was performed on

137

E X T R A

138

Dement Geriatr Cogn Disord Extra 2015;5:125–146 © 2015 S. Karger AG, Basel www.karger.com/dee

DOI: 10.1159/000375527

Shimizu et al.: Differential Effects of Acetylcholinesterase Inhibitors on Clinical Responses and Cerebral Blood Flow Changes in Patients with Alzheimer’s Disease

75 randomized

25 allocated to donepezil

25 allocated to rivastigmine

25 allocated to galantamine

4 lost to follow-up 2 lost to side effects (both nausea)

6 lost to follow-up 2 lost to side effects (1: skin problems, 1: nausea)

5 lost to follow-up 1 lost to side effects (agitation)

19 completed

17 completed

19 completed

Fig. 1. Study design.

a personal computer equipped with the Windows 2000 operating system, in which the MS-DOS version of NEUROSTAT was implemented. Each image set was realigned to the bicommissure stereotactic coordinate system [29]. Differences in individual brain sizes were adjusted by linear scaling, and regional anatomical differences were minimized by a nonlinear warping technique [30]. As a result, each brain was standardized anatomically to match a standard atlas brain while preserving regional perfusion activity. Subsequently, maximum cortical activity was extracted to adjacent predefined surface pixels on a pixel-by-pixel basis using the 3D-SSP technique [28]. To quantify perfusion changes, the normalized brain activity of each patient was compared with that of 28 normal controls using pixel-by-pixel Z-score analysis (normal mean – individual value/normal SD). Thus, the 3D-SSP technique can transform a SPECT image of a subject to Talairach coordinates (anatomical standardization), and the regions of the 3D-SSP Z-score image correctly correspond to the Talairach coordinates [28, 29]. A positive Z-score represented an increase in rCBF, and a negative Z-score represented a decrease in rCBF in the patient relative to the mean of the controls. Image Analysis To demonstrate regional changes in rCBF, differences between the baseline and the endpoint were compared in each group using the paired t test. For this comparison, we used a threshold of changes in Z-score ≥1.64 (corresponding to a p value ≤0.05). Moreover, we identified regions of Talairach coordinates with changes in Z-scores ≥3 (corresponding to a p value