Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

A simple method to evaluate the pentagon copy test of the Mini-Mental State Examination for the differentiation of dementia with Lewy bodies.

There are many commonalities between the clinical symptoms of dementia with Lewy bodies (DLB) and those of Alzheimer's disease (AD). The accurate differentiation of these two diseases is an important neuropsychological issue. The Mini-Mental State Examination (MMSE) is often used as a screening test for dementing disorders. We created evaluation items for the pentagon copy test of MMSE and developed a simple, highly accurate evaluation method for differentiating DLB in combination with conventional evaluation items such as the Qualitative Scoring MMSE Pentagon Test (QSPT). Subjects were divided into three groups: DLB (n = 119), AD (n = 50), and Normal (n = 26). The severities of DLB and AD ranged from mild cognitive impairment (MCI) to mild dementia. We compared the results of the pentagon copy test. We found that the rates of patients with abnormalities in "motor incoordination" and "gestalt destruction" were higher in the DLB group than the AD group. Furthermore, receiver operating characteristic curve analysis suggested the differentiation of DLB with high accuracy (sensitivity: 0.70, specificity: 0.78) using the criterion of patients meeting one of the following three characteristics: "the number of angles on QSPT: scores other than 4," "major tremor (Parkinsonism-related tremor) is present," and "gestalt destruction (distortion in overall coherence) is present." This evaluation method may be clinically useful for evaluating MCI to mild DLB patients because the burden on patients is low.

The Bender Gestalt Test is useful for clinically diagnosing dementia with Lewy bodies: Analysis of its sensitivity, specificity, and clinical characteristics of the figure copy.

A previous study that evaluated the ability of the Bender Gestalt Test (BGT) to discriminate between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) suggested that a total score of 98 is the optimal cutoff value for discriminating between these two diseases and that DLB tends to exhibit unique errors; i.e., "element deformation" and "gestalt destruction." The objectives of the present study were: (1) to examine the sensitivity and specificity of a total BGT score of 98 as a cutoff value in greater numbers of DLB patients than in the previous study, (2) to set a new cutoff value if a cutoff value of 98 is not optimal, and (3) to clarify the frequency of element deformation and gestalt destruction in DLB patients. The participants were 133 DLB patients, 65 AD patients, and 30 cognitively normal elderly people. All of the participants underwent the Mini-Mental State Examination, BGT, and brain magnetic resonance imaging. As a result, the total BGT score cutoff value of 98 showed low sensitivity (0.58), and a cutoff value of 84 was indicated to be the optimal cutoff value for discriminating between DLB and AD. In addition, 32 out of 133 DLB patients and one out of 65 AD patients exhibited element deformation or gestalt destruction. This study suggested that the BGT is a useful neuropsychological test for differentiating DLB from AD. In addition, the need to evaluate the spatial and perceptual difficulties of DLB patients with various types of visual stimulation is also discussed.

Evaluating depression in cognitively healthy elderly people by using Mini-Mental State Examination.

AIM: We examined a method for evaluating depression with the Mini-Mental State Examination in cognitively healthy elderly people and employed the projective perspective. METHODS: In MMSE three groups-normal, depressed tendency, and depressed-completed the Mini-Mental State Examination (MMSE) and a Japanese version of the 15-item Geriatric Depression Scale. The Mini-Mental State Examination evaluated individuals' writing based on a sentence, the number of written words, and sentence content; it also assessed their copying of drawn figures. RESULTS: In the depressed group, the proportion corresponding to the characteristics of (i) to (iii) was higher than in the other two groups: (i) the calculation score was 0 or 1; (ii) subjects scored above the median in sentence writing relative to similar subjects with the same language and clinical setting; and (iii) subjects expressed feelings in their writing. One point was given for each characteristic, and we calculated the sum. Depressed subjects had a score ≥2. CONCLUSIONS: This evaluation method can differentiate depressed subjects with high accuracy (sensitivity: 77.8%, specificity: 76.4%) without placing an extra burden on the subjects.

The Cingulate Island Sign on FDG-PET vs. IMP-SPECT to Assess Mild Cognitive Impairment in Alzheimer's Disease vs. Dementia with Lewy Bodies.

BACKGROUND AND PURPOSE: The cingulate island sign (CIS) on 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET); ie, the relative preservation of mid-posterior cingulate cortex metabolism, is a supportive biomarker in the diagnostic criteria for dementia with Lewy bodies (DLB). However, limited information is currently available on the diagnostic value of the CIS on FDG-PET or 123 I-iodoamphetamine single-photon emission computed tomography (IMP-SPECT) for differentiating between mild cognitive impairment (MCI) due to Alzheimer's disease (AD) (MCI-AD) and MCI due to DLB (MCI-DLB). METHODS: We examined the CIS ratio in 9 AD patients, 9 DLB patients, 8 patients with MCI-AD, and 9 patients with MCI-DLB using FDG-PET and IMP-SPECT. The CIS ratio was calculated using NEUROSTAT software. RESULTS: In the dementia groups, a receiver operating characteristic analysis of the CIS ratio showed significant accuracy for differentiating between AD and DLB on FDG-PET and IMP-SPECT. In the MCI groups, only the FDG-PET derived CIS ratio displayed significant accuracy for differentiating between AD and DLB. CONCLUSIONS: The FDG-PET and IMP-SPECT derived CIS ratios are both useful for differentiating between AD and DLB. The FDG-PET derived CIS ratio is more valuable than the IMP-SPECT derived CIS ratio for differential diagnosis in patients with MCI. A larger study is needed to confirm these results.

Characteristics of dementia patients who described or did not describe the relationship between two people on the COGNISTAT speech sample.

Speech sample of Cognitive Status Examination (COGNISTAT) is a task in which examinees freely talk about what is happening in a presented picture. We investigated whether there are differences in the characteristics between patients who described or did not describe the relationship between two people in the speech sample based on age, gender, cognitive dysfunction, and type of dementia (Alzheimer's disease and dementia with Lewy bodies). The participants were 60-year-old or older patients diagnosed with Alzheimer's disease or dementia with Lewy bodies who undertook the Mini-Mental State Examination (MMSE) and COGNISTAT at a general hospital specialized in care for the elderly. MMSE and COGNISTAT were performed by a female clinical psychologist in all patients. In a stepwise logistic regression analysis using the two groups (description and no description groups) as a response variable, and the age, gender, diagnosis, MMSE score, and score of each COGNISTAT subtest as explanatory variables, the MMSE score (OR = 1.09; 95% CI [1.03, 1.15]) and gender (OR = 1.79; 95% CI [1.09, 2.93]) factors were extracted. These results indicated that patients with severer overall cognitive dysfunction and male patients were unlikely to describe the relationship between two people in a speech sample.

The cingulate island sign in patients with dementia with Lewy bodies or Alzheimer's disease: A direct comparison between 18F-FDG PET and 123I-IMP SPECT.

The cingulate island sign (CIS) on 18F-fluorodeoxyglucose positron emission tomography (FDG PET); i.e., the relative preservation of mid-posterior cingulate cortex metabolism, is a supportive biomarker in the diagnostic criteria for dementia with Lewy bodies (DLB). Information is lacking, however, regarding the diagnostic value of the CIS on FDG PET or 123I-iodoamphetamine single-photon emission computed tomography (IMP SPECT) for differentiating between mild cognitive impairment (MCI) due to Alzheimer's disease (AD) (MCI-AD) and MCI due to DLB (MCI-DLB). We examined the CIS ratio for nine AD patients, nine DLB patients, eight patients with MCI-AD, and nine patients with MCI-DLB using FDG PET and IMP SPECT. The CIS ratio was calculated as the total count density for the mid-posterior cingulate cortex divided by the total count density for the precuneus and cuneus using the stereotactic extraction estimation method. In the dementia groups, receiver operating characteristic analysis of the CIS ratio showed significant accuracy for differentiating between AD and DLB on both FDG PET and IMP SPECT. In the MCI groups, only the FDG PET-derived CIS ratio displayed significant accuracy for differentiating between AD and DLB. A larger study is needed to replicate these findings.

123I-MIBG myocardial scintigraphy for the diagnosis of DLB: a multicentre 3-year follow-up study.

BACKGROUND AND PURPOSE: We previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD. METHODS: We undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline. RESULTS: Sixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline. CONCLUSIONS: Our follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested. TRIAL REGISTRATION NUMBER: UMIN00003419.

The Use of Short Versions of the Japanese WAIS-III to Aid in Differentiation Between Alzheimer's Disease and Dementia with Lewy Bodies.

OBJECTIVE: We examined the cognitive characteristics of patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) using the Wechsler Adult Intelligent Scale-Third Edition (WAIS-III). In addition, the utility of short versions of WAIS-III for estimating IQ scores and index scores were examined. METHODS: The subjects were 83 patients with probable AD, 33 patients with probable DLB, and 83 cognitively normal individuals. RESULTS: Patients with DLB showed significantly lower scores in Performance IQ and Processing Speed compared with those with AD. The short versions of WAIS-III with Information, Similarities, Arithmetic, Digit Span, Picture Completion, Digit Symbol-Coding, and Block Design demonstrated relatively small amount of error, high correlations, and reliabilities with the full version. CONCLUSIONS: The results indicated that Performance IQ and Processing Speed in WAIS-III can be an indicator for differentiating AD and DLB in WAIS-III, and a short version obtained by the Similarities, Information, Picture Completion, Block Design, Arithmetic, Digit Span, and Digit-Symbol Coding yields high accuracy and can be used to estimate full-scale IQ scores on the WAIS-III.

Differences in responses to the Rorschach test between patients with dementia with Lewy bodies and Alzheimer's disease -from the perspective of visuoperceptual impairment.

Patients with Dementia with Lewy bodies (DLB) tend to perform worse in tasks on visuoperception than patients with Alzheimer's disease (AD). The Rorschach inkblot test has its utility for assessing perceptual and visuospatial abilities. In this study, we examined the differences in responses to the Rorschach test between patients with DLB and those with AD in terms of visuoperception, and investigated the utility of the test for assessing visuoperceptual impairment in DLB. Using the comprehensive system of Rorschach test, six variables were significantly higher, and three variables were significantly lower in DLB patients compared to AD patients. Among those variables, PTI showed high sensitivity and specificity for differentiating DLB from AD. Furthermore, when the PTI score was combined with the Dd score and a number of times a patient saw an eye in a shading part of an inkblot, the sensitivity and specificity reached 90.6% and 73.1%, respectively. These results indicate that the patients with DLB perceive objects in the inkblot differently from patients with AD, and suggest that some variables of the Rorschach test could assist with neuropsychological examinations when differentiating DLB from AD.

123I-FP-CIT SPECT findings and its clinical relevance in prodromal dementia with Lewy bodies.

PURPOSE: Evidence for the prodromal stage of dementia with Lewy bodies (DLB) is very limited. To address this issue, we investigate the 123I-FP-CIT SPECT measure of dopamine transporter binding finding and its clinical relevance. METHODS: We enrolled subjects into a prodromal DLB group (PRD-DLB) (n = 20) and clinical DLB group (CLIN-DLB) (n = 18) and compared these groups with an Alzheimer's disease control group (AD) (n = 10). PRD-DLB was defined as patients having the non-motor symptoms associated with Lewy body disease (LBD) [i.e. REM sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysfunction, and depression] and showing characteristic diffuse occipital hypometabolism in 18F-FDG PET. CLIN-DLB was defined as patients fulfilling the established criteria of probable DLB. Striatal specific binding ratio (SBR) of 123I-FP-CIT SPECT was used for objective group comparisons. The correlations between SBR and cognitive function (MMSE), motor symptoms (UPDRS3), and duration of LBD-associated non-motor symptoms were compared between the two DLB groups. RESULTS: Mean SBR scores of both PRD-DLB and CLIN-DLB were significantly lower than those of AD. No correlation was found between SBR and MMSE scores. Both in the CLIN-DLB and total DLB groups, SBR scores were negatively correlated with UPDRS3 scores, whereas no correlation was found in PRD-DLB. Among the LBD-related non-motor symptoms, duration of olfactory dysfunction, and RBD demonstrated negative correlation with SBR scores in PRD-DLB. CONCLUSION: 123I-FP-CIT SPECT may play a role for detecting DLB among the subjects in prodromal stage. During this stage, long-term olfactory dysfunction and/or RBD may indicate more severe degeneration of the nigro-striatal dopaminergic pathway.

Characteristics of mild cognitive impairment tending to convert into Alzheimer's disease or dementia with Lewy bodies: A follow-up study in a memory clinic.

AIM: To determine characteristics of MCI that can predict whether patients will go on to develop AD or DLB. METHODS: Ninety-three patients diagnosed with MCI underwent neuropsychological and neuroimaging examinations, and were followed-up for a mean of 44.9±19.3months. They were divided into four MCI subtypes (amnestic/non-amnestic MCI, single/multiple domain) according to neuropsychological findings, and into three other MCI categories (AD-type PET, DLB-type PET, and unknown-type PET) based on (18)F-fluorodeoxyglucose PET findings. Patients who were eventually diagnosed with AD, DLB, other dementia, or remained MCI were analyzed in relation to the groups to which they had initially been allocated at the MCI stage. RESULTS: Clinical diagnosis after follow-up determined AD in 21 patients (22.6%), DLB in 12 patients (12.9%), other dementia in 2 patients (2.2%), and non-converter in 58 patients (62.3%). Amnestic single-domain MCI and AD-type PET tended to convert into AD. Amnestic multiple-domain MCI and DLB-type PET tended to convert into DLB. A few patients with AD-type PET later developed DLB, and some with DLB-type PET later developed AD. CONCLUSIONS: Predicting which type of dementia a person with MCI will later develop might be possible based on early assessment with clinical symptoms in conjunction with neuropsychological and (18)F-fluorodeoxyglucose PET findings.

A family with hereditary diffuse leukoencephalopathy with spheroids caused by a novel c.2442+2T>C mutation in the CSF1R gene.

Clinical phenotypes of hereditary diffuse leukoencephalopathy with spheroids (HDLS), a familial progressive neurodegenerative disorder affecting the white matter of the brain, are heterogenous and may include behavioral and personality changes, memory impairment, parkinsonism, seizure, and spasticity. Thus, HDLS is frequently unrecognized and misdiagnosed. Heterozygous mutations located within the kinase domain of the gene encoding the colony-stimulating factor 1 receptor (CSF1R), a cell surface receptor with key roles in development and innate immunity, have been shown in HDLS. These different gene mutations may be related to the various clinical phenotypes. We report here a newly identified family with HDLS harboring a mutation in the CSF1R gene. We examined clinical and neuropathological features in three members of this family. These patients presented with affective incontinence, memory impairment, and executive dysfunction at onset, and revealed nonfluent aphasia, parkinsonism, and seizure as the disease progressed. We identified a novel CSF1R splice site mutation (c.2442+2T>C) in intron 18 for two of the patients. MRI of these patients revealed progressive, frontotemporal-predominant, confluent leukoencephalopathy. We also observed severe myelin loss, axonal degeneration, and abundant axonal spheroids, astrocytes, and microglia in the cerebral white matter, consistent with HDLS neuropathological features. Additionally, we identified atypical neuropathological findings for HDLS, including neuronal loss and gliosis with ballooned neurons and central chromatolysis in the frontal cortex and hippocampus. This report provides further evidence for the clinical and neuropathological heterogeneity of HDLS.

Accumulated α-synuclein affects the progression of GM2 gangliosidoses.

The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional ß-subunit on the ß-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice. Our results show that Hexb-/- ASyn-/- mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons of Hexb-/- ASyn+/+ mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons of Hexb-/- ASyn+/+ mice. Interestingly, these dysfunctions improved in Hexb-/- ASyn-/- mice. But any clinical improvement were hardly observed in Hexb-/- ASyn-/- mice. Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies.

Early differential diagnosis between Alzheimer's disease and dementia with Lewy bodies: Comparison between (18)F-FDG PET and (123)I-IMP SPECT.

Both (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and (123)I-iodoamphetamine (IMP) single-photon emission computed tomography (SPECT) have been used for the differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Less information is available, however, regarding the differential diagnosis of mild cognitive impairment (MCI) due to AD and MCI due to DLB. We examined nine AD patients (AD group), nine DLB patients (DLB group), eight MCI due to AD patients (MCI-AD group), and nine MCI due to DLB patients (MCI-DLB group) with FDG PET and IMP SPECT using a well-characterized normal database and a stereotactic extraction estimation method. In the AD and DLB groups, receiver operating characteristic (ROC) analysis in the occipital regions showed significant accuracy of both FDG PET and IMP SPECT for the differential diagnosis. In the MCI-AD and MCI-DLB groups, ROC analysis showed significant accuracy of only FDG PET for the differential diagnosis. Both FDG PET and IMP SPECT would be useful for the differential diagnosis between AD and DLB. For the differential diagnosis of MCI-AD versus MCI-DLB, FDG PET would be more useful than IMP SPECT.

Prediction of later clinical course by a specific glucose metabolic pattern in non-demented patients with probable REM sleep behavior disorder admitted to a memory clinic: A case study.

The present study is a follow-up study of 11 non-demented patients with probable rapid eye movement (REM) sleep behavior disorder (RBD) at our memory clinic. During the follow-up period (mean±SD of 46.7±6.4 months), all 11 patients exhibited cognitive decline: four (Group A) exhibited core clinical features of dementia with Lewy bodies (DLB), along with severe cognitive decline, and were subsequently diagnosed as having probable DLB; four (Group B) did not exhibit core clinical features of DLB; and the remaining three (Group C) were diagnosed as having Parkinson's disease with dementia (PDD). Positron emission tomography with fluorodeoxyglucose-F18 at baseline revealed that Groups A and B exhibited glucose hypometabolism in the occipital lobe, especially in the primary visual cortex, and Group A tended to present hypometabolism in the parieto-temporal area as well. Group C tended to present hypometabolism in the medial prefrontal area and anterior cingulate gyrus. Neuropsychological examinations indicated poor performance in verbal memory and visuoperception in all groups. This case study suggests that patterns of hypometabolism and neuropsychological examinations at baseline may be indicators of the later clinical course of probable RBD patients.

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development.

BACKGROUND/AIMS: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision. METHODS: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres. RESULTS: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed. CONCLUSION: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.

Safety and pharmacokinetics of bapineuzumab in a single ascending-dose study in Japanese patients with mild to moderate Alzheimer's disease.

AIM: To evaluate the safety, tolerability and pharmacokinetic profile of bapineuzumab after a single intravenous injection in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Participants received either a placebo (n = 8), or bapineuzumab 0.15 (n = 6), 0.5 (n = 6), 1.0 (n = 6) or 2.0 (n = 6) mg/kg. Serum concentrations of bapineuzumab, antibapineuzumab antibody and total plasma ß-amyloidx-40 were assayed. RESULTS: Adverse events for bapineuzumab and placebo groups were 71% and 88%, respectively. Treatment-emergent adverse events (cataract, injection site hemorrhage, nasopharyngitis, pneumonia and muscle twitching) reported for ≥2 participants were mild or moderate in severity and unrelated to bapineuzumab dose. No deaths, serious adverse events or withdrawals were reported. Mean peak concentration for bapineuzumab increased with dose, from 3.3 ± 0.9 µg/mL with the 0.15 mg/kg dose to 61.0 ± 32.8 µg/mL with 2.0 mg/kg. Mean bapineuzumab exposure (area under the curve from time 0 to last measurable concentration; µg·h/mL) increased in a linear manner with increasing dose (mean 1260 for 0.15 mg/kg, 4264 for 0.5 mg/kg, 7818 for 1.0 mg/kg, 15 313 for 2.0 mg/kg). Mean half-life ranged from 15 to 28 days, and clearance was similar across dose groups (range 0.12-0.17 mL/h/kg). CONCLUSIONS: Plasma ß-amyloidx-40 levels increased with increasing doses of bapineuzumab. Bapineuzumab was safe and well tolerated at all doses in Japanese patients with mild to moderate Alzheimer's disease. Geriatr Gerontol Int 2016; 16: 644-650.