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Background A number of neuroimaging studies have addressed the specific effect of treatment with cholinesterase inhibitors on the frontal lobe in patients with Alzheimer's disease (AD). However, the neural effects of cholinesterase inhibitors on both apathy and executive dysfunction remain unclear. We examined whether baseline regional cerebral blood flow, as determined by using single-photon emission computed tomography, is capable of predicting changes in apathy and executive dysfunction in response to AD patients switching from donepezil to galantamine therapy. Methods We conducted a 24-week, prospective, open-label study of AD patients treated with galantamine who did not respond to previous treatment with donepezil. Single-photon emission computed tomography was performed at baseline, and behaviour and cognitive assessments including the Mini-Mental State Examination, the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale, the Frontal Assessment Battery, the Neuropsychiatry Inventory Brief Questionnaire Form, and the Dysexecutive Questionnaire were conducted at three time points (baseline and after 12 and 24 weeks of galantamine therapy). Results After galantamine therapy, the Neuropsychiatry Inventory Brief Questionnaire Form scores (apathy, irritability, and aberrant motor symptoms) and the Dysexecutive Questionnaire score improved significantly. The single-photon emission computed tomography findings showed that lower baseline regional cerebral blood flow values in several frontal areas, including the dorsolateral and ventrolateral prefrontal cortex, the anterior cingulate, and the orbitofrontal cortex, predicted greater reductions in the score for apathy (distress) on the Neuropsychiatry Inventory Brief Questionnaire Form and the Dysexecutive Questionnaire score after patients switched from donepezil to galantamine therapy. Conclusions Our study suggests that galantamine therapy, unlike donepezil, is characterized by a dual mechanism of action that may increase acetylcholine and the nicotinic receptor-modulation effect within the frontal lobe, both of which are associated with apathy and executive dysfunction in AD patients.

We report results of our investigation of the case of a 34-year-old woman (YJ) who showed persistent left unilateral spatial neglect (USN) in daily living, frequently hitting obstacles or bumping into the wall, although her visuospatial ability was mostly preserved in paper and pencil neuropsychological tests. In order to clarify this apparent discrepancy, her eye fixation pattern was monitored in testing situations and in natural daily activities using an eye camera. The results showed that when taking the standard tests YJ tended to shift her fixation point to the left edge of the testing frame to overcome over-searching tendency to the right as left hemianopics without left USN would do. However in natural situations, this compensatory leftward fixation was not found. This may be due to the lack of adequate frames of reference in the natural environment. Our findings suggest limitation of laboratory neuropsychologicial testing to fully appreciate the scope of a patient's disability in natural settings.

Background/Aims: Patients with idiopathic normal pressure hydrocephalus (iNPH) are often given shunt operations to reduce the triad symptoms (cognitive impairment, gait disturbance and urinary disturbance). We examined whether they also reduce caregiver burden. Methods: The personal strain (PS) and role strain (RS) factors, which are related to the stress and constraints, respectively, on the caregivers of 81 iNPH patients were evaluated with the Zarit burden interview (ZBI) and each of the triad symptoms was evaluated with the iNPH grading scale (iNPHGS) before and 1 year after the shunt operation. Results: Each of the iNPHGS scores, the total ZBI score and PS factor significantly improved after the shunt operation, but the RS factor did not. The improvement of cognitive impairment was the major factor in reducing caregiver burden. Conclusion: Shunt operations reduced the caregiver burden of iNPH patients.

記憶検査課題において，AD の虚再生 (非学習材料の産出) はよくみられる現象である。本研究では WMS-R 言語性対連合課題を用い，AD (59 名) の虚再生反応を調べ，記憶，注意，そして意味流暢性との関連を検討した。結果，(1) 虚再生は課題の学習難易度に影響を受けず，記憶障害と虚再生は相関しなかった。(2) 虚再生・無再生の出現量によって対象を3 群に分類し，各群の認知機能の特徴を比較したところ，学習難易度の高い対連合学習課題で虚再生が増えるほど，意味流暢性課題と数唱の成績が低下する傾向があった。以上より AD の虚再生は，意味記憶の非効率利用や注意および遂行機能低下との関連が深いと考えられた。

Background: The influence of depressive symptoms on awareness of memory disturbances in patients with Alzheimer disease (AD) and metamemory is unknown. Objective: We compared the level of awareness of memory disturbances in AD patients with and without depression using 2 measures: a questionnaire comparing discrepancies in patients/ caregivers' assessments and the patients' predictions of their own performances on a memory task. Methods: AD patients with depression (n = 21) or without depression (n = 21) were asked to complete an assessment of self-reported memory dysfunction (Short Memory Questionnaire; SMQ) and memory task performance prediction (10-words-recall Questionnaire). In addition, the caregivers' evaluations of the memory deficits in the study patients were assessed using the SMQ. Results: We observed a greater discrepancy in the SMQ scores given by the caregivers' and the patients' among AD patients without depression, compared with those with depression. A greater discrepancy was also observed in the ratio score (patient's predicted performance/actual performance) for the 10-words-recall Questionnaire in AD patients without depression than in those with depression. Conclusions: AD patients with depression may estimate their memory ability either more accurately or more negatively than AD patients without depression, as shown using the above 2 methods.

Background: Recent studies have emphasized specific deficits of attention and executive functions, such as those of cognitive flexibility, divided attention, in geriatric patients with depression. In Alzheimer’s disease (AD), depressive symptoms are known to occur even from an early stage of the disease. However, the nature of the impairment of executive functions in depression associated with AD remains unclear, because of the frequent occurrence of the apathy syndrome as a major confounding factor. Method: In this study, we conducted a comprehensive comparative neuropsychological assessment in AD patients with (n = 21) and without (n = 21) depression. The diagnosis of depression was based on provisional criteria proposed by Olin’s group. Results: In terms of apathy symptoms, both groups had a similar degree of deficits, which were mild as assessed according to Neuropsychiatric Inventory criteria. While no significant differences were observed in regard to the scores in general intellectual functioning, episodic memory and some attention and executive tasks between the two groups, AD patients with depression showed significantly lower scores in several attention and executive function tasks, such as the dual-task performance task administered to assess the capacity for divided attention, and the cognitive flexibility (Trail Making Test; Part B), than AD patients without depression. Conclusions: Our results suggest that depressive symptoms in AD patients increase the deficits of cognitive flexibility and divided attention. This is the first study to report a correlation between depressions, diagnosed based on the provisional criteria for depression in AD by Olin’s group, and an impaired capacity for divided attention in AD patients.

A number of neuroimaging studies have addressed the specific effect of treatment with cholinesterase inhibitors on the frontal lobe in patients with Alzheimer's disease (AD). However, the neural effects of cholinesterase inhibitors on both apathy and executive dysfunction remain unclear. We examined whether baseline regional cerebral blood flow, as determined by using single-photon emission computed tomography, is capable of predicting changes in apathy and executive dysfunction in response to AD patients switching from donepezil to galantamine therapy.We conducted a 24-week, prospective, open-label study of AD patients treated with galantamine who did not respond to previous treatment with donepezil. Single-photon emission computed tomography was performed at baseline, and behaviour and cognitive assessments including the Mini-Mental State Examination, the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale, the Frontal Assessment Battery, the Neuropsychiatry Inventory Brief Questionnaire Form, and the Dysexecutive Questionnaire were conducted at three time points (baseline and after 12 and 24 weeks of galantamine therapy).After galantamine therapy, the Neuropsychiatry Inventory Brief Questionnaire Form scores (apathy, irritability, and aberrant motor symptoms) and the Dysexecutive Questionnaire score improved significantly. The single-photon emission computed tomography findings showed that lower baseline regional cerebral blood flow values in several frontal areas, including the dorsolateral and ventrolateral prefrontal cortex, the anterior cingulate, and the orbitofrontal cortex, predicted greater reductions in the score for apathy (distress) on the Neuropsychiatry Inventory Brief Questionnaire Form and the Dysexecutive Questionnaire score after patients switched from donepezil to galantamine therapy.Our study suggests that galantamine therapy, unlike donepezil, is characterized by a dual mechanism of action that may increase acetylcholine and the nicotinic receptor-modulation effect within the frontal lobe, both of which are associated with apathy and executive dysfunction in AD patients.

Patients with Alzheimer’s disease (AD) are often unaware of their cognitive impairment. This unawareness might have a multifactorial etiology, including impairment of cognitive domains and psychiatric symptoms. We conducted this study to determine the factors underlying unawareness of memory impairment (UMI) in patients with AD. In 103 patients with mild AD, the UMI was quantified as the difference between the patient’s self-rating and the rating of the patient’s caregiver on a standardized memory questionnaire system, the Everyday Memory Checklist. We then examined the relationships between UMI and memory, attention, language, visuospatial/constructive perception, frontal lobe function, and psychiatric symptoms. UMI was positively associated with memory impairment and delusions when effects of age, sex, and education were partialled out, suggesting that these symptoms are involved in the formation of UMI in the patients. Thus, existing treatments for memory impairment and delusions may be beneficial for increasing the awareness of mild AD patients of their cognitive impairment.

Objective : To investigate the cerebral glucose metabolism of subjects who had a Clinical Dementia Rating (CDR) of 0.5, we studied 40 subjects whose CDR was 0.5 and 40 age-matched healthy subjects. Methods : Cerebral glucose image of each subject was obtained by [ 18 F]-2-fluoro-deoxy- d -glucose (FDG) positron emission tomography (PET). The anatomically standardized images were produced with NEUROSTAT. Then, the two groups were compared with the Statistical Parametric Mappings (SPM) 99. Results : A comparison with the SPM 99 revealed that relative cerebral glucose metabolism was lower in the posterior cingulate gyri and parietal lobules in the CDR 0.5 group than in the healthy subjects group. Conclusion : These findings are very similar to those in patients with probable Alzheimer's disease (AD) and suggest that the majority of subjects with CDR 0.5 are suffering from very mild AD or at least a prodromal state of AD.

To investigate a possible effect of the apolipoprotein (APOE) epsilon4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE epsilon3/3, epsilon3/4, or epsilon4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE epsilon4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE epsilon4 allele is related to an accelerated memory decline in AD.

We described a patient with bilateral striatal infarcts, in whom stereotyped and disinhibited behaviors were insidiously emerged over 2 years mimicking frontotemporal dementia (FTD). A positron emission tomography with 18-fluorodeoxy glucose showed a hypometabolism in the frontal lobes, basal ganglia, and thalami. The peculiar behavioral alterations remained unchanged for the following 7 years, suggesting that the disease is not degenerative but of vascular origin. A disruption of the fronto-subcortical circuits at the level of the striatum or the anterior thalamic peduncle is attributable to the FTD-like behavioral and cognitive syndrome.

The specific effects of visual and verbal memory on the ability of emotional arousal to enhance declarative memory were examined by using multiple linear regression analysis on data from a sample of 56 patients with probable Alzheimer's disease (AD). The enhancing effect of emotion on memory was evaluated by an illustrated story paradigm, and the visual and verbal memory by a standard memory test. In AD, memory enhancement by emotion was significantly correlated with visual memory but not with verbal memory, regardless of age, sex, educational attainment, and severity of dementia, suggesting a close association between memory enhancement by emotion and visual memory.

Personal semantic memory is factual knowledge about a person's own past. Although personal semantic memory is assumed to have features of both semantic memory and episodic memory, the relationship to episodic memory and to semantic memory have not been well documented. In patients with Alzheimer's disease, episodic memory, semantic memory, and personal semantic memory are all defective. In this study, the hypothesis that defective personal semantic memory is related to both semantic and episodic memory dysfunction was tested in patients with Alzheimer's disease. Functions of episodic, semantic, and personal semantic memory were examined by using the Wechsler Memory Scale-Revised (WMS-R), subtests of the WAIS-R (Information, Vocabulary, Comprehension and Similarities), and the Family Line Test (FLT) in 62 patients who met the NINCDS/ADRDA criteria for probable Alzheimer's disease. Specific effects of episodic and semantic memory on personal semantic memory were examined by using multiple linear regression analysis with the total score of the FLT as the dependent variable and the WMS-R Delayed Recall weighted sum score and the WAIS-R Semantic Memory score (a composite of standardized scores of the four subtests) as the independent variables. Personal semantic memory function was significantly correlated with both the episodic and semantic memory functions, after controlling age, sex, educational attainment, and severity of dementia. This result supports the hypotheses that personal semantic memory has features of both episodic and semantic memory, and that semantic memory is transformed from episodic memory.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that may be accompanied by dementia and parkinsonism as clinical symptoms. The purpose of this study was to elucidate cerebral metabolic differences of these two diseases with cognitive impairments by [18F] fluorodeoxyglucose (FDG) and positron emission tomography (PET).A total of 12 patients with PSP (age: 62.8+/-6.0 years old, m: 7, f: 5, Mini-Mental State Examination (MMSE): 23.4+/-2.6), 12 patients with CBD (age: 64.8+/-6.3 years old, m: 6, f: 6, MMSE: 22.9+/-4.5), and age-matched healthy subjects (normal control (NC)) (age: 63.8+/-7.7 years old, m: 7, f: 5) were subjected to FDG-PET to obtain glucose metabolic images. We compared regional cerebral metabolic images by a voxel-by-voxel analysis with statistical parametric mapping (SPM) among PSP, CBD, and NC subjects, and evaluated differences of hypometabolic regions.The patients with PSP showed reduced cerebral glucose metabolism in the medial and lateral frontal gyri, basal ganglia, and midbrain compared with NC, whereas the patients with CBD showed significant reduction in the parietal lobes (p0.001). SPM also revealed parietal hypometabolism in CBD patients compared with PSP patients (p0.001).The predominant parietal glucose metabolic reduction in CBD patients was different from previously reported findings. This finding would be the characteristic substance of patients with CBD accompanying cognitive impairments. Our findings suggest that measurement of glucose metabolism by PET and a voxel-based analysis is useful to understand the pathophysiology of these two diseases with cognitive impairments.

Background: Although the APOE e4 allele is a well-known risk factor for developing AD, the impact of the e4 allele on clinical manifestations in patients with AD is still controversial. One possible reason for this controversy is that previous studies did not consider the effect of patient age at symptom onset. Objective: To investigate the possible impact of patient age at onset of AD on the effect of APOE genotype on regional cerebral glucose metabolism (rCMRglc). Methods: The authors compared rCMRglc between probable AD patients (based on criteria of the National Institute of Neurologic Disease and Stroke/AD and Related Disorders Association) with APOE e4/4 and APOE e3/3 alleles in early-onset (≤65 years old) and late-onset (>65 years old) groups. In each group, the patients with APOE e4/4 and APOE e3/3 alleles were comparable for age at onset, age at examination, sex, disease duration, education level, and severity of dementia. Results: In the early-onset group, the patients with the APOE e4/4 genotype showed a significant decrease of rCMRglc in the medial temporal lobe and a significant increase of rCMRglc in the inferior parietal and posterior temporal cortices as compared with those patients with the APOE e3/3 genotype. In the late-onset group, there were no significant differences in the rCMRglc pattern between the patients with APOE e4/4 and APOE e3/3 alleles. Conclusions: The current findings indicate that the impact of the APOE e4 genotype on cerebral glucose metabolism of patients with AD may be a function of age at symptom onset.

Although apolipoprotein E epsilon4 is an established risk factor for Alzheimer's disease, its effect on the rate of progression of Alzheimer's disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty-five patients with probable Alzheimer's disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1-year interval. On a two-way analysis of variance, the effect of the apolipoprotein E epsilon4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one-way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 +/- 4.27%) and without the apolipoprotein E epsilon4 allele (6.99 +/- 4.24%). Apolipoprotein E epsilon4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E epsilon4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimer's disease and should be taken into consideration in longitudinal studies including clinical drug trials.

Koichi Banno,1 Shutaro Nakaaki,2 Junko Sato,1 Katsuyoshi Torii,1 Jin Narumoto,3 Jun Miyata,4 Nobutsugu Hirono,5 Toshi A Furukawa,6 Masaru Mimura,2 Tatsuo Akechi1 1Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 2Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; 3Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 4Department of Neuropsychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 5Department of Psychology, Kobe Gakuin University; Hyogo, Japan; 6Departments of Health Promotion and Human Behavior and of Clinical Epidemiology, Graduate School of Medicine/School of Public Health, Kyoto University, Kyoto, Japan Background: Agitated behaviors are frequently observed in patients with Alzheimer disease (AD). The neural substrate underlying the agitated behaviors in dementia is unclear. We hypothesized that different dimensions of agitated behaviors are mediated by distinct neural systems. Methods: All the patients (n=32) underwent single photon emission computed tomography (SPECT). Using the Agitated Behavior in Dementia scale, we identified the relationships between regional cerebral blood flow (rCBF) patterns and the presence of each of three dimensions of agitated behavior (physically agitated behavior, verbally agitated behavior, and psychosis symptoms) in AD patients. Statistical parametric mapping (SPM) software was used to explore these neural correlations. Results: Physically agitated behavior was significantly correlated with lower rCBF values in the right superior temporal gyrus (Brodmann 22) and the right inferior frontal gyrus (Brodmann 47). Verbally agitated behavior was significantly associated with lower rCBF values in the left inferior frontal gyrus (Brodmann 46, 44) and the left insula (Brodmann 13). The psychosis symptoms were significantly correlated with lower rCBF values in the right angular gyrus (Brodmann 39) and the right occipital lobe (Brodmann 19). Conclusion: Our results support the hypothesis that three different agitated behaviors may represent distinct neural networks in AD patients. Keywords: physically agitated behavior, verbally agitated behavior, psychosis, SPECT

The Cognitive Fluctuation Inventory (CFI) was developed to evaluate cognitive fluctuation in patients with dementia with Lewy bodies (DLB). The objective of this study was to assess the content validity and inter-rater reliability of the CFI.Nine specialists in DLB treatment were invited to participate in the survey to assess the content validity of the CFI. They were asked to assess the relevance and comprehensibility of the question items. In the validation study, inter-rater reliability was assessed using the intraclass correlation coefficient (ICC).Regarding content validity, all nine specialists considered the main question and sub-questions to be relevant to cognitive fluctuation in patients with DLB. Eight out of nine specialists considered the CFI to be a comprehensive measure for detecting cognitive fluctuation in patients with DLB. In the analysis, which used data from 29 patients and their caregivers, the ICC of the CFI was 0.746, which suggests good inter-rater reliability.We found that the CFI showed good content validity and inter-rater reliability for evaluating cognitive fluctuation in patients with DLB.

BackgroundIn an earlier study we showed that a powerful emotional experience (the Kobe earthquake) reinforced memory retention in patients with Alzheimer's disease, but we could not control factors other than the emotional impact of the earthquake.AimsTo test our previous findings in a controlled experimental study.MethodRecall tests consisting of two short stories were administered to 34 patients with Alzheimer's disease and 10 normal subjects. The two stories were identical except for one passage in each story: one was emotionally charged (arousing story) and the other (neutral story) was not.ResultsIn both groups, the emotionally charged passage in the arousing story was remembered better than the counterpart in the neutral story. In addition, the extent of the memory improvement was similar in the subjects and in the controls.ConclusionsThe results provide further evidence that emotional arousal enhances declarative memory in patients with Alzheimer's disease, and give a clue to the management of people with dementia.

There is evidence of two neuronal systems for visual cognition which are referred to as spatial vision and object vision. We subjected 49 patients with mild-to-moderate probable Alzheimer's disease (AD) to tasks associated with these two types of visual cognition. Visual counting was employed as a task to assess visuospatial recognition. Identification of overlapping figures and discrimination of visual forms were used as visuoperceptual tasks that require an ability to recognize objects. Regional cerebral glucose metabolism (rCMRglc) of the subjects was also determined by positron emission tomography. Multivariate statistics controlling for the confounding factors assessed the correlation between the task performances and the rCMRglc. The visual counting score significantly correlated with the metabolic rate of the bilateral inferior parietal lobules. On the other hand, the scores of the visuoperceptual tasks significantly correlated with the metabolic rate of the right middle temporal gyrus and the right inferior parietal lobule. The present study showed that visuospatial disturbance was related to bilateral parietal metabolism, and that visuoperceptual disturbance was related to right temporo-parietal metabolism in patients with mild-to-moderate AD.

To determine the characteristics of cortical atrophy in corticobasal degeneration and Alzheimer disease by using a hemispheric surface display generated with magnetic resonance (MR) images.The magnitude and extent of cortical atrophy were evaluated with MR hemispheric surface display and volumetric measurement in three groups: 17 patients with corticobasal degeneration, 17 matched patients with Alzheimer disease, and 17 matched healthy control subjects.The extent and magnitude of cortical atrophy were larger in the group with corticobasal degeneration than in the group with Alzheimer disease. The parasagittal and paracentral regions were significantly more atrophic in patients with corticobasal degeneration than in patients with Alzheimer disease (P.05). The mean hemispheric-to-total intracranial volume ratios were significantly smaller in the patients with corticobasal degeneration (61%) and those with Alzheimer disease (64%) than in control subjects (69%). Asymmetry of hemispheric volume was significantly larger in the group with corticobasal degeneration than in the control group.The extent of cortical atrophy in corticobasal degeneration is more widespread than was previously thought. Parasagittal and paracentral atrophy is a distinctive feature of corticobasal degeneration and distinguishes it from Alzheimer disease.

Objective: To compare the validity of the Mini Mental State Examination (MMSE) and the Short-Memory Questionnaire (SMQ) as screening tests to detect dementia in the elderly general population. Subjects: Six hundred and sixty-two subjects and their informants from the elderly general population sample who had completed these tests. Setting: One rural community survey in Japan. Method: We used receiver-operating characteristic analysis to compare the performance of the MMSE and the SMQ with the clinical diagnosis of dementia according to DSM-III-R. Results: The areas under the receiver-operating characteristic curve of the MMSE and the SMQ were 0.980 (SE = 0.006) and 0.982 (SE = 0.008), respectively. This differed from chance to a highly significant degree for both the MMSE and the SMQ, but the difference between the two scales was not statistically significant. Conclusion: As screening tests to detect dementia in the elderly general population, the SMQ which is assessed by informants demonstrates a statistically significant discriminating ability as well as the MMSE.

We evaluated remote autobiographical memory impairment in 25 patients with probable Alzheimer’s disease (AD) and 25 sex-, age- and education-matched healthy subjects by using a newly developed, highly effective assessment tool for remote memory, the Family Line Test (FLT). The FLT yields a total score, scores for 3 lifetime periods and the duration of remote memory impairment. In the patients with AD, the total score was significantly lower and the duration of remote memory impairment was significantly longer than in the healthy controls. A prominent temporal gradient in remote memory impairment was documented in the patients with AD. The total FLT score and duration of remote memory impairment correlated with recent memory and general cognitive dysfunctions.

There are various types of underlying damage to tissue and vessels in vascular dementia, including (1) single or multiple infarcts that involve association and limbic cortices, (2) small subcortical infarcts disrupting cortico-subcortical circuits, and (3) white matter lesions. The clinical picture of vascular dementia varies, and the role of functional brain imaging of cerebral blood flow and metabolism would be expected to be different among subtypes of vascular dementia. The role and value of functional brain imaging is limited for cortical infarcts; it is very valuable in assessing the impact on cortical function for small subcortical infarcts; and it is probably useful for evaluating white matter lesions, but this needs to be determined in further studies. At least in research of vascular dementia, functional brain imaging criteria should be included for proper patient selection. Careful studies using functional imaging tools in a well-characterized patient population will be needed.

OBJECTIVE—Presenilin-1 is a major causative gene for early onset familial Alzheimer's disease, and the apolipoprotein E e4 allele is a major genetic risk factor known to influence late onset and sporadic early onset Alzheimer's disease. The presenilin-1 1/1 genotype has recently been reported to be associated with sporadic Alzheimer's disease. The purpose of this study is to determine whether Alzheimer's disease is associated with presenilin-1 gene polymorphism and the apolipoprotein E genotype in an extended case-control study. METHODS—An examination was conducted on 217 patients with Alzheimer's disease, along with an equal number of age and sex matched controls derived from the same community in a Japanese population, by using a χ2 test for homogeneity and a logistic regression analysis. A meta-analysis of data from the literature on allele frequencies in Alzheimer's disease and control populations was used for comparison with the Japanese allele frequencies obtained in this study. RESULTS—The presenilin-1 allele-1 frequencies were similar in patients with early onset Alzheimer's disease (0.61) and younger controls (0.61), and in those with late onset Alzheimer's disease (0.63) and elderly controls (0.63). We found no evidence for a possible association between the presenilin-1 polymorphism and the apolipoprotein E e4 allele. However, the meta-analysis showed that the association between the presenilin-1 1/1 genotype and Alzheimer's disease was significant (Peto odds ratio=1.16, 95% confidence interval=1.04-1.31). CONCLUSIONS—These results suggest a subtle but positive association of presenilin-1 gene polymorphism with Alzheimer's disease, although Japanese data in this study which failed to support such a relation would indicate an ethnic variation.

The association between the apolipoprotein E epsilon 4 (APOE E4) allele and a wide spectrum of behavioral symptoms of Alzheimer's disease (AD) was investigated. Neither the severity nor the presence of any behavioral changes was associated with the number of APOE E4 alleles, even after controlling for the effects of age at onset, sex, education level, duration of illness, and severity of dementia. The findings do not support the hypothesis that neuropsychiatric manifestations of AD are different in patients with the APOE E4 allele.

Everyday experience suggests that highly emotional events are often the most memorable. Experimental work in animals and humans has demonstrated that the amygdaloid complex plays a crucial role in emotional memory, i.e., memory of events arousing strong emotions. The aim of this study was to elucidate the relationship between medial temporal damage and impaired memory of real-life emotional events in patients with Alzheimer's disease.In 36 patients with probable Alzheimer's disease who experienced the 1995 earthquake in Kobe, Japan, memories of events surrounding the earthquake were examined as an index of emotional memory with the use of a semistructured interview, and amygdalar and hippocampal volumes were quantified by magnetic resonance imaging. The effects of the atrophy of these structures on recall performance were determined by multiple regression analysis.Irrespective of generalized brain atrophy and cognitive impairments, emotional memory was correlated more with normalized amygdalar volume (right and left averaged) than with normalized hippocampal volume. General knowledge of the earthquake was correlated with neither amygdalar nor hippocampal volume.The results indicate that impairment of emotional event memory in patients with Alzheimer's disease is related to intensity of amygdalar damage and provide evidence of the amygdala's involvement in emotional memory in humans.

Parietal cerebral glucose metabolism is reduced before substantial impairments appeared in subjects carrying the apolipoprotein E (APOE) epsilon4 allele, but the effect of the APOE epsilon4 allele on cerebral metabolism in Alzheimer disease (AD) is still undetermined. To investigate the effect of the APOE epsilon4 allele on cerebral metabolism in AD, we examined regional cerebral glucose metabolism in 83 patients with AD by using 18F-fluorodeoxyglucose and positron emission tomography. Cerebral glucose metabolism in the fronto-parieto-temporal association and limbic cortices was significantly decreased in the AD patients compared with 26 age- and sex-matched normal controls. Regional cerebral glucose metabolic rate was not correlated significantly with the number of APOE epsilon4 alleles in any region, which was consistent even after controlling the effects of age, sex, and severity of dementia, and in a subgroup analysis of those aged between 60 and 75. These results supported the view that the APOE epsilon4 allele is not associated with specific deficits in brain metabolism in AD despite evidence of preclinical alterations.

OBJECTIVES—The ability to calculate, which is an important aspect of social daily living, is commonly impaired in patients with Alzheimer's disease even early in the course of the disease. Dyscalculia is often accompanied by focal brain damage, and has been argued to be an independent sign localised around the left temporoparietal region. However, the region most responsible for dyscalculia in Alzheimer's disease has not been determined. The relation between calculation ability and regional cerebral glucose metabolism in Alzheimer's disease was therefore examined. METHODS—The calculation ability, In 91 patients with probable Alzheimer's disease of minimal to moderate severity, was assessed using the arithmetic subtest of the Wechsler adult intelligence scale-revised and the performance correlated with regional cerebral glucose metabolism determined by 18F-fluorodeoxyglucose and PET. RESULTS—Regional glucose metabolism in the left inferior parietal lobule and in the left inferior temporal gyrus was significantly correlated with the calculation performance irrespective of age, sex, education, and severity of disease. CONCLUSIONS—The results suggest that dysfunction of the left inferior parietal lobule and the left inferior temporal gyrus plays an important part in producing dyscalculia in patients with Alzheimer's disease.

The authors examined 65 patients with Alzheimer's disease for delusions and explored the relationship of delusions with regional cerebral glucose metabolism determined by [18F]fluorodeoxyglucose PET. In patients with delusions (n = 26), normalized glucose metabolism was significantly increased in the left inferior temporal gyrus and significantly decreased in the left medial occipital region as compared with those without delusions (n = 39). The two groups were similar in age, sex, and dementia severity. These results suggest that delusions in Alzheimer's disease are attributable to a dysfunction in specific brain areas rather than a simple reaction to intellectual deficits.

BackgroundEmotional memory is a special category of memory for events arousing strong emotions. To investigate the effects of emotional involvement on memory retention in individuals with Alzheimer's disease we studied peoples' memories of distressing experiences during a devastating earthquake.MethodFifty-one subjects with probable Alzheimer's disease who experienced the Kobe earthquake at home in the greater Kobe area were studied. Memories of the earthquake were assessed 6 and 10 weeks after the disaster in semi-structured interviews, and were compared with memories of a magnetic resonance imaging (MRI) examination given after the earthquake.ResultsForty-four (86.3%) of the subjects remembered the earthquake and 16 (31.4%) of subjects remembered the MRI experience. Factual content of the earthquake was lost in most of the subjects.ConclusionsFear reinforces memory retention of an episode in subjects with Alzheimer's disease but does not enhance retention of its context, despite repeated exposure to the information.

The diagnostic utility of the Fuld cholinergic deficit profile (Fuld, 1984) to dementia of the Alzheimer type (DAT) was evaluated on the Japanese version of the WAIS-R. Profiles were calculated for groups of subjects with DAT(n = 236), vascular dementia (n = 29), frontotemporal dementia (n = 22), and hydrocephalic dementia (n = 10). The frequency of positive profile occurrence for the subject groups was as follows: 23/236 for DAT (9.7%), 2/29 (6.9%) for vascular dementia, 2/22 (9.1%) for frontotemporal dementia, and 2/10 (20%) for hydrocephalic dementia. No significant difference in the frequency of positive profile occurrence was revealed across four types of dementia. We conclude from these findings that the Fuld profile lacks the diagnostic utility on the Japanese WAIS-R.

Objective: Both the magnitude of brain atrophy and premorbid brain size determine the volume of the brain affected by Alzheimer’s disease. To examine the possibility that premorbid brain volume is a determinant of cognitive reserve in patients with Alzheimer’s disease, the relation between diffuse brain atrophy and cognitive decline and the impact of premorbid brain size on cognitive decline were studied in patients with Alzheimer’s disease. Method: By measuring whole brain volume and intracranial volume in 60 patients with probable Alzheimer’s disease, mild to moderate in severity, with the use of high-resolution magnetic resonance imaging and image processing, the authors studied the impact of premorbid brain volume and magnitude of diffuse brain atrophy on cognitive functions. On the basis of the normative brain-calvarium relationship derived from data an 28 healthy adults and the total intracranial volume measure of each patient, the magnitude of brain atrophy and premorbid brain volume were estimated. Results: After control for the effects of age, sex, and education as confounding factors, it was found that the Alzheimer’s disease patients’ intelligence was correlated both positively with premorbid brain volume and negatively with magnitude of brain atrophy, while impairments in language and memory were correlated with magnitude of brain atrophy but not with premorbid brain volume. Conclusions: These findings partially support the hypothesis that premorbid brain volume is a determinant of reserves against intellectual decline in Alzheimer’s disease. (Am J Psychiatry 1997; 154:18‐24)

Motor, perceptual, and cognitive skill learning abilities of mild Alzheimer's disease (AD) patients were compared to sex-, age-, and education-matched controls. We excluded patients who were unable to perform each skill learning task with a predetermined criterion. In those who completed the task, skill learning was as good as in normal controls. On the cognitive and perceptual skill learnings, some of the AD patients, whose cognitive but not declarative memory functions were more severely impaired than in those who completed the whole session, failed to complete the task, while all patients could complete the motor task. These results support that view that patients with mild AD can acquire motor, perceptual, and cognitive skills and that the neural system subserving procedural skill is not related to the neural systems for declarative memory.

Thirty-one patients with mild-to-moderate Alzheimer's disease (AD) underwent a test battery of complex visual tasks. We assessed the scores using a principal-factor analysis to elucidate the underlying deficits. There were three independent factors: The first factor included the tasks of identifying and comparing forms of visual stimuli. The second factor consisted of digit span and digit symbol tasks, and the third factor consisted of a specified visual counting task. We considered these three factors as representing the dysfunctions of object recognition, general attention and spatial recognition, respectively. These results underline the disturbances of the two visual systems, object vision and spatial vision, in early-AD patients.

The term "caring" refers to the process aimed at enabling people with disabilities to achieve and maintain optimal functioning. According to the International Classification of Functioning, Disability and Health (ICF) proposed by the World Health Organization in 2001, the functioning involves all aspects of daily life and applies to 3 levels: body functions and structures, activities, and participation. Caring is of 2 types; (1) therapeutic care, which restores and maintains the body functions; and (2) compensatory care, which compensates for the impairment of body functions and thus enhances and maintains the level of activity and participation. Alzheimer disease impairs multiple domains, including cognitive function and behaviors; therefore, it is very important to systematically and individually assess these impairments in each domain. Because there is inadequate data on the efficacy of cognitive training, compensatory care is principally used to overcome cognitive dysfunction. Caregivers should be equipped with skills required to cope with behavioral problems so that they can compensate for and even reduce these problems. Further, caregivers should not be overburdened, as this is reported to be a significant predictor for the poor outcome of patients with Alzheimer disease. Therefore, appropriate information regarding the disease, the impairments caused by it, the skills required to cope with these impairments, and social support services should be provided to the caregivers.

Repeated falls are reported as one of the clinical characteristics in dementia with Lewy bodies (DLB). We examined the incidence of fall-related injuries in 561 dementia patients with various clinical diagnoses, including DLB and Alzheimer's disease (AD), in a ward established for dementia research. The incidence of fall-related injuries was significantly higher in DLB patients (10.7%) than in AD patients (1.1%) (P < 0.001). The high incidence in those patients with DLB cannot be attributed to Parkinsonism because none of the DLB patients with injuries showed extrapyramidal sign. Our observations suggest that patients with a clinical diagnosis of DLB have a high risk of fall-related injuries, even though they do not show Parkinsonism. An appropriate clinical discrimination between DLB and AD is recommended to manage and prevent fall-related injuries.

Neuropsychiatric disturbances are common and burdensome symptoms of dementia. Assessment and measurement of neuropsychiatric disturbances are indispensable to the management of patients with dementia. Neuropsychiatric Inventory (NPI) is a comprehensive assessment tool that evaluates psychiatric symptoms in dementia. The Nursing Home Version (NPI-NH) of NPI was developed for use in extended care facilitate caring for residents with dementia. We translated the NPI-NH into Japanese and examined their validity and reliability.The subjects were 100 demented inpatients and the nurses in charge of them. The Mini-Mental State Examination (MMSE) was conducted with all patients and NPI-NH, Cohen-Mansfield Agitation Inventory (CMAI), Cornell Scale for Depression in Dementia (CSDD), and Behavior Pathology in Alzheimer's Disease (BEHAVE-AD) Rating Scale were conducted with the nurses. We examined validity of NPI-NH by comparing its score with the CMAI, CSDD, and BEHAVE-AD. In order to evaluate test-retest reliability, NPI-NH was re-adopted to 30 randomly selected nurses in charge inpatients by a different examiner 1 week later.The frequency score, severity score and occupational disruptiveness score in each NPI-NH item were significantly correlated with the score of the correspondent item in BEHAVE-AD. The agitation score of NPI-NH was significantly correlated with CMAI and the depression score of NPI-NH was significantly correlated with CSDD. Test-retest reliability of the scores of NPI-NH was acceptably high.The Japanese version of NPI-NH demonstrated sufficient validity and reliability as well as the original version of them. It is a useful tool for evaluating psychiatric symptoms in demented inpatients.

Background: Apathy and depression may be strongly associated with executive dysfunction in Alzheimer's disease (AD). The Frontal Assessment Battery (FAB) is an instrument for assessing executive function. The dual task paradigm is also useful for assessing divided attention. However, the association between apathy/depression and these tasks is unclear.Methods: Both the FAB and the dual task were used to evaluate AD patients. A two-way analysis of variance was then conducted between the FAB and dual task results and the absence versus the presence of depression or the absence versus the presence of apathy.Results: Of 88 patients with AD, 26 had both apathy and depression, 26 had depression only, 18 had apathy only, and 18 had neither. Total FAB scores and dual task scores differed significantly between the AD patients with depression and those without depression; the scores were also different between those with apathy and those without apathy. Also, a significant interaction between depression and apathy was noted for the total FAB and dual task scores.Conclusions: The deficits in the total FAB and dual task scores were larger in AD patients with both apathy and depression compared with patients with either apathy or depression alone. AD patients with both symptoms may have greater deficits in frontal lobe function relative to AD patients with either apathy or depression alone.

The relation between orientation for time and place and regional cerebral glucose metabolism was examined in 86 patients with probable Alzheimer's disease of minimal to moderate severity. Regional glucose metabolic rates in the posterior cingulate gyri and in the right middle temporal gyrus were significantly correlated with temporal orientation, and the glucose metabolic rate in the right posterior cingulate gyrus was significantly correlated with locational orientation irrespective of age, sex, education, and memory impairment. The results suggest that dysfunction of these structures plays an important part in producing disorientation in patients with Alzheimer's disease.

Background: Despite many studies about the association between caregiver burden and behavioral and psychological symptoms of dementia (BPSD), there have been no population-based studies to evaluate caregiver burden associated with each BPSD. Objective: To evaluate caregiver burden associated with the individual BPSD in elderly people living in the community. Methods: The subjects were 67 participants with dementia living with their caregivers (diagnosed in the third Nakayama study): 51 Alzheimer’s disease, 5 vascular dementia and 11 other. The Neuropsychiatric Inventory (NPI) and NPI Caregiver Distress Scale (NPI-D) were used to assess subjects’ BPSD and related caregiver distress, respectively. Results: In the subjects exhibiting BPSD, aberrant motor behavior had the highest mean NPI score, and depression/dysphoria had the lowest. Agitation/aggression had the highest mean NPI-D score, and euphoria/elation had the lowest. Delusion, agitation/aggression, apathy/indifference, irritability/lability and aberrant motor behavior showed a correlation between the NPI and NPI-D scores. Conclusion: The burden associated with BPSD is different for each symptom and does not always depend on frequency and severity of BPSD. These findings suggest that some symptoms, such as agitation/aggression and irritability/lability, may affect the caregivers significantly, although their frequency and severity are low.

Neuropsychiatric disturbances are common and burdensome symptoms of dementia. Assessment and measurement of neuropsychiatric disturbances are indispensable to the management of patients with dementia. Neuropsychiatric Inventory (NPI) is a comprehensive assessment tool that evaluates psychiatric symptoms in dementia. We translated the NPI-Caregiver Distress Scale part of NPI (NPI-D) and NPI-Brief Questionnaire Form (NPI-Q) into Japanese and examined their validity and reliability.The subjects were 152 demented patients and the caregivers who lived with them. These patients consisted of 76 women and 76 men; their mean age was 73.9 +/- 7.8 (S.D.; range: 49 to 93) years. Their caregivers consisted of 46 men and 106 women; their mean age was 65.0 +/- 11.4 (S.D.; range: 35 to 90) years. The Mini-Mental State Examination (MMSE) was conducted with all patients and NPI-Q, NPI, NPI-D, and the Zarit caregiver burden interview (ZBI) were conducted with all caregivers. We examined validity of NPI-D by comparing its score with the MMSE and ZBI scores, and the validity of NPI-Q by comparing its score with the NPI and NPI-D scores. In order to evaluate test-retest reliability, NPI-D was re-adopted to 30 randomly selected caregivers by a different examiner one month later and NPI-Q was re-executed by 27 randomly selected caregivers one day later.Total NPI-D score was significantly correlated with ZBI (rs = 0.59, p0.01). Test-retest reliability of NPI-D was adequate (ri = 0.47, p0.01). Total NPI-Q severity score and distress score were strongly correlated with NPI (r = 0.77, p0.01) and NPI-D (r = 0.80, p0.01) scores, respectively. Test-retest reliability of the scores of NPI-Q was acceptably high (the severity score; ri = 0.81, p0.01, the distress score; ri = 0.80, p0.01).The Japanese version of NPI-D and NPI-Q demonstrated sufficient validity and reliability as well as the original version of them. These are useful tools for evaluating psychiatric symptoms in demented patients and their caregivers' distress attributable to these symptoms.

By using [(18)F]-2-fluoro-deoxy-d-glucose and positron emission tomography, the authors studied changes in regional glucose metabolism after a 1-year interval in patients with mild Alzheimer's disease (AD). Glucose metabolism declined over time in the bilateral precuneus and posterior cingulate gyri and in the frontal, temporal, and parietal cortices. Glucose metabolism in these regions may be a useful measure of the progression of AD and a valid surrogate outcome measure of clinical drug trials.

We evaluated everyday memory impairment in 24 patients with mild cognitive impairment (MCI) with the Rivermead Behavioral Memory Test (RBMT) and compared the scores with those of 48 age-, sex- and education-matched normal controls (NC) and 48 age-, sex- and education-matched Alzheimer disease (AD) patients. Overall everyday memory was impaired in MCI patients but the severity was milder than that in AD patients. The MCI patients showed impairment of everyday memory tasks requiring delayed recall. But they could normally perform tasks immediately after memorizing, except for recalling and retracing a simple new route. The total Profile score correctly classified 100% of the MCI patients and 91.7% of NC, thus demonstrating the usefulness of the RBMT for diagnosing MCI patients. Prospective memory tasks were not useful for detecting the patients with MCI.

The decision of long-term institutionalization of patients with Alzheimer's disease (AD) is based on multiple patients' and caregivers' characteristics. It is very important to find out factors associated with institutionalization for the timely institutionalization, i.e. for the prevention of premature institutionalization. Among those factors, caregiver burden is reportedly one of the most important factors in Europe and North America. However, no studies have been carried out in Japan. In order to address this issue, we studied outcome of patients with AD.Subjects were 211 patients who fulfilled the criteria of the National Institute of Neurological Disease and Stroke/Alzheimer's Disease and Related Disorders Association for probable AD. Diagnosis of AD was made through extensive examinations including MRI and PET/SPECT of the brain. The patients included 149 women and 62 men; the mean age was 73.1 +/- 8.0 (SD) years. The Japanese version of Zarit Caregiver Burden Interview (ZBI), which is a validated tool for assessment of the burden of caregivers for dementia patients, was used to evaluate caregivers' burden through the interview of a principal caregiver by trained nurses. Cognitive, functional, and neuropsychiatric impairments were assessed with standardized instruments of the Mini-Mental State Examination (MMSE), Hyogo Activities of Daily Living Scale (HADLS), Neuropsychiatric Inventory (NPI), respectively. We annually sent a questionnaire to the caregivers to collect information on the patients' status. It included questions whether and when they died or were institutionalized and whether they had used formal social supports such as home care, day care, and respite care services.Time to death or institutionalization.One-hundred and fifty subjects were followed for at least one year and 51 of them met either end point. The Cox proportional hazard model demonstrated that the baseline caregiver burden was a significant predictor of the end point even after controlling possible confounders. Among these, the use of day care and home care services during the course were significant protective factors. The baseline cognitive and functional disturbances but not neuropsychiatric manifestations were significantly associated with the end point.The caregiver burden is a significant predictor for the death or institutionalization of the patients with AD. The caregiver education which decrease the caregiver burden and prompt the usage of the social care services are necessary to protect premature institutionalization.

To validate the Japanese version of Rivermead Behavioural Memory Test (RBMT) in evaluating everyday memory function in patients with mild Alzheimer's disease (AD).Subjects were 100 patients with probable AD of very mild or mild stages of dementia as measured by the Clinical Dementia Rating (CDR). Scores of the Japanese version of RBMT were correlated with scores of the Alzheimer's Disease Assessment Scale-Cognitive part (ADAS-J Cog) and of the Wechsler Memory Scale-Revised (WMS-R). The everyday disability caused by the impairment of memory function was also assessed with the Memory Checklist (CL), and was correlated with the RBMT scores. In addition, the diagnostic value of the RBMT was examined in 46 pairs of AD patients and healthy subjects; the patients were chosen from the present subjects and the healthy subjects from the participants in the previous RBMT standardization study as one-by-one matched for age, sex, and educational level.Both of the total screening score and profile score of RBMT were significantly correlated with all of the weighted sum scores of verbal, visual, general, and delayed memory tests of the WMS-R and the word recall subtest score of the ADAS-J Cog. Both of the RBMT scores were also highly correlated with the CL score and the memory subscale of the CDR. In the analysis of the diagnostic accuracy, both of the RBMT scores correctly classified 98% of AD patients and 96% of normal volunteers by setting the cut-off scores of 6/5 for the total screening score and of 14/13 for the total profile score.The RBMT is a useful tool in evaluating everyday memory function in patients with mild AD. This test also accurately differentiates AD patients from healthy individuals.