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1.  The type of Aβ-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid β-peptide (APP48) transgenic mice 
The deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer’s disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.
Tracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.
These results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.
Electronic supplementary material
The online version of this article (doi:10.1186/2051-5960-1-77) contains supplementary material, which is available to authorized users.
PMCID: PMC4046770  PMID: 24252227
Intracellular amyloid β-protein; Extracellular amyloid β-protein; Mitochondria; Dendrites; Toxicity; Degeneration
2.  Evaluation of Anosognosia in Alzheimer's Disease Using the Symptoms of Early Dementia-11 Questionnaire (SED-11Q) 
The objective is to propose a brief method to evaluate anosognosia in Alzheimer's disease (AD) using the Symptoms of Early Dementia-11 Questionnaire (SED-11Q), a short informant-based screening questionnaire for identifying dementia.
The participants were 107 elderly individuals: 13 with a Clinical Dementia Rating (CDR) of 0.5, 73 with mild AD of CDR 1, and 21 with moderate AD of CDR 2. The patients and caregivers answered the SED-11Q independently, and the degree of discrepancy indicated the severity of anosognosia.
The scores were as follows: caregiver scores were 2.46 ± 1.85 (mean ± SD) in CDR 0.5, 6.36 ± 3.02 in CDR 1, and 9.00 ± 1.14 in CDR 2; patient scores were 2.00 ± 1.78, 2.55 ± 2.33, and 1.33 ± 2.46, respectively. Discrepancy was 0.46 ± 1.61, 3.81 ± 3.95, and 7.67 ± 2.87, respectively, and the caregiver assessments were significantly higher than the patient assessments in CDR 1 and CDR 2 (p < 0.001 in both groups). The SED-11Q for anosognosia was validated with the standardized Anosognosia Questionnaire for Dementia (AD-Q). The caregiver scores were moderately correlated with behavioral and psychological symptoms of dementia scores (r = 0.524), and the patient scores were moderately correlated with depression scores (r = 0.561).
The SED-11Q serves a dual purpose: caregiver assessment is useful for the screening of dementia, and any discrepancy between the patient and the caregiver assessment is considered as an indication of the severity of anosognosia; this can be informative for caregivers and essential for successful care.
PMCID: PMC3884202  PMID: 24403907
Anosognosia; Dementia; Alzheimer's disease; Behavioral and psychological symptoms of dementia; Metacognition; Caregiver burden; Dementia care; Mild cognitive impairment; Screening test

3.  Symptoms of Early Dementia-11 Questionnaire (SED-11Q): A Brief Informant-Operated Screening for Dementia 
The aim of this study was to develop a brief informant-based questionnaire, namely the Symptoms of Early Dementia-11 Questionnaire (SED-11Q), for the screening of early dementia. 459 elderly individuals participated, including 39 with mild cognitive impairment in the Clinical Dementia Rating scale (CDR) 0.5, 233 with mild dementia in CDR 1, 106 with moderate dementia in CDR 2, and 81 normal controls in CDR 0. Informants were required to fill out a 13-item questionnaire. Two items were excluded after analyzing sensitivities and specificities. The final version of the SED-11Q assesses memory, daily functioning, social communication, and personality changes. Receiver operator characteristic curves assessed the utility to discriminate between CDR 0 (no dementia) and CDR 1 (mild dementia). The statistically optimal cutoff value of 2/3, which indicated a sensitivity of 0.84 and a specificity of 0.90, can be applied in the clinical setting. In the community setting, a cutoff value of 3/4, which indicated a sensitivity of 0.76 and a specificity of 0.96, is recommended to avoid false positives. The SED-11Q reliably differentiated nondemented from demented individuals when completed by an informant, and thus is practical as a rapid screening tool in general practice, as well as in the community setting, to decide whether to seek further diagnostic confirmation.
PMCID: PMC3656692  PMID: 23687508
Dementia screening; Dementia; Alzheimer's disease; Activities of daily living; Cognitive deficits; Early detection; Mild cognitive impairment; Non-Alzheimer's disease

4.  A Randomized Controlled Trial of Brain-Activating Rehabilitation for Elderly Participants with Dementia in Residential Care Homes 
We aimed to prove the effectiveness of brain-activating rehabilitation for dementia, which consisted of 5 principles: pleasant atmosphere, communication, praising, social role, and supportive care.
The design was a randomized controlled trial that was not blinded. Fifty-four elderly participants with dementia (mean age: 85.2 years) were selected. Intervention based on the 5 principles of brain-activating rehabilitation was conducted for 1 h, twice a week, for 12 weeks (24 sessions). The control group had no treatment. Outcome measures consisted of two observation scales, namely sum of boxes in clinical dementia rating (CDR-SB) and the multidimensional observation scale for elderly subjects (MOSES), and two cognitive tests: the Hasegawa dementia scale revised (HDS-R) and trail making test A.
Repeated measure ANCOVA showed a significant interaction for total score of CDR-SB (F = 7.190, p = 0.015) and MOSES (F = 4.525, p = 0.038). There were no significant changes in the two cognitive test scores.
Intervention based on the principles of brain-activating rehabilitation was effective in maintaining and improving daily life functions in elderly participants with dementia in residential care homes.
PMCID: PMC3529563  PMID: 23300492
Alzheimer's disease; Brain activity; Dementia care; Non-pharmacological therapies; Randomized clinical trials; Rehabilitation; Reminiscence therapy
5.  Benefits of off-campus education for students in the health sciences: a text-mining analysis 
BMC Medical Education  2012;12:84.
In Japan, few community-based approaches have been adopted in health-care professional education, and the appropriate content for such approaches has not been clarified. In establishing community-based education for health-care professionals, clarification of its learning effects is required. A community-based educational program was started in 2009 in the health sciences course at Gunma University, and one of the main elements in this program is conducting classes outside school. The purpose of this study was to investigate using text-analysis methods how the off-campus program affects students.
In all, 116 self-assessment worksheets submitted by students after participating in the off-campus classes were decomposed into words. The extracted words were carefully selected from the perspective of contained meaning or content. With the selected terms, the relations to each word were analyzed by means of cluster analysis.
Cluster analysis was used to select and divide 32 extracted words into four clusters: cluster 1—“actually/direct,” “learn/watch/hear,” “how,” “experience/participation,” “local residents,” “atmosphere in community-based clinical care settings,” “favorable,” “communication/conversation,” and “study”; cluster 2—“work of staff member” and “role”; cluster 3—“interaction/communication,” “understanding,” “feel,” “significant/important/necessity,” and “think”; and cluster 4—“community,” “confusing,” “enjoyable,” “proactive,” “knowledge,” “academic knowledge,” and “class.”
The students who participated in the program achieved different types of learning through the off-campus classes. They also had a positive impression of the community-based experience and interaction with the local residents, which is considered a favorable outcome. Off-campus programs could be a useful educational approach for students in health sciences.
PMCID: PMC3479041  PMID: 22928985
Community-based education; School of health sciences; Early exposure; Role model; Text-mining methods
6.  Yamaguchi Facial Expression-Making Task in Alzheimer's Disease: A Novel and Enjoyable Make-a-Face Game 
To assess the ability to make emotional facial expressions, we newly developed the Yamaguchi facial expression-making task (Y-FEMT).
We recruited 20 normal controls and 61 outpatients: 10 with amnestic mild cognitive impairment (aMCI), 34 with mild Alzheimer's disease (AD), and 17 with moderate AD. In the Y-FEMT, smile and anger expressions were made by arranging face parts. We examined the relationship between each Y-FEMT score and the Mini-Mental State Examination (MMSE) score or overlapping figure identification test (Fig-test).
The Total score (0–20) was nearly achieved in controls (18.9 ± 1.4) and declined with AD progression (aMCI 17.2 ± 2.4, mild AD 15.7 ± 2.6, moderate AD 12.3 ± 2.7). The Anger score (0–10) was significantly lower than the Smile score (0–10) in mild and moderate AD (p = 0.007 and p = 0.006, respectively). The Structure score (0–6 each) correlated well with both the MMSE score (r = 0.44, p < 0.001) and Fig-test (r = 0.45, p < 0.001), whereas the Expression score (0–4 each) correlated only with the MMSE score (r = 0.33, p = 0.01). The Subjective scores (0–4), evaluated by 10 therapists, highly correlated with the Total score. Additionally, the Y-FEMT promoted laughter and a convivial atmosphere.
The Y-FEMT pleasantly assessed the ability to make emotional facial expressions without special equipment. Furthermore, the Y-FEMT may provide helpful clues for caregivers to achieve good communication with AD patients for better care.
PMCID: PMC3398831  PMID: 22811688
Dementia; Facial expression; Dementia care; Caregivers; Emotional reactions to dementia; Cognitive tests; Behavioral/psychiatric symptoms of dementia
7.  Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease 
EMBO Molecular Medicine  2012;4(4):344-352.
We investigated why the cerebrospinal fluid (CSF) concentrations of Aβ42 are lower in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Because Aβ38/42 and Aβ40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain γ-secretase activity, and were quantified by specific enzyme-linked immunosorbent assays in the CSF from controls and MCI/AD patients. Decreases in the levels of the precursors, Aβ42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, Aβ38 and 40, respectively. The ratios Aβ40/43 versus Aβ38/42 in CSF (each representing cleavage efficiency of Aβ43 or Aβ42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that γ-secretase activity in MCI/AD patients is enhanced at the conversion of Aβ43 and 42 to Aβ40 and 38, respectively. Consequently, we measured the in vitro activity of raft-associated γ-secretase isolated from control as well as MCI/AD brains and found the same, significant alterations in the γ-secretase activity in MCI/AD brains.
PMCID: PMC3376855  PMID: 22354516
amyloid β-protein; CSF; γ-secretase; NSAID; stepwise processing
8.  Intraneuronal Amyloid β Accumulation and Oxidative Damage to Nucleic Acids in Alzheimer Disease 
Neurobiology of disease  2009;37(3):731-737.
An in situ approach was used to identify amyloid-β (Aβ) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal specific antibodies directed against Aβ40 and Aβ42 were used for immunocytochemical analyses, Aβ42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Aβ-oligomer. In comparison to the Aβ42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Aβ42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r = − 0.61, p < 0.02). Together with recent evidence that the Aβ peptide can act as an antioxidant, these results suggest that intraneuronal accumulation of non-oligomeric Aβ may be a compensatory response in neurons to oxidative stress in Alzheimer disease.
PMCID: PMC2825655  PMID: 20034567
Alzheimer disease; 8-hydroxyguanosine; intraneuronal amyloid-β; nucleic acids; oligomer; oxidative stress
9.  Amyloid Beta Annular Protofibrils in Cell Processes and Synapses Accumulate with Aging and Alzheimer-Associated Genetic Modification 
Amyloid β (Aβ) annular protofibrils (APFs) have been described where the structure is related to that of β barrel pore-forming bacterial toxins and exhibits cellular toxicity. To investigate the relationship of Aβ APFs to disease and their ultrastructural localization in brain tissue, we conducted a pre-embedding immunoelectron microscopic study using anti-annular protofibril antiserum. We examined brain tissues of young- and old-aged amyloid precursor protein transgenic mice (APP23), neprilysin knockout APP23 mice, and nontransgenic littermates. αAPF-immunoreactions tended to be found (1) on plasma membranes and vesicles inside of cell processes, but not on amyloid fibrils, (2) with higher density due to aging, APP transgene, and neprilysin deficiency, and (3) with higher positive rate at synaptic compartments in aged APP23, especially in neprilysin knockout APP23 mice. These findings imply that APFs are distinct from amyloid fibrils, interact with biological membranes, and might be related to synaptic dysfunction in Alzheimer model mouse brains.
PMCID: PMC2925098  PMID: 20798763

Results 1-9 (9)