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Background: Time disorientation is one of the main symptoms observed in patients with dementia; however, their clock-reading ability has not been fully reported. Objective: This study aimed to investigate the clock-reading ability of both digital and analog clocks in patients with dementia. We newly devised the clock-reading test (CRT) and the number-reading test (NRT) to assess cognitive factors that may affect clock-reading ability. Furthermore, the discriminating power of the CRT was calculated. Methods: 104 participants were categorized based on their Mini-Mental State Examination (MMSE) scores as follows: subjective cognitive decline ∼ mild cognitive impairment (SCD∼MCI, N = 43), early Alzheimer’s disease (AD) (N = 26), and middle-to-late AD (N = 35). Their cognitive abilities were evaluated using the clock-drawing test (CDT), CRT, and NRT. Results: Cognitive decline leads to impairment of clock-reading ability which is more pronounced in the analog clocks than digital ones. This deficit in clock-reading is attributed to a loss of semantic memory regarding clocks at all stages. Additionally, visuospatial dysfunction and reduced ability of number recognition may lead to deficit in clock-reading in the advanced stage of AD. The discriminating power of the CRT (analog) (AUC = 0.853) was high enough to detect cognitive decline. Conclusion: Digital clocks are more readable by patients with dementia. Since reading clocks is closely associated with daily life, the CRT has proved to be a useful tool. A decline of analog clock-reading may be an early detector for the onset of dementia in elderly patients.

Purpose: This 4-year prospective observational study aimed to examine the relationship between self-reported chewing ability and incidents of stroke in community-dwelling older adults in Japan. Methods: A total of 5,093 adults aged 65 years and older who were neither disabled nor living in long-term care facilities completed the baseline survey in April 2013. In February 2017, a follow-up survey was conducted for 3,606 older adults who were not disabled and had not died. All data were obtained from self-reported questionnaires. Participants were classified into a normal or an impaired chewing ability group. Using multivariable logistic regression analysis, odds ratios and 95% confidential intervals were calculated for the risk of stroke, adjusting for sex, age, physical activities, BMI, medications, and wearing a denture. Results: The final analysis included 2,099 participants with no history of cardiovascular disease or severe hypertension in 2013, excluding those with missing main data. During the 4-year follow-up period, the incidence of stroke was 2.8% and 3.6% for the normal chewing ability group and 5.9% and 4.7% for the impaired chewing ability group in participants 65–74 years old and 75 years old or older, respectively. The adjusted ORs were 2.29 for chewing ability impairment, 8.57 with mobility impairment, and 4.09 with cognitive impairment; however, there were no significant differences in participants 75 years old or older, except for those with a physical impairment. Conclusion: Our results suggested that impaired chewing ability independently predicted stroke, especially for those with physical or cognitive frailty in a community.

Background: With the rapid aging of the population, the issue of driving by dementia patients has been causing increasing concern worldwide. Objective: To investigate the driving difficulties faced by senior drivers with cognitive impairment and identify the specific neuropsychological tests that can reflect specific domains of driving maneuvers. Methods: Senior drivers with cognitive impairment were investigated. Neuropsychological tests and a questionnaire on demographic and driving characteristics were administered. Driving simulator tests were used to quantify participants’ driving errors in various domains of driving. Results: Of the 47 participants, 23 current drivers, though they had better cognitive functions than 24 retired drivers, were found to have impaired driving performance in the domains of Reaction, Starting and stopping, Signaling, and Overall (wayfinding and accidents). The parameters of Reaction were significantly related to the diagnosis, and the scores of MMSE, TMT-A, and TMT-B. As regards details of the driving errors, “Sudden braking” was associated with the scores of MMSE (ρ= –0.707, p

With the deterioration of cognitive functions, the capability to obtain information with speed, one of the essential elements needed to perform safe driving, may be impacted. We aimed to compare the legibility of analogue and digital speedometers for senior drivers with cognitive impairment, and examined the demographic, cognitive, and driving-related variables that predict their speedometer-reading performance.A total of 50 senior drivers with cognitive impairment were investigated and asked to complete an office-based speedometer-reading test using an iPad. Two general types of speedometers (analogue and digital) were tested in this study.The age of the participants ranged from 61 to 92 years (mean (SD), 79.10 (6.973)), and 29 were male. The mean (SD) score of the Mini-Mental State Examination was 22.48 (6.089). The median (QA digital speedometer was found to be easier for absolute value reading for senior drivers with cognitive impairment, compared to an analogue speedometer. Senior drivers with subjective cognitive decline may also have impairments in obtaining the speed information through an analogue speedometer. General cognitive function and attention may influence the speed-reading performance on the digital speedometer.

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2 R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 sec than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

Reminiscence therapy is garnering attention for stimulating seniors’ cognitive functions. It could be inferred that that synergistic effects could be created by combining virtual reality (VR), which can project realistic images, with recall, which stimulates memory. We hypothesized that by projecting realistic memories to stimulate recall, VR-based reminiscence therapy would stimulate cognitive function better than conventional photo-based reminiscence therapy. We randomly assigned total 52 people with mild cognitive impairment to eight weeks of reminiscence therapy using either tablet VR panoramas or conventional still photos with 26 participants in each group. Before and after therapy, we tested their cognitive functions with the mini-mental state examination (MMSE), the revised PGC morale scale, multidimensional observation scale for elderly subjects, trail making tests A and B, and the word fluency test. The total scores of MMSE showed improvement for both groups, but did not show statistical significance of the VR panoramas group over the conventional still photos group. However, of the two groups, only the VR panoramas group showed considerable improvement from the baseline. In addition, the analysis of secondary outcome showed that the revised PGC morale scale scores rose considerably higher in the VR panoramas group than in the still photos group. No definite differences were observed in other scales. Contrary to our primary hypothesis, reminiscence therapy produced cognitive improvement regardless of whether its stimuli were still photos or VR panoramas. However, the greater improvement in VR participants’ revised PGC morale scale scores shows enhancement of patients’ subjective well-being.

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2 R714G, I715D, or GD) that confers resistance to proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 sec than WT and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

Background Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer's disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear. Objective This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse. Methods BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. Results Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP. Conclusion SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses.

Introduction In hospitals, the nurse uses the bed alarm system for patients’ safety, which may have some forms of physical restraints included, depending on the situation. However, the nurses’ perceptions of the bed alarm system with reference to restraints are yet to be clarified. Moreover, there were no reports that can shed light upon the factors that relate to nurses’ perceptions about the bed alarm system in Japan. The objective of this study is to investigate the nurses’ perception on whether the bed alarm can be considered as a form of physical restraint and to elucidate the factors that pertain to the nurses’ perceptions regarding the bed alarm. Methods This study conducted a quantitative cross-sectional survey. We used bivariate logistic regression analyses to investigate the nurses’ perception and the factors affecting these perception. Ethical approval was obtained from the research ethics committee of the Kyoto University. Participants opted for answering the questionnaire voluntarily. Results The sample population comprised of 289 nurses from 10 acute-care hospitals. Out of these, 214 (74.0%) nurses considered the bed alarm system as a form of restraint, and 75 nurses (26.0%) did not. Furthermore, the nurses’ perception was relevant to the hospitals that they belonged to, their years of experience, and the content of education. It was especially interesting that the group of nurses with little experience had the consciousness of being considered the bed alarm as restraint compared with nurses with many years of experience. Conclusion The alarm systems are gradually being considered to be classified as a restraint. Hospitals should ensure providing an ethically sensitive climate and appropriate educational opportunities to help nurses build these perceptions for patient care. An ethically sensitive climate and appropriate educational opportunities would lead to an environment that nurtures nurses with the ability to recognize problems in daily care.

Accumulation of amyloid β (Aβ40 and Aβ42) in the brain is a characteristic of Alzheimer's disease (AD). Because neprilysin (NEP) is a major Aβ-degrading enzyme, NEP delivery in the brain is a promising gene therapy for AD. Borna disease virus (BoDV) vector enables long-term transduction of foreign genes in the central nerve system. Here, we evaluated the proteolytic ability of NEP transduced by the BoDV vector and found that the amounts of Aβ40 and Aβ42 significantly decreased, which suggests that NEP expressed from the BoDV vector is functional to degrade Aβ.

Patients' irritability and aggression have been linked to caregiver depression, but the behaviors that most burden caregivers are not yet definitively identified. This study examines the connection between behavioral and psychological symptoms of dementia (BPSD) and the burnout of caregivers caring for home-dwelling elders with dementia symptoms in Japan.80 Japanese rural and urban family caregivers completed detailed questionnaires about their experiences in caring for demented family members. We statistically analyzed the results for correlations between types of dementia, Pines Burnout, and Caregiver Distress.BPSD symptom severity significantly correlated with caregiver distress. The dementia symptoms most strongly correlated with caregiver burnout were: aggression, irritability, abnormal motor behavior, and hallucinations.Among the commonest symptoms, apathy, anxiety, and depression did not seriously aggravate caregiver burnout. Caregivers displayed higher burnout facing agitation/aggression, irritability, aberrant motor behavior, and hallucinations. Caregivers' reported distress was surprisingly dissimilar to their burnout scores; patients' delusions and anxiety led to higher distress reporting but not to burnout.Advance diagnosis of BPSD symptoms should be helpful to support nurses and caregivers of dementia patients. Particular support should be considered for caregivers and nurses of patients expressing aggression, irritability, abnormal motor behavior, and hallucination.

Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily - the bone morphogenetic proteins (BMPs) - in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post-mortem human brain samples as follows: 7 SVD patients (4 males, 76-90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67-93 years old) and 6 age-matched disease controls (3 males, 68-78 years old). We subsequently investigated the effects of oxygen-glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen-glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD.

The susceptibility to neurological and psychiatric disorders reveals sexual dimorphism in the structure and function of human brains. Recent evidence has also demonstrated the sex-related differences in cellular components of the brain, including neurons, microglia, astrocytes, and endothelial cells. Oligodendrocyte precursor cells (OPCs) regulate the neuronal system in various ways and play crucial roles in brain homeostasis beyond their well-known role as a reservoir for mature oligodendrocytes. Although recent studies have shown regional diversities and heterogeneities of OPCs, sex-related differences in OPCs are largely unknown. Here, we revealed transcriptomic differences in OPCs isolated from male and female neonatal rat brains. Furthermore, we demonstrated sex-dependent differences in OPCs regarding proliferation, migration, differentiation, tolerance against ischemic stress, energy metabolism, and the ability to regulate the blood-brain barrier integrity.

Background: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. Objective: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. Methods: We analyzed CSF concentrations of tau, amyloid-β (Aβ) 42 and 40, and leucine rich α-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). Results: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aβ42 (LD/FD = 0.80, p

Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-β 42 (Aβ42)/Aβ40 and Aβ43/Aβ40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery.

Background As the Japanese population ages, the number of cancer patients will likely increase. Therefore, qualified cancer health care providers should be recruited and retained. Nurse job satisfaction is influenced by numerous factors and may affect staff turnover and patient outcomes. Objectives To evaluate the job satisfaction of certified nurses and nurse specialists in Japanese cancer care and elucidate factors associated with job satisfaction. Methods Participants in this cross-sectional study comprised 200 certified nurse specialists and 1,472 certified nurses working in Japanese cancer care. A chi-square test and logistic regression analysis were conducted to identify job satisfaction factors. Results Job satisfaction was present in 38.45% and 49.00% of certified nurses and nurse specialists, respectively. Certified nurses associated job satisfaction with cross-departmental activities (OR 2.24, p

Accumulation of amyloid β (Aβ40 and Aβ42) in the brain is a characteristic of Alzheimer's disease (AD). Because neprilysin (NEP) is a major Aβ-degrading enzyme, NEP delivery in the brain is a promising gene therapy for AD. Borna disease virus (BoDV) vector enables long-term transduction of foreign genes in the central nerve system. Here, we evaluated the proteolytic ability of NEP transduced by the BoDV vector and found that the amounts of Aβ40 and Aβ42 significantly decreased, which suggests that NEP expressed from the BoDV vector is functional to degrade Aβ.

Recently, dementia patients have been increasing in number worldwide, necessitating the development of techniques to detect dementia as early as possible. Considering that a typical symptom of dementia, especially Alzheimer's disease, is language impairment, speech-based dementia detection approaches have drawn much attention. This paper presents a smartphone-based dementia screening application, VocabChecker, which measures language abilities from a speech narrative via automatic speech recognition (ASR). It measures four language abilities related to dementia: number of tokens (token), number of types (type), type token ratio (TTR), and potential vocabulary size (PVS). We also reported that the use of VocabChecker has distinguished dementia patients from elderly people.

The expression of FNDC5 did not change the level of C99. These blots show that expression of FNDC5 did not change the level of C99 (A). The quantified results were shown in (B). The band intensity in the group of C99-myc + pcDNA3.1 is referred to as 100%. (PPTX 224 kb)

The deposition of Amyloid-beta peptides (Aβ) is detected at an earlier stage in Alzheimer’s disease (AD) pathology. Thus, the approach toward Aβ metabolism is considered to play a critical role in the onset and progression of AD. Mounting evidence suggests that lifestyle-related diseases are closely associated with AD, and exercise is especially linked to the prevention and the delayed progression of AD. We previously showed that exercise is more effective than diet control against Aβ pathology and cognitive deficit in AD mice fed a high-fat diet; however, the underlying molecular mechanisms remain poorly understood. On the other hand, a report suggested that exercise induced expression of fibronectin type III domain-containing protein 5 (FNDC5) in the hippocampus of mice through PGC1α pathway. Thus, in the current study, we investigated a possibility that FNDC5 interacts with amyloid precursor protein (APP) and affects Aβ metabolism. As a result, for the first time ever, we found the interaction between FNDC5 and APP, and forced expression of FNDC5 significantly decreased levels of both Aβ40 and Aβ42 secreted in the media. Taken together, our results indicate that FNDC5 significantly affects β-cleavage of APP via the interaction with APP, finally regulating Aβ levels. A deeper understanding of the mechanisms by which the interaction between APP and FNDC5 may affect Aβ production in an exercise-dependent manner would provide new preventive strategies against the development of AD. Electronic supplementary material The online version of this article (10.1186/s13041-018-0401-8) contains supplementary material, which is available to authorized users.

Computational prediction of the irisin-APP672–699 complex structure. This is the additional technical information about in silico simulation of the interaction between irisin and APP672–699. (PDF 149 kb)

The top ten-ranked binding modes of APP672–699 on irisin. The Irisin dimer and APP672–699 structures assigned to each conformational cluster are represented by the ribbon model. In irisin, the putative functional loop regions (residues 30–32, 55–58, and 106–108) are colored by red, and other regions are colored by orange. In APP, residues 672–687 and 688–728 are colored by cyan and blue, respectively. The binding free energy (ΔG) of each conformational cluster is calculated by averaging the values of its members and indicated as a criterion of the irisin- APP672–699 binding affinity. (PPTX 1729 kb)

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimer's disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD.