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Seizures are increasingly being recognized as the hallmark of Alzheimer's disease (AD). Neuronal hyperactivity can be a consequence of neuronal damage caused by abnormal amyloid β (Aß) depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aß-independent mechanisms. Various studies using animal models have shown that Ca2+ is released from the endoplasmic reticulum (ER) via type 1 inositol triphosphate receptors (InsP3R1s) and ryanodine receptors (RyRs). To investigate which is the main pathophysiological mechanism in human neurons, we measured Ca2+ signaling in neural cells derived from three early-onset AD patients harboring Presenilin-1 variants (PSEN1 p.A246E, p.L286V, and p.M146L). Of these, it has been reported that PSEN1 p.A246E and p.L286V did not produce a significant amount of abnormal Aß. We found all PSEN1-mutant neurons, but not wild-type, caused abnormal Ca2+-bursts in a manner dependent on the calcium channel, Ryanodine Receptor 2 (RyR2). Indeed, carvedilol, an RyR2 inhibitor, and VK-II-86, an analog of carvedilol without the β-blocking effects, sufficiently eliminated the abnormal Ca2+ bursts. In contrast, Dantrolene, an inhibitor of RyR1 and RyR3, and Xestospongin c, an IP3R inhibitor, did not attenuate the Ca2+-bursts. The Western blotting showed that RyR2 expression was not affected by PSEN1 p.A246E, suggesting that the variant may activate the RyR2. The RNA-Seq data revealed that ER-stress responsive genes were increased, and mitochondrial Ca2+-transporter genes were decreased in PSEN1A246E cells compared to the WT neurons. Thus, we propose that aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 variants and cell-intrinsic hyperactivity prior to deposition of abnormal Aß, offering prospects for the development of targeted prevention strategies for at-risk individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Dementia often results in postural control impairment, which could signify central nervous system dysfunction. However, no studies have compared postural control characteristics among various types of dementia. This study aimed to compare static postural control in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD)., Methods: Cross-sectional relationship between the clinical diagnoses (AD, DLB, VaD, or normal cognition [NC]) of outpatients at a memory clinic and their upright postural control characteristics were examined. In the postural control test, participants were instructed to maintain a static upright standing on a stabilometer for 60 seconds under the eyes-open and eyes-closed conditions. Forty postural control parameters, including distance, position, and velocity in the anterior-posterior and medio-lateral directions, derived from the trajectory of the center of mass sway, were calculated. The characteristics of each type of dementia were compared to those of NC, and the differences among the 3 types of dementia were evaluated using linear regression models., Results: The study included 1 789 participants (1 206 with AD, 111 with DLB, 49 with VaD, and 423 with NC). Patients with AD exhibited distinct postural control characteristics, particularly in some distance and velocity parameters, only in the eyes-closed condition. Those with DLB exhibited features in the mean position in the anterior-posterior direction. In patients with VaD, significant differences were observed in most parameters, except the power spectrum., Conclusions: Patients with AD, DLB, and VaD display disease-specific postural control characteristics when compared to cognitively normal individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid β (Aβ)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aβ uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-pharmacological interventions effective for depressive mood and bilateral relationships among persons with cognitive impairment (PwCI) and their family caregivers (FCGs) have not been established., Objective: To examine the feasibility of a newly developed group-based art appreciation and self-expression program (NCGG-ART) for dyads of PwCI and their FCGs., Methods: This pilot randomized control trial included 34 dyads of PwCI diagnosed with mild to moderate Alzheimer's disease or mild cognitive impairment, and their FCGs, from an outpatient rehabilitation service (Holistic Physio-Cognitive Rehabilitation [HPCR]). Participants were randomly divided equally into the HPCR (control group) or NCGG-ART and HPCR (intervention group) groups. Both included 1-hour weekly, 6-week programs. The primary outcome was depressive symptoms among FCGs assessed using the Patient Health Questionnaire-9 (PHQ-9). Feasibility outcomes included participant satisfaction and motivation. FCGs were interviewed about their experiences and feelings regarding the program, which were analyzed using content analysis., Results: Thirty-two dyads (intervention group:16; control group:16) completed the study period. High participation rates, satisfaction, and motivation were demonstrated throughout the intervention. Scores in the PHQ-9 among FCGs did not show positive effects: mean changes in the score were 1.3 for the intervention group and -0.8 for the control group (Cohen d:0.56). However, the qualitative analysis revealed favorable experiences and feelings of the FCGs, such as positive emotions, social interactions, and person-centered attitudes to and positive relationships with PwCI., Conclusions: This program demonstrated high feasibility with FCGs' favorable responses to emotions and relationships with PwCI, ensuring future investigations with a confirmatory study design.

Background: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD., Methods: We selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation ( 11 C-DPA-713-binding potential in the area of Braak 1-3 [ 11 C-DPA-713-BP ND ]) on global cognition and memory using a stepwise regression analysis., Results: The final multiple regression model of annual changes in global cognition and memory scores included 11 C-DPA-713-BP ND as the predictor. The CSF Aβ42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11 C-DPA-713-BP ND as the predictor of decline in global cognition and memory., Conclusions: Translocator protein-PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease., Objective: We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort., Methods: The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9; female, 1,953) was classified into six groups: normal cognition (NC), mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC., Results: Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks: 2.61-5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ɛ4 allele., Conclusion: Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. Although recent reports have noted that cognitive impairment is common in NMOSD, little longitudinal information is available on the trajectories of cognitive function in the disease. Here, we report a case of a 55-year-old woman with an 11-year history of NMOSD who visited our memory clinic for progressive memory loss. She was diagnosed with early-onset Alzheimer disease based on amyloid and tau positron emission tomography imaging biomarkers. This is the first report of early-onset Alzheimer disease in a patient with NMOSD. Complications of Alzheimer disease should be considered when patients with NMOSD exhibit rapid cognitive decline. More longitudinal studies of NMOSD with cognitive impairment are needed., Competing Interests: The authors declare no conflicts of interest.

Background: Few studies have examined the relationship between non-cognitive factors and activities of daily living (ADL) according to Alzheimer's disease (AD) stage., Objective: We aimed to identify the differences in non-cognitive factors according to AD stages and their involvement in basic and instrumental ADL performance by using intrinsic capacity (IC) in groups with cognition ranging from normal to moderate or severe AD., Methods: We enrolled 6397 patients aged≥65 years who visited our memory clinic. Non-cognitive IC was assessed using the locomotion, sensory, vitality, and psychological domains. Multiple logistic regression was performed to identify how non-cognitive IC declines over the AD course and examine the correlation between non-cognitive IC and basic and instrumental ADL performance., Results: Non-cognitive IC declined from the initial AD stage and was significantly correlated with both basic and instrumental ADL performance from the aMCI stage through all AD stages. In particular, the relationship between IC and basic ADL was stronger in mild and moderate to severe AD than in the aMCI stage. On the other hand, the relationship between IC and instrumental ADL was stronger in aMCI than in later AD stages., Conclusions: The results show non-cognitive factors, which decline from the aMCI stage, are correlated with ADL performance from the aMCI stage to almost all AD stages. Considering that the relationship strength varied by ADL type and AD stage, an approach tailored to ADL type and AD stage targeting multiple risk factors is likely needed for effectively preventing ADL performance declines.

Background: The evaluation of 11 C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11 C-DPA713-binding potential (BP ND ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients., Methods: Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11 C-DPA713-BP ND and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11 C-DPA713-BP ND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis., Results: A positive correlation was found between the severity of agitation and 11 C-DPA713-BP ND in the Braak 1-3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11 C-DPA713-BP ND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini-Mental State Examination score, cerebrospinal fluid amyloid β 42/40 ratio, and apolipoprotein E4 positivity, on either the 11 C-DPA713-BP ND or agitation score., Conclusions: Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia., (© 2022 The Authors. Psychogeriatrics published by John Wiley & Sons Australia, Ltd on behalf of Japanese Psychogeriatric Society.)

Background: Periodontal disease (PeD) is a risk factor of Alzheimer's disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified., Objective: To evaluate associations between PeD and subitems of neuropsychological tests., Methods: We performed a cross-sectional analysis of data of 183 participants (women: 50%, mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and PeD using multivariable logistic regression analyses., Results: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04-4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41-5.32, p = 0.003)., Conclusions: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis.

Background & Aims: While cross-sectional studies report associations between behavioral and psychological symptoms of dementia (BPSD) and nutritional status as a modifiable factor, their causal relationship remains unclear. Therefore, this study investigated the impact of nutritional status on BPSD., Methods: This study included women with mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD) from Memory Clinic, National Center for Geriatrics and Gerontology. The participants were assessed for nutritional status and BPSD using the Mini Nutritional Assessment Short-Form (MNA-SF) and the Dementia Behavior Disturbance Scale (DBD), respectively. Based on their MNA-SF scores, the subjects were classified as well-nourished, at risk of malnutrition, or malnourished. Nutritional status and change in BPSD was examined for association by univariate and multivariate linear regression analyses., Results: This study analyzed 181 women (79 with MCI and 102 with early-stage AD). The multivariate analysis showed that the malnourished subjects or those at risk of malnutrition (54.1%) were significantly associated with increased DBD scores (β = 0.255, P = 0.003) during follow-up. In addition, multivariate regression analysis incorporating change in DBD sub-score as a dependent variable showed that the malnourished subjects or those at risk of malnutrition were associated with increased DBD sub-scores for "verbal aggressiveness/emotional disinhibition" (β = 0.247, P = 0.005)., Conclusions: Poor nutritional status increased BPSD, especially verbal aggressiveness/emotional disinhibition, in those with MCI and early-stage AD during 2.5-year follow-up. Patients with MCI and early-stage AD may need to be assessed for nutritional status from early on, at the onset of mild cognitive decline, and require intervention to prevent worsening of BPSD. Further intervention studies in large prospective cohorts are needed to establish nutritional measures to prevent progression of BPSD in older adults with cognitive impairment., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective Dementia with Lewy bodies (DLB) is the second-most common form of neurodegenerative dementia after Alzheimer's disease (AD). Falls are a vital prognostic factor in patients with dementia and are a characteristic feature of DLB. This study investigated the screening potential of the fall risk evaluation for DLB and compared it with that of AD to facilitate an accurate diagnosis. Methods We enrolled patients diagnosed with DLB (n=410) and AD (n=2,683) and categorized the participants into 3 groups depending on their physical ability, age, cognitive function, and fall events. Using the Fall Risk Index-21 (FRI-21) questionnaire, we evaluated and comparatively analyzed the fall risk between DLB and AD patients in three defined groups of participants. Results The FRI-21 score was significantly higher in DLB patients than in AD patients in every group. Using this score, we were able to distinguish between DLB and AD patients in each group. Among the three groups, the group with a young age, relatively mild cognitive dysfunction, and no fall events exhibited the best specificity for DLB (0.895). Conclusions The FRI-21 is a useful tool for screening for DLB and differentiating it from AD. This questionnaire can be used at a relatively early stage of the disease in young patients with mild cognitive dysfunction and no history of falling. These preliminary results need to be validated in an interventional study to evaluate the effectiveness of rehabilitative measures and daily environmental changes carried out to prevent falls using this tool.

Introduction: 11 C-DPA-713 is a positron emission tomography (PET) radiotracer developed for imaging the expression of the translocator protein (TSPO) in glial cells, which is considered to be a marker of the neuroinflammatory burden. This study investigated the pharmacokinetic profile of 11 C-DPA-713 and evaluated kinetic modeling and non-invasive TSPO quantification using dynamic PET imaging data in the Alzheimer's disease (AD) and cognitive normal (CN) participants., Methods: Eleven patients with AD and 6 CN participants were examined using dynamic 11 C-DPA-713 PET imaging for 60 min with arterial blood sampling. Time-activity curves were calculated from the cerebellum and three composite regions of interest (ROIs), according to the anatomical definitions of Braak's stages 1 to 3, stage 4, stage 5, and stage 6 that correspond to the pathological stages of tangle deposition. The total distribution volume (V T ) was evaluated using compartmental modeling and graphical analysis. Reference region-based methods were implemented using an optimal area that was assumed to be void of the radiotracer target as reference tissue., Results: The concentration of radioactivity in plasma demonstrated rapid clearance. 11 C-DPA-713 peaked rapidly in the gray matter. Compartmental modeling resulted in a good fit, and the one-tissue model with estimated blood volume correction (1Tv) showed the best performance. The estimated V T obtained from the graphical plasma methods was highly correlated with that obtained from 1Tv. Reference region-based analysis was conducted using the Braak 6 area as the reference region, and the estimated non-displaceable binding potential was highly correlated with that obtained from 1Tv., Conclusion: 11 C-DPA-713 possesses properties suitable for TSPO quantification with PET imaging. The Braak 6 area was shown to be a useful reference region in the patients with AD and the CN participants, and non-invasive reference tissue models using the Braak 6 area as a reference region can be employed for TSPO quantification with 11 C-DPA-713-PET imaging as an alternative to the invasive compartmental model., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A lower body mass is associated with the progression of Alzheimer's disease (AD) and the risk of mortality in patients with AD; however, evidence of genetic determinants of decreased body mass in cognitively impaired older adults is limited. We therefore investigated the genetic effect of APOE-ε4 on body composition in older adults with mild cognitive impairment (MCI) and early-to-moderate-stage AD. A total of 1631 outpatients (aged 65-89 years) with MCI and early-to-moderate-stage AD were evaluated for the association between body composition and APOE-ε4 status. After adjusting for covariates, including cognitive function evaluated with the Mini-Mental State Examination, the presence of the APOE-ε4 was associated with lower weight (β = -1.116 ± 0.468 kg per presence, p = 0.017), fat mass (β = -1.196 ± 0.401 kg per presence, p = 0.003), and percentage of body fat (β = -1.700 ± 0.539% per presence, p = 0.002) in women but not in men. Additionally, the impact of APOE-ε4 on measures of body composition in women was more remarkable in MCI than in AD patients. The presence of the APOE-ε4 allele was associated with lower fat mass, particularly in women with MCI, independent of cognitive decline.

Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and neurofilament light chain (NfL; a disease-nonspecific biomarker of neural damage) remain controversial., Objective: To evaluate the associations between plasma NfL, gut microbiota, and cognitive function., Methods: We performed a cross-sectional sub-analysis of data from our prospective cohort study that was designed to investigate the relationship between gut microbiota and cognitive function. Patients who visited our memory clinic were enrolled and demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites were assessed. We evaluated the relationships between the gut microbiome, microbial metabolites, and plasma NfL. Moreover, the relationships between plasma NfL and cognitive function were assessed using multivariable logistic regression analyses., Results: We analyzed 128 participants (women: 59%, mean age: 74 years). Participants with high (above the median) plasma NfL concentrations tended to be older, women, and hypertensive and have a history of stroke, chronic kidney disease, and dementia. Plasma NfL was also associated with cerebral small vessel disease. However, plasma NfL levels were not significantly correlated with gut microbial metabolites. Multivariable analyses revealed that a higher plasma NfL concentration was independently associated with the presence of dementia (odds ratio: 9.94, 95% confidence interval: 2.75-48.2, p < 0.001)., Conclusion: High plasma NfL concentration was independently associated with the presence of dementia as previously reported. However, plasma NfL levels were not significantly correlated with gut microbial metabolites in this preliminary study.

Background: Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases., Objective: Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET., Methods: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage., Results: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment., Conclusion: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Background: With increasingly aging societies, a comprehensive strategy for dementia research is important. The Organized Registration for the Assessment of dementia by the Nationwide General consortium toward Effective treatment (ORANGE) Registry is the first longitudinal multicenter prospective trial-ready cohort in Japan., Objective: To establish a large cohort for use in clinical trials and research in Japan., Methods: This registry, based on communities, hospitals, and nursing homes, covers three dementia stages (preclinical, mild cognitive impairment [MCI], and advanced dementia), and includes more than 30 hospitals. We analyzed enrollment and 1-year follow-up data for disease progression., Results: There were 1450 registered patients (649 men, 801 women; mean age, 77.92±6.70 years; mean Mini-Mental State Examination [MMSE] score, 25.19±2.76). The conversion rates from MCI to dementia and MCI to normal were 14.3% and 1.1%, respectively. High Clinical Dementia Rating score (odds ratio [OR] = 11.085, 95% confidence interval [CI]:1.619-75.913, p = 0.014), low MMSE score (OR = 0.835, 95% CI: 0.761-0.917, p < 0.001), high Geriatric Depression Scale score (OR = 1.093, 95% CI: 1.005-1.189, p = 0.038), and low body mass index (OR = 0.895, 95% CI: 0.829-0.967, p = 0.005) at enrollment were significant factors for conversion., Conclusion: The ORANGE MCI Registry is an established registry that facilitates creation of trial-ready cohorts to accelerate promotion of clinical trials with low reversion rates as it originates from a hospital. One-year follow-up analysis suggested assessing various factors for conversion risk. Further analyses will be possible in future with registry expansion. We will continue to refine this registry, including how it can be used more efficiently.

Background: Gait disturbance and musculoskeletal changes are evident in persons living with Alzheimer's disease (AD). Because complex gait control requires the integration of neural networks, cerebral small vessel disease (SVD), which is highly prevalent in persons with AD, might have an additional impact on gait disturbance. This study investigated whether white matter hyperintensities (WMH) are more predominantly associated with gait disturbance in persons with AD than in individuals with mild cognitive impairment (MCI) and normal cognition (NC) and further identified the regional impact of WMH on specific gait changes., Methods: This study included 396 subjects (aged 65 to 86 years, 63.9% female) diagnosed with AD (n = 187), MCI (n = 118), or NC (n = 91). WMH, lacunes, perivascular spaces, and cerebral microbleeds were assessed as markers of SVD. The volume of WMH was quantified in each brain lobe (frontal, temporal, occipital, and parietal) and sublobar regions in the basal ganglia and thalamus. Gait function was assessed using an electronic walkway. We investigated the association between regional WMH and gait disturbance in individuals with AD, MCI, and NC, adjusted for classical and musculoskeletal confounders., Results: Among markers of SVD, WMH were most associated with gait disturbance. In AD subjects, periventricular WMH in the frontal and parietal lobes were associated with slow gait speed (r s  = -0.21, P = 0.007 and r s  = -0.18, P = 0.019, respectively). These lesions were also associated with changes in stride time, double-leg support time, and walking angle (all r s  > 0.20, P < 0.01). Lesions in the basal ganglia and thalamus were associated with slow gait speed (r s  = -0.16, P = 0.034 and r s  = -0.18, P = 0.023, respectively) and greater gait speed variability (r s  = 0.16, P = 0.034 and r s  = 0.20, P = 0.010, respectively). MCI subjects showed only associations between sublobar lesions and shorter stride length (r s  = -0.24, P = 0.016) and increased walking angle (r s  = 0.32, P = 0.002). NC subjects did not show associations between WMH and gait parameters. MCI and NC subjects were more affected by muscle weakness than WMH for global gait function (r s  = 0.42, P < 0.001 and r s  = 0.23, P = 0.046, respectively)., Conclusions: Persons with AD showed a predominant association between WMH and gait disturbance compared with MCI and NC subjects, and regional WMH had a detrimental effect on specific gait changes., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Aim: Executive dysfunction is pathognomonic for dementia and impedes the activities of daily living (ADL). This study aimed to examine the relationship of dementia severity with executive dysfunction and ADL in mild cognitive impairment and dementia., Methods: This single-center study enrolled 86 patients (men, 40; women, 46; mean age, 76.1 ± 7.5 years) referred for cognitive and physical rehabilitation between October 2015 and September 2020. The Clinical Dementia Rating (CDR) was 0.5, 1, and ≥2 in 45, 30, and 11 patients, respectively. The presence and severity of executive dysfunction were assessed using the Behavioral Assessment of the Dysexecutive Syndrome-Japanese version (BADS). The ADL and instrumental ADL (IADL) were assessed using the Barthel Index and Frenchay Activities Index (FAI), respectively. We examined the relationship between CDR severity and overall BADS profile score and its sub-items, and that between the overall BADS profile score and IADL., Results: The cognitive and executive functional assessment scores differed significantly depending on the CDR severity. The CDR severity and overall BADS profile score exhibited significant correlations. The BADS found cognitive impairment in 31%, 70%, and 100% of patients with CDR0.5, CDR1, and CDR≥2, respectively. The FAI score differed according to the CDR severity in women but not in men. The overall profile and age-adjusted BADS scores were strongly correlated with the IADL in women but not in men., Conclusions: The greater the severity of executive dysfunction, the greater the difficulty in performing ADL. This effect was more pronounced in women and may predict dementia progression. Geriatr Gerontol Int 2021; 21: 1111-1117., (© 2021 Japan Geriatrics Society.)

Aim: The amyloid cascade hypothesis posits that the accumulation of amyloid β (Aβ) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging., Methods: Path analysis was used to estimate the relationships among Aβ accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aβ-positive subjects. We also performed additional regression analyses to evaluate the effect of Aβ on the toxicity of tau aggregation/neuroinflammation., Results: Path analysis supported our hypothesized model: Aβ accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB-positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB-positive and PiB-negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant., Conclusion: Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aβ not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease., (© 2020 Japanese Psychogeriatric Society.)

Background: There is a dearth of longitudinal data on body composition, function, and physical performance in persons with Alzheimer's disease (AD)., Objectives: The aim was to describe the trajectories of function, body composition, and physical performance in older adults with AD., Methods: In this retrospective cohort study, data were collected from older adults (n=1402) diagnosed with AD (mean age: 78.1 y old, women: 69.3%). Cognitive function was assessed using the mini-mental state examination. Proxy-reported instrumental and basic activities of daily living were assessed using the Lawton and Barthel indexes. Body composition was assessed using bioelectrical impedance analysis. Physical performance was assessed using the timed up and go test and grip strength., Results: Median (interquartile range) of follow-up time was 2.2 (1.2 to 3.6) years. Participants' mini-mental state examination score, Barthel index, and Lawton index declined over time. Skeletal muscle mass index and physical performance (timed up and go test and grip strength) decreased, while fat mass index increased with time. No significant changes or slight decline in weight and body mass index was observed., Conclusions: Muscle mass and physical performance are likely to decline in older adults with AD. Clinicians should assess muscle mass and physical performance trajectories regularly in these patients and intervene appropriately., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mild cognitive impairment (MCI) is a precursor to Alzheimer's disease (AD), but not all MCI patients develop AD. Biomarkers for early detection of individuals at high risk for MCI-to-AD conversion are urgently required., Methods: We used blood-based microRNA expression profiles and genomic data of 197 Japanese MCI patients to construct a prognosis prediction model based on a Cox proportional hazard model. We examined the biological significance of our findings with single nucleotide polymorphism-microRNA pairs (miR-eQTLs) by focusing on the target genes of the miRNAs. We investigated functional modules from the target genes with the occurrence of hub genes though a large-scale protein-protein interaction network analysis. We further examined the expression of the genes in 610 blood samples (271 ADs, 248 MCIs, and 91 cognitively normal elderly subjects [CNs])., Results: The final prediction model, composed of 24 miR-eQTLs and three clinical factors (age, sex, and APOE4 alleles), successfully classified MCI patients into low and high risk of MCI-to-AD conversion (log-rank test P = 3.44 × 10 -4 and achieved a concordance index of 0.702 on an independent test set. Four important hub genes associated with AD pathogenesis (SHC1, FOXO1, GSK3B, and PTEN) were identified in a network-based meta-analysis of miR-eQTL target genes. RNA-seq data from 610 blood samples showed statistically significant differences in PTEN expression between MCI and AD and in SHC1 expression between CN and AD (PTEN, P = 0.023; SHC1, P = 0.049)., Conclusions: Our proposed model was demonstrated to be effective in MCI-to-AD conversion prediction. A network-based meta-analysis of miR-eQTL target genes identified important hub genes associated with AD pathogenesis. Accurate prediction of MCI-to-AD conversion would enable earlier intervention for MCI patients at high risk, potentially reducing conversion to AD.

Background: With demographic shifts toward older populations, the number of people with dementia is steadily increasing. Alzheimer's disease (AD) is the most common cause of dementia, and no curative treatment is available. The current best strategy is to delay disease progression and to practice early intervention to reduce the number of patients that ultimately develop AD. Therefore, promising novel biomarkers for early diagnosis are urgently required., Methods: To identify blood-based biomarkers for early diagnosis of AD, we performed RNA sequencing (RNA-seq) analysis of 610 blood samples, representing 271 patients with AD, 91 cognitively normal (CN) adults, and 248 subjects with mild cognitive impairment (MCI). We first estimated cell-type proportions among AD, MCI, and CN samples from the bulk RNA-seq data using CIBERSORT and then examined the differentially expressed genes (DEGs) between AD and CN samples. To gain further insight into the biological functions of the DEGs, we performed gene set enrichment analysis (GSEA) and network-based meta-analysis., Results: In the cell-type distribution analysis, we found a significant association between the proportion of neutrophils and AD prognosis at a false discovery rate (FDR) < 0.05. Furthermore, a similar trend emerged in the results of routine blood tests from a large number of samples (n = 3,099: AD, 1,605; MCI, 994; CN, 500). In addition, GSEA and network-based meta-analysis based on DEGs between AD and CN samples revealed functional modules and important hub genes associated with the pathogenesis of AD. The risk prediction model constructed by using the proportion of neutrophils and the most important hub genes (EEF2 and RPL7) achieved a high AUC of 0.878 in a validation cohort; when further applied to a prospective cohort, the model achieved a high accuracy of 0.727., Conclusions: Our model was demonstrated to be effective in prospective AD risk prediction. These findings indicate the discovery of potential biomarkers for early diagnosis of AD, and their further improvement may lead to future practical clinical use.

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Aim: To investigate the association between decline of basic activities of daily living (ADL) in each dimension and change in caregiver burden in patients with mild-to-moderate Alzheimer's disease., Methods: This retrospective study included 117 outpatients with Alzheimer's disease who presented to the Memory Clinic at the National Center for Geriatrics and Gerontology in Japan between September 2010 and April 2014 (mean age 77.3 ± 6.4 years; 68.6% women). Patients and their caregivers completed comprehensive geriatric assessment at baseline and at the 3-year follow up. Caregiver burden was assessed using the Japanese version of the Zarit Burden Interview. ADL were assessed by the Barthel Index. Among patients with full points on each subitem of the Barthel Index at baseline, incident ADL decline was defined as a loss of at least 5 points at the 3-year follow up. Other confounding factors including demographic data, cognitive function, vitality, and behavioral and psychiatric symptoms of dementia were also assessed. The longitudinal relationship between incident ADL decline and changes in caregiver burden was evaluated by multivariate linear regression, adjusted for confounding variables., Results: In descending order, declines in ADL at 3 years were noted in bathing (25.4%), bowel control (25.4%), grooming (22.9%) and bladder control (22.9%). On multivariate analyses, ADL declines in feeding (b = 17.2, P < 0.01) and bathing (b = 11.0, P = 0.02) were significantly associated with increased caregiver burden., Conclusion: Incident ADL declines in feeding and bathing are significant risk factors for increased caregiver burden in patients with Alzheimer's disease. Geriatr Gerontol Int 2019; 19: 1243-1247., (© 2019 Japan Geriatrics Society.)

We examined the nutritional status and its association with behavioral psychiatric symptoms of dementia (BPSD) among 741 memory clinic patients (normal cognition (NC), 152; mild cognitive impairment (MCI), 271; early-stage Alzheimer disease (AD), 318). Nutritional status and BPSD were assessed using the Mini Nutritional Assessment Short-Form (MNA-SF) and the Dementia Behavior Disturbance Scale (DBD), respectively. Compared to subjects with NC, more subjects with MCI and early-stage AD were at risk of malnutrition (MNA-SF, 8-11: NC, 34.2%; MCI, 47.5%; early-stage AD, 53.8%) and were malnourished (MNA-SF, 0-7: NC, 4.6%; MCI, 5.9%; early-stage AD, 8.2%). Among patients with MCI or early-stage AD, those at risk of/with malnutrition showed higher DBD scores than those well-nourished (12.7 ± 9.0 vs. 9.5 ± 7.3; p < 0.001). Moreover, analysis of covariance adjusting for confounders showed that nutritional status was significantly associated with specific BPSD, including "verbal aggressiveness/emotional disinhibition" (F = 5.87, p = 0.016) and "apathy/memory impairment" (F = 15.38, p < 0.001), which were revealed by factor analysis of DBD. Our results suggest that malnutrition is common among older adults with mild cognitive decline, and possibility that nutritional problems are associated with individual BPSD.

Objective: The aim of this study was to clarify the association of physical frailty with behavioral and psychological symptoms of dementia (BPSD) and caregiver burden in patients with Alzheimer's disease (AD)., Methods: The subjects were 1,193 AD patients who presented to the Memory Clinic at the National Center for Geriatrics and Gerontology of Japan during the period from October 2010 to February 2015 (mean ± SD age = 78.8 ± 6.3 years; female, 68.6%). AD was diagnosed based on the criteria of the National Institute on Aging and Alzheimer's Association workgroups. The Frailty Index (FI) was calculated as the ratio of actual to 38 potential deficits. BPSD and caregiver burden were assessed by using the Dementia Behavior Disturbance Scale (DBD) and the Japanese version of Zarit Burden Interview (J-ZBI). Multiple linear regression analyses and structural equation modeling (SEM) were performed to examine the relationship between the FI, DBD, and J-ZBI., Results: The subjects' mean FI score was 0.16 ± 0.10, with 663 (55.6%) and 198 (16.6%) subjects shown to be pre-frail (0.08 ≤ FI < 0.25) and frail (FI ≥ 0.25), respectively. Multiple linear regression analyses and SEM showed that the FI was independently associated with both DBD (β = 0.30, P < .001) and J-ZBI (β = 0.13, P < .001). Moreover, when the FI was considered as a categorical variable, even pre-frailty was associated with increased DBD score (β = 0.16, P < .001) and J-ZBI score (β = 0.09, P = .003)., Conclusions: The presence of not only physical frailty but also pre-frailty, as determined by the FI, could increase BPSD and caregiver burden in patients with AD., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Although the aggregation of amyloid-β peptide (Aβ) clearly plays a central role in the pathogenesis of Alzheimer's disease (AD), endosomal traffic dysfunction is considered to precede Aβ aggregation and trigger AD pathogenesis. A body of evidence suggests that the β-carboxyl-terminal fragment (βCTF) of amyloid-β precursor protein (APP), which is the direct precursor of Aβ, accumulates in endosomes and causes vesicular traffic impairment. However, the mechanism underlying this impairment remains unclear. Here we identified TMEM30A as a candidate partner for βCTF. TMEM30A is a subcomponent of lipid flippase that translocates phospholipids from the outer to the inner leaflet of the lipid bilayer. TMEM30A physically interacts with βCTF in endosomes and may impair vesicular traffic, leading to abnormally enlarged endosomes. APP traffic is also concomitantly impaired, resulting in the accumulation of APP-CTFs, including βCTF. In addition, we found that expressed BACE1 accumulated in enlarged endosomes and increased Aβ production. Our data suggested that TMEM30A is involved in βCTF-dependent endosome abnormalities that are related to Aβ overproduction., Competing Interests: The authors have declared that no competing interests exist.

Aim: Appetite loss has been associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Among older people, decreased appetite can result in poor nutrition and subsequent loss of independent living. We examined the factors related to appetite loss in persons with AD and MCI to provide evidence for countermeasures to prevent appetite loss and progression of cognitive impairment., Methods: We included 1238 older adults undergoing outpatient treatment at the Center for Comprehensive Care and Research on Memory Disorders (Medical Center for Dementia) at the National Center for Geriatrics and Gerontology in Obu, Japan. The Council on Nutrition Appetite Questionnaire, an appetite questionnaire for older people, was used to evaluate appetite. Appetite loss in persons diagnosed with AD or MCI was divided into two groups according to the Council on Nutrition Appetite Questionnaire scores, and logistic regression analysis was carried out to identify independent factors associated with appetite loss. The following variables were used to evaluate for covariates: general information, functional evaluation and medications., Results: The AD and MCI groups contained 853 and 385 individuals, respectively. In both groups, depression and difficulty in maintaining attention while eating were significantly associated with poor appetite. Among persons with AD, lower vitality, more comorbidities, non-use of antidementia drugs and use of psychotropic drugs were also significantly associated with poor appetite., Conclusions: The present study recognized possible factors individually associated with appetite loss among persons with AD or MCI. Future studies are required to examine supportive strategies to treat poor appetite in these populations. Geriatr Gerontol Int 2018; 18: 1236-1243., (© 2018 Japan Geriatrics Society.)

Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-β deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-β-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-β-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-β-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-β-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-β deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-β deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.

Aim: The principal aim of the present study was to clarify what type of cognitive decline results in a decrease in the ability to carry out activities of daily living (ADL) in patients with Alzheimer's disease (AD)., Methods: The participants comprised 1384 outpatients with mild AD. We used the Mini-Mental State Examination (MMSE) and Barthel Index (BI) as indicators of basic ADL, and the Lawton Index (LI) as an indicator of instrumental ADL (IADL). We then analyzed the relationships between MMSE and BI, as well as between MMSE and LI. We also carried out a logistic regression analysis with BI and LI subitems as dependent variables, and MMSE subitems as independent variables., Results: For almost all BI and LI subitems, significantly high odds ratios (OR) were noted in MMSE "Copy the design shown" (e.g. dressing OR 3.66, toilet use OR 3.60 and transfers OR 2.80) and "Write a sentence" (e.g. ability to use telephone OR 5.24, laundry OR 2.60, grooming OR 2.50; P < 0.05)., Conclusions: Visuospatial cognition had an important effect on the decrease in basic ADL and IADL. Furthermore, the subitems with minimal effect on the decrease of basic ADL and IADL differed. Therefore, it appears that specific activities have little effect on the maintenance of ADL and IADL, and that determining residual cognitive function and utilizing this as a means of compensating for decreased ADL is a useful strategy. Geriatr Gerontol Int 2018; 18: 50-56., (© 2017 Japan Geriatrics Society.)

Objectives: We investigated the differences in the physical function test results across stages from normal cognition (NC) to moderate Alzheimer disease (AD) and how risk factors of physical function decline are correlated with the physical function test results., Design: A cross-sectional study of outpatients at the Memory Disorder Outpatient Center of Japan's National Center of Geriatrics and Gerontology., Participants: We enrolled 882 individuals aged ≥65 diagnosed with NC (n = 210), amnestic mild cognitive impairment (aMCI; n = 273), mild AD (n = 181) or moderate AD (n = 197)., Measurements: We measured the participants' results for functional reach (FR), the one-leg standing (OLS) test, the Timed Up and Go (TUG) test, tandem gait (TG), and grip strength (GS). A one-way analysis of covariance (ANCOVA) was used to identify significant differences among the groups' results on the physical function tests, controlling for age, sex, educational year, Mini-Nutritional Assessment, senior activity and exercise frequency, low-density lipoprotein, body mass index, free-fat mass index, and assistance for the TUG test. Multiple regression analysis was also used to investigate the correlation between these covariates and physical function tests results., Results: The ANCOVA showed that FR, OLS, and TG were significantly worse among the individuals with aMCI, mild AD, or moderate AD compared with NC. However, TUG was significantly worse only in the moderate AD group compared with the NC, aMCI, and mild AD group. Multiple regression analysis showed that aging was correlated with poorer scores on all physical function tests, women had poorer scores on FR and GS than men, and low frequency of senior activity was significantly correlated with poorer scores on FR, OLS, and TG., Conclusion: Postural impairment and instability on TG was seen in earlier AD stages compared with instability on TUG. As were the covariates of age and sex, senior activity frequency was significantly related to 2 or more physical function tests., (Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Instrumental activities of daily living (IADL) start to decline during the progression of amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD). Cognitive and physical decline are involved in the loss of functional independence. However, little is known about AD-related neural change that leads to IADL impairment. The purpose of this study was to clarify the effects of regional white matter hyperintensity (WMH) on IADL impairment in persons with AD and aMCI., Methods: The participants were 347 female subjects aged 65-85 years diagnosed with AD (n = 227), aMCI (n = 44) or normal cognition (n = 76). IADL was assessed by the Lawton Index. Cognition, mood and mobility function were evaluated by comprehensive geriatric assessment batteries. WMH and brain atrophy were analyzed with brain magnetic resonance imaging, using an automatic segmentation program. Regional WMH was measured in the frontal, temporal, occipital and parietal lobes., Results: Ability to carry out IADL of shopping, food preparation, mode of transportation, responsibility for own medication, and ability to handle finances was obviously impaired in the early stage of AD. Frontal WMH was specifically associated with disability to do shopping and food preparation even after adjusting for several confounders including brain atrophy., Conclusions: IADL subcategories were differentially impaired along with cognitive status in persons with AD and aMCI. Frontal WMH was an important predictor of impaired ability to do shopping and food preparation. A preventive strategy for WMH might lead to suppression of IADL disability and slow the progression of AD.

Background: Weight loss is frequently observed in patients with Alzheimer's disease (AD); however, the underlying mechanisms are not well understood., Objects: To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI., Methods: The subjects were 34 amyloid-β (Aβ)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aβ-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between nutritional status and brain changes were examined by multiple regression analysis using statistical parametric mapping., Results: In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aβ deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas., Conclusion: This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role.

Background: Urinary incontinence (UI) is frequently observed in patients with Alzheimer's disease (AD). Although previous works highlight the association between frontal lobe-related function and UI, causal relationship is unclear., Objects: To clarify the longitudinal association between frontal lobe function and the incidence of UI at 1 year in patients with AD., Methods: The subjects were 215 continent AD patients who attended the Memory Clinic of the National Center for Geriatrics and Gerontology of Japan during the period from March 2011 to December 2014. The absence or presence of UI was operationally assigned by the dementia behavior disturbance scale subscale, which was completed by the patients' caregivers. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB). Other confounding factors including demographic data, cognitive status, vitality, mood, physical performance, and use of medication (cholinesterase inhibitors, calcium channel blockers [CCBs], diuretics, alpha blockers and anticholinergic drugs) were assessed., Results: During 1-year follow up (mean: 377.4±83.7 days), the incidence of UI was 12.1% (n = 26). Patients with UI had significantly lower FAB performance at baseline (no UI versus UI = 9.3±2.8 versus 7.8±2.7). In multivariate analysis, stepwise logistic regression analysis demonstrated that FAB (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.66-0.94) and the use of CCB (OR = 2.72, 95% CI = 1.09-6.77) were significantly associated with UI at 1 year., Conclusion: The results of study indicate that frontal lobe dysfunction is predictor for UI in patients with AD.

Amyloid-β (Aβ) oligomers are recognized as the primary neurotoxic agents in Alzheimer's disease (AD). Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline in AD. Nicotinamide adenine dinucleotide (NAD(+)), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in Aβ toxicity in AD. One of the key precursors of NAD(+) is nicotinamide mononucleotide (NMN), a product of the nicotinamide phosphoribosyltransferase reaction. To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the NAD(+) precursor NMN on Aβ oligomer-induced neuronal death and cognitive impairment were studied in organotypic hippocampal slice cultures (OHCs) and in a rat model of AD. Treatment of intracerebroventricular Aβ oligomer infusion AD model rats with NMN (500mg/kg, intraperitoneally) sustained improvement in cognitive function as assessed by the Morris water maze. In OHCs, Aβ oligomer-treated culture media with NMN attenuated neuronal cell death. NMN treatment also significantly prevented the Aβ oligomer-induced inhibition of LTP. Furthermore, NMN restored levels of NAD(+) and ATP, eliminated accumulation of reactive oxygen species (ROS) in the Aβ oligomer-treated hippocampal slices. All these protective effects were reversed by 3-acetylpyridine, which generates inactive NAD(+). The present study indicates that NMN could restore cognition in AD model rats. The beneficial effect of NMN is produced by ameliorating neuron survival, improving energy metabolism and reducing ROS accumulation. These results suggest that NMN may become a promising therapeutic drug for AD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Protein inclusions in neurodegenerative diseases are associated with p62, which has an important role in autophagic clearance of polyubiquitinated proteins. Selective autophagy is regulated by S403-phosphorylation of p62, and S403-phosphorylated p62 (S403-phos-p62) accumulates in Atg5 conditional knockout (Atg5CKO) mice in which autophagosome formation is impaired. We performed immunohistochemical tests for the presence of S403-phos-p62 in postmortem brain of neurodegenerative disease cases, and found accumulations in amyotrophic lateral sclerosis and Alzheimer's disease tissues. In Atg5CKO and HD190QG (Huntington's disease model) mice, however, we found a postmortem decrease in S403-phos-p62 immunoreactivity, suggesting that post-mortem changes should be considered when interpreting human data., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Aim: Lower urinary tract symptoms often limit activities of daily life and impair quality of life in the elderly. The purpose of the present study was to determine whether regional white matter hyperintensity (WMH) can predict lower urinary tract symptoms in elderly with amnestic mild cognitive impairment or Alzheimer's disease., Methods: The participants were 461 patients aged 65-85 years diagnosed with amnestic mild cognitive impairment or Alzheimer's disease. Patients and their caregivers were asked about symptoms of lower urinary tract symptoms (urinary difficulty, frequency and incontinence). Cognition, behavior and psychological symptoms of dementia and medication were evaluated. WMH and brain atrophy were analyzed using an automatic segmentation program. Regional WMH was evaluated in the frontal, parietal, temporal and occipital lobes., Results: Patients with urinary incontinence showed significantly greater volume of WMH. WMH increased with age, especially in the frontal lobe. WMH in the frontal lobe was closely associated with urinary incontinence after adjustment for brain atrophy and classical confounding factors., Conclusions: Frontal WMH was a predictive factor for urinary incontinence in older adults with amnestic mild cognitive impairment or Alzheimer's disease. Urinary incontinence in demented older adults is not an incidental event, and careful insight into regional WMH on brain magnetic resonance imaging might greatly help in diagnosing individuals with a higher risk of urinary incontinence., (© 2015 Japan Geriatrics Society.)

Background: To date, very little is known about the nature of sarcopenia in subjects with cognitive impairment. The aims of this study were firstly to clarify the prevalence of sarcopenia at various stages of cognitive impairment, and secondly to examine factors related to sarcopenia in men and women with cognitive impairment., Method: The subjects were 418 outpatients (normal cognition; NC: 35, amnestic mild cognitive impairment; aMCI: 40, Alzheimer disease; AD: 343) who attended the Memory Clinic at the National Center for Geriatrics and Gerontology of Japan during the period from October 2010 to July 2014. Cognitive status, vitality, depressive mood, body mass index, hand grip strength, timed up and go test, skeletal muscle mass and serum levels of 25-hydroxyvitamin D, albumin and creatinine were assessed. Sarcopenia was defined as the presence of both poor muscle function (low physical performance or low muscle strength) and low muscle mass. We performed the univariate and multivariate logistic regression analyses to explore factors associated with sarcopenia., Results: The overall prevalence of sarcopenia was 21.1% (NC = 8.6%, aMCI = 12.5%, AD = 23.3%). In both sexes, factors associated with sarcopenia were age (P < .01), body mass index (P < .001) and vitality (P < .05). In women, serum level of 25-hydroxyvitamin D was associated with sarcopenia (P < .05)., Conclusion: Low vitality could be a dementia-specific risk factor for sarcopenia. Prevention of sarcopenia in patients with cognitive impairment should be approached from physical and psychologic points of view.

Alzheimer's disease (AD) is a major neurodegenerative disease of old age, characterized by progressive cognitive impairment, dementia and atrophy of the central nervous system. Amyloid-β (Aβ) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and recognized as the primary neurotoxic agents in AD. Pyruvate has a protective effect against Aβ oligomer-induced neuronal cell death and inhibition of long-term potentiation (LTP) in hippocampal slice cultures, leading us to investigate the effect of systemic pyruvate administration in an intracerebroventricular Aβ oligomer infusion model. We found that sodium pyruvate (500 mg/kg, intraperitoneally) improved neuron survival and sustained improvement in cognitive function as assessed by the Morris water maze. Pyuvate prevented the Aβ oligomer-induced inhibition of LTP and protein phosphatase 2A (PP2A) activation. Pyruvate suppressed the Aβ oligomer-induced poly[adenosine diphosphate (ADP) ribose] polymerase-1 (PARP-1) activity and ameliorated Aβ oligomer-induced decrease of NAD(+) level. Moreover, pyuvate, but not lactate, decreased reactive oxygen species (ROS) accumulation in hippocampus of Aβ1-42 oligomer-injection rat model. These results suggest that systemic pyruvate administration could significantly ameliorate Aβ oligomer-induced spatial learning and memory impairment by the improvement of neuron survival and prevention of LTP inhibition, and the beneficial effect of pyruvate could be linked, at least in part, to the elimination of ROS accumulation, prevention of PP2A activation, amelioration of NAD(+) level and suppression of PARP-1 activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: It has been reported that periodontitis is associated with Alzheimer's disease. However, the association between paranasal sinusitis and Alzheimer's disease has not been studied, although olfactory dysfunction frequently precedes the progress of dementia or Alzheimer's disease., Methods: We studied 783 patients (283 men, 500 women; mean age 77.0 ± 7.9 years) who visited the Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, and 2139 control subjects who participated in a population-based study conducted by the National Institute for Longevity Sciences - Longitudinal Study of Aging (NILS-LSA) in Japan. Sinusitis was evaluated using magnetic resonance imaging (MRI) according to the Lund-Mackay scoring system. A sinusitis score of ≥ 4 was classified as positive and a score of ≤ 3 was classified as negative., Results: The prevalence of positive sinusitis was 6.3% in patients with a mini-mental state examination (MMSE) score of < 24 (n = 507), and 5.7% in patients with Alzheimer's disease (n = 280). The rate of positive sinusitis was7.2% in the control group. The prevalence of sinusitis was not significantly different between normal controls and patients with dementia or Alzheimer's disease after adjustments for age and sex. The rate of positive sinusitis was higher in male than in female subjects in both groups., Conclusion: The prevalence of sinusitis in patients with Alzheimer's disease or dementia was not higher than in the general population.

Aim: To investigate factors associated with caregiver burden (CB) in persons caring for older adults with various cognitive stages of Alzheimer's disease (AD)., Methods: Participants were 1127 outpatients and their caregivers. Participants comprised 120 older adults with normal cognition (NC), 126 with amnestic mild cognitive impairment (aMCI) and 881 with AD. AD patients were subclassified into four groups by Mini-Mental State Examination (MMSE) score: AD29-24 (n = 117), AD23-18 (n = 423), AD17-12 (n = 254) and AD11-0 (n = 87). Participants and their caregivers underwent comprehensive geriatric assessment batteries including Zarit Burden Interview (ZBI) Barthel Index, Lawton Index, Dementia Behavior Disturbance Scale (DBD) to evaluate CB, Instrumental and Basic Activity of Daily Living (IADL/BADL), and Behavioral and Psychological Symptoms of Dementia (BPSD). The comorbidity of geriatric syndrome and the living situation of the patient/caregiver were also assessed., Results: ZBI score was higher in patients with lower MMSE score. Multivariate regression analysis identified that DBD was consistently associated with CB in all patients; symptoms related to memory deficit were related to CB in aMCI; differential IADL, such as inability to use a telephone, use transportation, manage finances, shop, cook and take responsibility for own medication, were related to CB in AD29-24, AD23-18 and AD17-12, and geriatric syndrome including falls and motor disturbance, sleep problems, urinary incontinence, and fatigue was related to CB in AD23-18 and AD17-12., Conclusions: Multiple factors including BPSD, impaired life function and geriatric syndrome were cognitive stage-dependently associated with CB. Preventive treatment of BPSD and comorbidity, and effective assistance for IADL deficits could contribute to alleviation of CB., (© 2014 Japan Geriatrics Society.)

Aim: The clinical management of diabetic elderly patients with Alzheimer's disease (AD) is hindered by several difficulties. The present study aimed to clarify the clinical characteristics and pathophysiological properties of AD in diabetic older adults., Methods: A total of 91 patients with type 2 diabetes mellitus and 161 non-diabetic individuals who were diagnosed with AD were recruited. Diabetic patients were classified into two groups with glycated hemoglobin (HbA1c) < 7.0% or ≥ 7.0%. The demographics, cognition, daily-life function, metabolic changes, treatment, and behavioral and psychological symptoms of dementia (BPSD), as well as brain pathophysiology, were compared among the three groups., Results: Patients with higher HbA1c had increased diabetic vascular complications and impaired activities of daily living with decreased levels of serum high-molecular-weight adiponectin and 25-hydroxyvitamin D. Although cognitive status was similar among the three groups, BPSD, including apathy, overeating and excessive daytime sleeping appeared to be increased in the patients with HbA1c ≥ 7.0%. The frequency of apolipoprotein E4 carriers and of posterior cerebral hypoperfusion (AD-pattern) on single-photon emission computed tomography in poorly controlled diabetic subjects was similar to that in non-diabetic AD patients, whereas diabetic patients with HbA1c <7.0% included fewer apolipoprotein E4 carriers and fewer patients with an AD pattern on single-photon emission computed tomography., Conclusion: Subtypes of older diabetic patients with AD were identified based on clinical features and brain pathophysiology. Physical and psychological complications of dementia are prevalent in patients with higher HbA1c. It seems likely that difficulties in the management of diabetes with AD are due not only to non-adherence to diabetes treatment, but also several symptoms and pathophysiological characteristics of dementia., (© 2014 Japan Geriatrics Society.)

Objectives: Preventive strategy for falls in demented elderly is a clinical challenge. From early-stage of Alzheimer's disease (AD), patients show impaired balance and gait. The purpose of this study is to determine whether regional white matter lesions (WMLs) can predict balance/gait disturbance and falls in elderly with amnestic mild cognitive impairment (aMCI) or AD., Design: Cross-sectional., Settings: Hospital out-patient clinic., Participants: One hundred sixty-three patients diagnosed with aMCI or AD were classified into groups having experienced falls (n = 63) or not (n = 100) in the previous year., Measurements: Cognition, depression, behavior and psychological symptoms of dementia, medication, and balance/gait function were evaluated. Regional WMLs were visually analyzed as periventricular hyperintensity in frontal caps, bands, and occipital caps, and as deep white matter hyperintensity in frontal, parietal, temporal, and occipital lobes, basal ganglia, thalamus, and brain stem. Brain atrophy was linearly measured., Results: The fallers had a greater volume of WMLs and their posture/gait performance tended to be worse than nonfallers. Several WMLs in particular brain regions were closely associated with balance and gait impairment. Besides polypharmacy, periventricular hyperintensity in frontal caps and occipital WMLs were strong predictors for falls, even after potential risk factors for falls were considered., Conclusions: Regional white matter burden, independent of cognitive decline, correlates with balance/gait disturbance and predicts falls in elderly with aMCI and AD. Careful insight into regional WMLs on brain magnetic resonance may greatly help to diagnose demented elderly with a higher risk of falls., (Copyright © 2014 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most common and devastating dementia. Simple and practical biomarkers for AD are urgently required for accurate diagnosis and to facilitate the development of disease-modifying interventions. The subjects for the study were selected on the basis of PiB amyloid imaging by PET. Forty PiB-positive (PiB+) individuals, including cognitively healthy controls (HC), and mild cognitive impairment and AD individuals, and 22 PiB-negative (PiB-) HC participated. Employing our novel highly sensitive immunoprecipitation-mass spectrometry, we measured plasma amyloid β-proteins (Aβs; Aβ1-40 and Aβ1-42) and Aβ-approximate peptides (AβAPs), which were cleaved from amyloid precursor protein (APP). Among the AβAPs, APP669-711 appeared to be a good reference for deciphering pathological change of Aβ1-42. We evaluated the performance of the ratio of APP669-711 to Aβ1-42 (APP669-711/Aβ1-42) as a biomarker. APP669-711/Aβ1-42 significantly increased in the PiB+ groups. The sensitivity and specificity to discriminate PiB+ individuals from PiB- individuals were 0.925 and 0.955, respectively. Our plasma biomarker precisely surrogates cerebral amyloid deposition.