An 18-month multimodal intervention trial for preventing dementia: J-MINT PRIME Tamba.

BACKGROUND: The number of people with dementia is increasing in Japan, and establishing evidence for preventing dementia is necessary. METHODS: This study was a randomized controlled trial in cognitively normal community-dwelling older adults aged 65 to 85 with diabetes and/or hypertension. Participants were randomly assigned in a 1:1 ratio. The intervention group underwent 90 min of group-based weekly physical exercise, cognitive training, nutritional counseling, and vascular risk management for 18 months. The primary endpoint was the change in a cognitive composite score calculated by averaging the z-scores of seven neuropsychological tests from baseline to 18 months. RESULTS: We randomly assigned 203 participants to two groups, and 178 (87.7%) completed the 18-month follow-up. There was a significant group difference in the cognitive composite score change at 18 months (mean difference 0.16, 95% confidence interval: 0.04 to 0.27; p = 0.009). DISCUSSION: An 18-month multimodal intervention for older adults at risk of dementia could improve their cognitive function. The trial was registered in the Clinical Trial Registration System (UMIN000041938). HIGHLIGHTS: Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT) PRIME Tamba was a randomized controlled trial to prevent dementia. We provided a multifactorial intervention based on the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial methodology. The primary outcome, the cognitive composite score, improved with our intervention. Executive function/processing speed and memory improved in the intervention group. Intervention adherence was high, and no serious adverse events occurred.

Dorsal Anterior Cingulate Cortex Coordinates Contextual Mental Imagery for Single-Beat Manipulation during Rhythmic Sensorimotor Synchronization.

Flexible pulse-by-pulse regulation of sensorimotor synchronization is crucial for voluntarily showing rhythmic behaviors synchronously with external cueing; however, the underpinning neurophysiological mechanisms remain unclear. We hypothesized that the dorsal anterior cingulate cortex (dACC) plays a key role by coordinating both proactive and reactive motor outcomes based on contextual mental imagery. To test our hypothesis, a missing-oddball task in finger-tapping paradigms was conducted in 33 healthy young volunteers. The dynamic properties of the dACC were evaluated by event-related deep-brain activity (ER-DBA), supported by event-related potential (ERP) analysis and behavioral evaluation based on signal detection theory. We found that ER-DBA activation/deactivation reflected a strategic choice of motor control modality in accordance with mental imagery. Reverse ERP traces, as omission responses, confirmed that the imagery was contextual. We found that mental imagery was updated only by environmental changes via perceptual evidence and response-based abductive reasoning. Moreover, stable on-pulse tapping was achievable by maintaining proactive control while creating an imagery of syncopated rhythms from simple beat trains, whereas accuracy was degraded with frequent erroneous tapping for missing pulses. We conclude that the dACC voluntarily regulates rhythmic sensorimotor synchronization by utilizing contextual mental imagery based on experience and by creating novel rhythms.

Efficacy of a non-pharmaceutical multimodal intervention program in a group setting for patients with mild cognitive impairment: A single-arm interventional study with pre-post and external control analyses.

Aim: This study aimed to evaluate the efficacy of a non-pharmaceutical multimodal intervention program consisting of physical exercise, cognitive stimulation, and health education in a group setting to slow the progression of mild cognitive impairment (MCI). Methods: A single-arm interventional study was conducted on 27 patients with MCI. To evaluate the efficacy of the intervention program, a pre-post analysis was performed using EuroQol-5 Dimension (EQ-5D), Mini-Mental State Examination (MMSE), Cognitive Function Instrument (CFI), 5 Cog test, depression, and physical performance before and after the 8-month intervention. Additionally, propensity score and the semi-Bayes analyses were performed to compare the intervention program with standard medical care, using the external control patients' data for MMSE scores. Results: Twenty-four patients completed the intervention program. During the study period, although EQ-5D and MMSE scores remained unchanged (mean change 0.02 [95 % confidence interval (CI): -0.004, 0.04], 0.5 [-0.2, 1.3]), CFI and the subcategories of 5Cog (attention and reasoning) improved (mean change -1.23 [-2.24, -0.21], 4.3 [0.9, 7.7], 3.0 [0.4, 5.6]). In the additional analysis comparing changes in MMSE scores, patients who underwent the intervention program had less decline than the external control patients (mean change -1.7 [-2.1, -1.3]) with an observed mean difference of 2.25 [1.46, 3.03], and propensity score-adjusted difference of 2.26 [1.46, 3.05]. The semi-Bayesian approach also suggested that the intervention slowed the progression of MCI. Conclusion: A non-pharmaceutical multimodal intervention program could contribute to slowing cognitive decline in patients with MCI.

Combining plasma Aß and p-tau217 improves detection of brain amyloid in non-demented elderly.

BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-ß (Aß)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aß-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aß and p-tau217 assessments, and Aß-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aß(1-42) (Aß42) and Aß(1-40) (Aß40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aß-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aß42/Aß40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aß-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aß42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aß42/Aß40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aß42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aß42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aß42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aß-related biomarkers and p-tau217 exhibits high performance when predicting Aß-PET positivity. Adding basic clinical information (i.e., age, sex, APOE Îµ genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aß-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.

Survey on the current situation for early diagnosis of dementia and contributing factors in Japan.

BACKGROUND: Early diagnosis of dementia is important for both initiation of non-pharmacological activities to slow cognitive decline as well as the development of disease-modifying drugs; however, it appears there may be a tendency for formal diagnosis to be delayed. Since the current status of diagnosis in Japan is unclear, we conducted a survey with family caregivers of patients with dementia using questionnaires and interviews to investigate the factors regarding the dementia diagnosis process in Japan. METHODS: We distributed questionnaires to family caregivers of people with dementia and conducted additional follow-up interviews with approximately half of them. We calculated odds ratios for the time to diagnosis using logistic regression analysis for each characteristic from the questionnaire data. We also created co-occurrence networks from the interview data in order to provide qualitative context to the questionnaire data. RESULTS: We collected 68 questionnaires and conducted 32 interviews. The median time to diagnosis was 12 months, and logistic regression analysis showed a significant trend toward shorter time to diagnosis in the absence of other caregivers. In addition, there were significant differences in age, relationship with patients and the time from the first visit to the final diagnosis between groups with and without other caregivers. CONCLUSIONS: The results of this study suggest that the presence or absence of other caregivers may affect caregivers' behaviour and the time taken to receive a diagnosis of dementia. These findings indicate it may be beneficial to predict inhibiting factors and change approaches based on caregivers' and patients' background to promote early diagnosis.

Tooth Loss as a Predictor of Long-Term Care Requirements in the Elderly: A Study in Kobe City, Japan.

INTRODUCTION: The Kobe project, which utilizes prospective data from the national health insurance system, focuses on early detection and preventive strategies through the Frail Kenshin health check-up program. Previous research has underscored the correlation between tooth loss and the decline in physical and cognitive functions. In this study, using Kobe project data, we examined the link between remaining teeth and long-term care needs in individuals aged 64-65 years, with primary and secondary objectives involving various health parameters and quality of life. METHODS: We analyzed baseline data from a prospective study conducted alongside the Frail Check program for generally healthy individuals aged 64-65 years to examine the relationship between the number of remaining teeth and various health indicators. This study focused on citizens aged 64-65 years to identify those at risk of needing long-term care by the age of 65 years. RESULTS: Data from 1,530 participants were obtained, excluding eight individuals for specific reasons. At the end of the follow-up period, 41 (2.7%) individuals required support and 15 (1.0%) needed long-term care alone. The data revealed a significant association between the number of remaining teeth and the need for long-term care or support, as demonstrated by the Cochran-Armitage trend test (p<0.001). Although trends were noted for nutrition and total Cognitive Functional Instrument Self scores, they did not reach statistical significance. Additionally, a decrease in the number of remaining teeth was significantly associated with worse European Quality of Life Five Dimensions (EQ-5D-5L) visual analog scale scores, mobility, and regular activities (p<0.001). CONCLUSION: Tooth loss indicates the potential long-term care needs of older adults. Monitoring oral health is crucial for addressing care requirements.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Action-rule-based cognitive control enables efficient execution of stimulus-response conflict tasks: a model validation of Simon task performance.

Introduction: The human brain can flexibly modify behavioral rules to optimize task performance (speed and accuracy) by minimizing cognitive load. To show this flexibility, we propose an action-rule-based cognitive control (ARC) model. The ARC model was based on a stochastic framework consistent with an active inference of the free energy principle, combined with schematic brain network systems regulated by the dorsal anterior cingulate cortex (dACC), to develop several hypotheses for demonstrating the validity of the ARC model. Methods: A step-motion Simon task was developed involving congruence or incongruence between important symbolic information (illustration of a foot labeled "L" or "R," where "L" requests left and "R" requests right foot movement) and irrelevant spatial information (whether the illustration is actually of a left or right foot). We made predictions for behavioral and brain responses to testify to the theoretical predictions. Results: Task responses combined with event-related deep-brain activity (ER-DBA) measures demonstrated a key contribution of the dACC in this process and provided evidence for the main prediction that the dACC could reduce the Shannon surprise term in the free energy formula by internally reversing the irrelevant rapid anticipatory postural adaptation. We also found sequential effects with modulated dip depths of ER-DBA waveforms that support the prediction that repeated stimuli with the same congruency can promote remodeling of the internal model through the information gain term while counterbalancing the surprise term. Discussion: Overall, our results were consistent with experimental predictions, which may support the validity of the ARC model. The sequential effect accompanied by dip modulation of ER-DBA waveforms suggests that cognitive cost is saved while maintaining cognitive performance in accordance with the framework of the ARC based on 1-bit congruency-dependent selective control.

Association between locomotive syndrome and anemia among community-dwelling older adults.

AIM: To investigate the association between locomotive syndrome and anemia among community-dwelling older adults. METHODS: This cross-sectional study was conducted at specific health checkup centers in Japan between 2019 and 2020. We sent a questionnaire to older adults aged ≥65 years who participated in health checkups. A total of 2507 community-dwelling older adults were included in this study (mean age = 72.3 years, 51.4% women). Locomotive syndrome was measured using a 25-question Geriatric Locomotive Function Scale with a score range of 0-100, and was defined as ≥16 points. Anemia was defined using World Health Organization criteria, as a hemoglobin concentration of <13.0 g/dL in men and <12.0 g/dL in women. Logistic regression analyses were performed to investigate the association between locomotive syndrome and anemia, adjusted for age, sex, body mass index, depression symptoms, self-reported comorbidities (cancer, rheumatoid arthritis, knee osteoarthritis, fractures, and spinal disease), hypertension, and renal function. RESULTS: Of all the participants, 11.6% had locomotive syndrome and 12.8% had anemia. Even after adjustment, a relationship between locomotive syndrome and anemia was observed (adjusted odds ratio = 1.9, 95% confidence interval = 1.3-2.7). CONCLUSIONS: Community-dwelling older adults with anemia had a significantly higher prevalence of locomotive syndrome than those without. This finding suggests that older adults with anemia are at risk of locomotive syndrome, and appropriate measures should be taken for prevention. Geriatr Gerontol Int 2023; 23: 426-429.

The Japan-Multimodal Intervention Trial for Prevention of Dementia PRIME Tamba (J-MINT PRIME Tamba): Study protocol of a randomised controlled multi-domain intervention trial.

The Japan-Multimodal Intervention Trial for Prevention of Dementia PRIME Tamba (J-MINT PRIME Tamba) is a randomised controlled trial to prevent cognitive decline in community-dwelling cognitively ordinary older people at risk of dementia. Participants are aged 65-85 years living in a rural area in Japan, aware of very mild decline in cognitive function or abilities of activities of daily living, have at least one vascular risk (e.g. hypertension or diabetes), and have a Mini-Mental State Examination score of 24 or higher. Approximately 200 participants are randomly divided into two groups, with the intervention group receiving a multi-modal intervention, including lifestyle-related disease management, physical exercise, cognitive training, and nutritional counselling, over 18 months. The primary outcome is change in the composite score of seven neuropsychological tests, including the Free and Cued Selective Reminding Test, Logical Memory I and II subsets of the Wechsler Memory Scale-Revised, and Digit Symbol Substitution Test of the Wechsler Adult Intelligence Scale. In addition, changes in a wide range of other parameters such as physical function, blood test results, sleep, and frailty are also analysed as secondary outcomes. We believe that this study's results will contribute significantly to the development of dementia prevention measures in Japan. Clinical trial registration number: UMIN000041938.

Self Assessment Memory Scale (SAMS), a new simple method for evaluating memory function.

We have developed a new method for easy self-assessment of changes in memory recall impairment, which can be used during the very early stages of dementia. An 8-picture recall and a 16-word regression were assessed, respectively, and the index was calculated by adding up the ratio of correct responses to both tests. A total of 85 subjects including 12 MCI, 8 AD, and 65 older persons with normal cognitive function were evaluated, and the correlation with the WMS-R Logical Memory II score was examined. The results showed that there was a statistically significant correlation between the 8-picture recall (R = 0.872, p < 0.0001) and the index (R = 0.857, p < 0.0001), respectively, with the Logical Memory score. We have named this index as Self Assessment Memory Scale (SAMS), and are now developing a digital tool to enable easy and self-administered evaluation of recall.

Implication of using cognitive function-related simple questions to stratify the risk of long-term care need: population-based prospective study in Kobe, Japan.

BACKGROUND: This study investigated how cognitive function-related simple questions can be used to identify older individuals who are at risk of needing long-term care. METHODS: This cohort study was conducted in Kobe city, Japan. In 2015, the municipal office distributed the Kihon Checklist by post, a 25-item questionnaire including three cognitive function-related questions (questions 18, 19, 20) to citizens aged ≥ 70 years. Need certification is routinely done by Kobe city as part of the national Long-Term Care Insurance Act. The answers to the 2015 questionnaire were merged with need certification data between the questionnaire delivery and the end of December 2019. RESULTS: Of the 77,877 citizens (age: 72.9 ± 2.7 years) who received the questionnaire, 50,154 responded (response rate: 64.4%). During the study period, the cumulative incidence of the need for long-term care was higher in those who did not respond than in those who did (12.5% vs 8.4%; P < 0.001). Among those who responded, the incidence of the need for long-term care was progressively greater as the number of negative answers to cognitive function-related questions increased (5.0%, 8.4%, 15.7% and 30.2% at 4 years' follow-up, for respondents with, respectively, 0, 1, 2 and 3 negative answers). Similarly, when the need certification for long-term care was confined to that accompanied by dementia, the incidence also rose as the number of negative responses to the cognitive function-related questions increased (3.4%, 6.5%, 13.7% and 27.9% for respondents with, respectively, 0, 1, 2 and 3 negative answers). Using multivariate Cox regression analysis, all three cognitive function-related questions were predictive of the need for long-term care, and question 18 (about memory loss) had the highest hazard ratio for predicting the need for long-term care accompanied by dementia. CONCLUSIONS: Use of cognitive function-related simple questions may help identify older adults at risk for needing long-term care, suggesting their potential value for use in administrative and policy approaches aimed at reducing the societal burden of dementia.

Discrepancy between distribution of alpha-synuclein oligomers and Lewy-related pathology in Parkinson's disease.

The pathological hallmarks of Parkinson's disease (PD) are α-synuclein (αSYN)-positive inclusions referred to as Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology (LRP). LRP is thought to propagate in an ascending manner throughout the brain as the disease progresses. LRP is visible with histologic methods and is thought to represent a later stage of the disease process, while αSYN oligomers, which are not visible with routine histologic methods, are considered earlier. There is increasing evidence to suggest that αSYN oligomers may be more toxic than visible LRP. Detecting αSYN oligomers requires special techniques, and their distribution and association with clinical features are important research objectives. In this report, we describe the distribution of αSYN oligomers in multiple cortical and subcortical regions of PD using a proximity ligation assay (PLA). We observe widespread distribution of αSYN oligomers with PLA and more restricted distribution of LRP with αSYN immunohistochemistry. The distribution of αSYN oligomers differed from LRP in that αSYN oligomer burden was significantly greater in the neocortex, while LRP was greater in vulnerable subcortical regions, including the brainstem. We also found that cognitive impairment was associated with αSYN oligomers in the hippocampus. These results suggest that αSYN oligomers may be widely distributed in PD early in the disease process and that they may contribute to cognitive impairment in PD.

Immunotherapy-responsive Non-paraneoplastic Encephalitis with Antibodies against GAD, LGI1, and GABAA Receptor.

A 62-year-old man showed abnormal behavior. Brain magnetic resonance imaging revealed multifocal lesions on T2-weighted images. Initial screening revealed that he was seropositive for antibodies against glutamate decarboxylase, which usually indicates treatment resistance to autoimmune encephalitis (AE). Intensive immunosuppressive therapies, however, improved the neurological symptoms. In line with this, we also detected seropositivity for antibodies against leucine-rich glioma-inactivated 1 and gamma-aminobutyric acid A receptor (GABAAR). Brain imaging and treatment responsiveness suggested that antibodies against GABAAR were the main cause of symptoms. Furthermore, the patient showed the presence of triple anti-neural antibodies in the absence of malignancy and had a favorable clinical course.

Effect of a Combined Exercise and Cognitive Activity Intervention on Cognitive Function in Community-dwelling Older Adults: A Pilot Randomized Controlled Trial.

OBJECTIVE: The purpose of this study is to investigate the effect of an intervention combining exercise and cognitive activity on cognitive function in healthy older adults. METHODS: This pilot randomized controlled trial recruited 33 eligible, healthy communitydwelling older adults (mean age, 77.1 years old; women, 51.5%), who were divided into intervention and waitlist control groups. The intervention group was engaged weekly in a group activity comprising exercise and discussions of homework, which included reading aloud, simple arithmetic, and simple activities, like spotting differences, for cognitive stimulation. They were also required to complete cognitive activity homework twice a week. The waitlist control group received no intervention. The main outcomes were cognitive function assessed using the Mini-Mental State Examination, delayed recall score on the Logical Memory IIA of the Wechsler Memory Scale Revised, Trail Making Test, and digit symbol substitution test. RESULTS: According to the results, Mini-Mental State Examination scores were maintained in the intervention group but declined in the control group [Mean change in outcomes in control group (95% confidence interval): -1.68 (-2.89 to -0.48)]. Additional mean change in outcomes in intervention group were found [1.68 (0.02 to 3.35)]. CONCLUSIONS: Interventions combining exercise and cognitive activity can be helpful for preserving cognitive function in healthy older adults.

Kobe project for the exploration of newer strategies to reduce the social burden of dementia: a study protocol of cohort and intervention studies.

INTRODUCTION: This research project addresses the lack of screening tools for the early detection of high-risk individuals for long-term care, through four individual studies.Study 1 investigates the predictive ability of the 'Kihon Check List', study 2 the 'Cognitive Function instrument' and EuroQol-5 Dimension (EQ-5D) and study 3 the 'Cognitive Function instrument' and EQ-5D as well as the 'Frail Kenshin' health check-up, for incident long-term care certification over a follow-up period of up to 4 years. This is the first large prospective study to evaluate the predictive ability of these tools for the outcome measure long-term care certification. The last subsection of this project study four aims to explore a mixed methods intervention for delaying the need for long-term care. This section is purely exploratory, looking for clues for further studies. METHODS AND ANALYSIS: Baseline data have been collected through local government programs, as well as through postal self-reported questionnaires. The primary outcome variable for all studies is long-term care certification data. Statistical analysis will be carried out using Kaplan-Meier, Multiple Cox regression as well as logistic regression. CONCLUSION: This project hopes to identify tools effective in predicting long-term care need. This will enable identification of citizens that are of higher risk for long-term care in the near future. This subset of high-risk individuals can in the future be addressed for extra support/intervention. ETHICS AND DISSEMINATION: All studies have been approved by respective institutional ethical committees and the WHO ethical committee ERC.0002899. In addition, all studies conform to the provisions of the Declaration of Helsinki and are conducted in accordance with Japan's 'Ethical Guidelines for Medical and Health Research Involving Human Subjects'. All findings will be disseminated at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000023283.

[Paraneoplastic Neurological Syndrome].

Paraneoplastic neuropathy (PNS) is a neuromuscular disorder caused by the remote effects of tumors and is presumed to be primarily caused by an immune-mediated mechanism due to the appearance of anti-neuronal antibodies. In addition to the classical PNS syndromes already established as syndromes, there are an increasing number of reports of PNS that target membrane proteins on the cell surface such as channels. Diagnosing PNS, which often precedes associated tumors, is clinically important because it allows for early detection of tumors and early intervention.

Galectin 3-binding protein suppresses amyloid-ß production by modulating ß-cleavage of amyloid precursor protein.

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of ß-amyloid (Aß) peptides. Aß is produced from amyloid precursor protein (APP) that is sequentially cleaved by ß- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aß production, we performed a gene microarray-based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aß production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in Aß production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3-binding protein (GAL3BP), which suppressed Aß production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aß production by directly interacting with APP and thereby inhibiting APP processing by ß-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.

Validation of the Guy's Neurological Disability Scale as a screening tool for cognitive impairment in multiple sclerosis.

OBJECTIVES: Cognitive impairment is a common symptom affecting daily activities of the patients with multiple sclerosis (MS). Various cognitive evaluation tests are available, yet most of them are complex and time-consuming to perform in outpatient clinics. In this study, we aimed to validate a Japanese version of the Guy's Neurological Disability Scale (GNDS) as a user-friendly tool to evaluate comprehensive disabilities in MS including cognitive function. METHODS: Questions of the GNDS were translated into Japanese and named GNDS-J. Forty-four patients were examined by the Expanded Disability Status Scale (EDSS), the Paced Auditory Serial Addition Test (PASAT), the Symbol Digit Modalities Test (SDMT), the vitality scale, and the GNDS-J in the same time at remission state. RESULTS: The GNDS-J scores correlated with the EDSS scores(r = 0.61), and inversely correlated with the PASAT2/1(r=-0.56/-0.49) scores and the SDMT scores (r=-0.68), whereas the GNDS-J did not show any correlation with the vitality scale. Furthermore, eleven patients were evaluated over 5 years for changes in these scores. Eight out of 11 patients had exacerbated GNDS, and all of these patients experienced clinical relapse during this period. CONCLUSION: The GNDS-J is a valid tool to perform in outpatient clinics, which could provide a comprehensive scale for evaluating symptoms of MS, thus the disease activity by repeated measure.