Usability of a Web-Based Registry for Preclinical Alzheimer's Disease: Implications from a Cross-Sectional Online Survey.

BACKGROUND: We have been conducting a Japanese trial-ready cohort web study since 2019 as a web-based online registry to enroll individuals with preclinical Alzheimer's disease to facilitate trials on Alzheimer's disease prevention. The usability of a website might be an important factor in determining user participation and retention. OBJECTIVES: We conducted a user questionnaire survey to analyze the usability of the Japanese trial-ready cohort website and user characteristics for future website improvement. DESIGN: This was a cross-sectional prospective observational study. SETTING: Online survey using Google Forms. PARTICIPANTS: Among the Japanese trial-ready cohort web study participants, we enrolled those who provided consent to participate in the study and had completed one or more Cognitive Function Instrument tests before May 2, 2023. We sent an invitation e-mail, including the questionnaire web address, to eligible participants on July 21 and 22, 2023. MEASUREMENTS: We analyzed the questionnaire answers, including the system usability scale score and time of response (in 24 h). We also compared the respondents' characteristics with that of all the Japanese trial-ready cohort web study participants to identify features associated with an increased/decreased response rate to the questionnaire. RESULTS: Among the 10,112 Japanese trial-ready cohort web study participants that we sent invitation e-mails, we received 1,574 eligible responses (15.6%) within three weeks of the response acceptance period. The mean system usability scale score was 67.6, and no difference in system usability scale scores was observed in terms of age or sex. Approximately half of the respondents of the Japanese trial-ready cohort web study heard about it online, whereas one-fourth heard about it via newspapers. Contribution to drug development for dementia treatment was the most frequent motivation for participating in the Japanese trial-ready cohort web study (51.5%), followed by participation in the latest research (48.1%), concerns about self-memory (43.4%), and a family history of dementia (34.6%). Female respondents responded approximately 1.5 h later than male respondents. Lastly, those who had participated in the Japanese trial-ready cohort onsite study, were in their 70's, or had a larger number of Cognitive Function Instrument or Cogstate tests completion history were more likely to respond to the current online survey (relative risk of response > 1). CONCLUSIONS: We conducted an online survey using Google Forms for participants in the Japanese trial-ready cohort web study to determine the usability. The results of this study might help to improve the user experience of the Japanese trial-ready cohort website itself, increase the web study registrants, maintain user retention, facilitate future online surveys, and serve as a reference for other web-based registries of presymptomatic disease status.

Characterization of a retroreflector array for 320-GHz interferometer system in Heliotron J.

A retroreflector array, composed of a cluster of small retroreflectors, is experimentally studied for application to a Michelson-type interferometer system in the fusion plasma experiment. Such a new-type reflector has the potential to be a vital and effective tool at a spatially limited location, such as on the vacuum chamber wall of plasma experimental devices. To investigate the effect of retroreflector array on the reflected beam properties, a tabletop experiment is performed with the retroreflector array composed of 4 mm corner-cube retroreflectors and with a 320-GHz (λ ∼ 0.937 mm) submillimeter wave source. An imaging camera is utilized to measure the submillimeter wave beam profile and is scanned perpendicularly to the beam propagation direction if necessary. The experimental result exhibits a diffraction effect on the reflected beam, resulting in the emergence of discrete peaks on the reflected beam profile, as predicted in the past numerical study; however, the most reflected beam power converges on the one reflected into the incident direction, resulting from a property as a retroreflector. Furthermore, the dependence of the reflected beam on the incident beam angle is characterized while fixing the detector position, and the retroreflection beam intensity is found to vary due to the diffraction effect. Such an undesired variation of beam intensity induced by the diffraction can be suppressed with a focusing lens placed in front of the detector in the practical application to an interferometer.

Development and initial results of 320 GHz interferometer system in Heliotron J.

A new 320 GHz solid-state source interferometer is installed in the Heliotron J helical device to explore the physics of high-density plasmas (ne > 2-3 × 1019 m-3, typically) realized with advanced fueling techniques. This interferometry system is of the Michelson type and is based on the heterodyne principle, with two independent solid-state sources that can deliver an output power of up to 50 mW. A high time resolution measurement of <1 µs can be derived by tuning the frequency of one source in the frequency range of 312-324 GHz on the new system, which can realize the fluctuation measurement. We successfully measured the line-averaged electron density in high-density plasma experiments. The measured density agreed well with a microwave interferometer measurement using a different viewing chord, demonstrating that the new system can be used for routine diagnostics of electron density in Heliotron J.

Measurement of Paα line from pellet ablation cloud in Heliotron J.

The Paα line (1875.13 nm) in the near-infrared (NIR) region was evaluated to apply Stark broadening of the line spectrum to the electron density measurement of the small-pellet ablation cloud in Heliotron J, a medium-sized helical-axis heliotron device. Paα is three-to-four times broader than the visible Hß line (486.13 nm) for the same electron density. Using a portable NIR spectrometer, preliminary proof-of-concept experiments determined the marginal density, below which the broadening was undetectable. The lower detection density limit can be decreased using a narrower entrance slit or a denser grating.

Three-dimensional dynamics of fluctuations appearing during pellet ablation process around a pellet in a fusion plasma experiment.

Understanding pellet ablation physics is crucial to realizing efficient fueling into a high temperature plasma for the steady state operation of ITER and future fusion reactors. Here we report the first observation of the formation of fluctuation structures in the pellet plasmoid during the pellet ablation process by a fast camera in a medium-sized fusion device, Heliotron J. The fluctuation has a normalized fluctuation level of ~ 15% and propagates around the moving pellet across the magnetic field. By comparing the fluctuation structures with the shape of magnetic field lines calculated with the field line tracing code, we successfully reconstruct the spatio-temporal structure of the fluctuations during the pellet ablation process. The fluctuations are located at the locations displaced toroidally from the pellet and propagate in the cross-field direction around the pellet axis along the field line, indicating a three-dimensional behavior and structure of fluctuations. The fluctuation would be driven by a strong inhomogeneity formed around the pellet and invoke the relaxation of the gradient through a cross-field transport induced by the fluctuations, which could affect the pellet ablation and pellet fueling processes. Such fluctuations can be ubiquitously present at the inhomogeneity formed around a pellet in the pellet ablation process in fusion devices.

Peripheral Blood BRCA1 Methylation Positively Correlates with Major Alzheimer's Disease Risk Factors.

BACKGROUND: Recent biomarker studies demonstrated that the central nervous system (CNS) environment can be observed from peripherally-derived samples. In a previous study, we demonstrated significant hypomethylation of the BRCA1 promoter region in neuronal cells from post-mortem brains of Alzheimer's disease patients through neuron-specific methylome analysis. Thus, we investigate the methylation changes in the BRCA1 promoter region in the blood samples. OBJECTIVES: To analyze the methylation level of the BRCA1 promoter in peripheral blood from AD patients and normal controls. DESIGN, SETTING, PARTICIPANTS: Genomic DNA samples from peripheral blood were obtained from the J-ADNI repository, and their biomarker data were obtained J-ADNI from the National Bioscience Database Center. Genomic DNA samples from an independent cohort for validation was obtained from Niigata University Hospital (Niigata, Japan). Amyloid positivity was defied by visual inspection of amyloid PET or a CSF Aß42 value ≤ 333 pg/mL at the baseline. MEASUREMENTS: Methylation level of the BRCA1 promoter was analyzed by pyrosequencing. RESULTS: Compared to normal controls, methylation of the BRCA1 promoter in AD patients was not significantly changed; however, in AD patients, it showed a positive correlation with AD risk factors. CONCLUSIONS: Our data confirmed the importance of cell-type specific methylome analysis and also suggested that environmental changes in the CNS can be detected by observing the peripheral blood, implying that the peripheral BRCA1 methylation level can be a surrogate for AD.

A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer's Disease.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

Cohort-Specific Optimization of Models Predicting Preclinical Alzheimer's Disease, to Enhance Screening Performance in the Middle of Preclinical Alzheimer's Disease Clinical Studies.

BACKGROUND: Models that can predict brain amyloid beta (Aß) status more accurately have been desired to identify participants for clinical trials of preclinical Alzheimer's disease (AD). However, potential heterogeneity between different cohorts and the limited cohort size have been the reasons preventing the development of reliable models applicable to the Asian population, including Japan. OBJECTIVES: We aim to propose a novel approach to predict preclinical AD while overcoming these constraints, by building models specifically optimized for ADNI or for J-ADNI, based on the larger samples from A4 study data. DESIGN AND PARTICIPANTS: This is a retrospective study including cognitive normal participants (CDR-global = 0) from A4 study, Alzheimer Disease Neuroimaging Initiative (ADNI), and Japanese-ADNI (J-ADNI) cohorts. MEASUREMENTS: The model is made up of age, sex, education years, history of AD, Clinical Dementia Rating-Sum of Boxes, Preclinical Alzheimer Cognitive Composite score, and APOE genotype, to predict the degree of amyloid accumulation in amyloid PET as Standardized Uptake Value ratio (SUVr). The model was at first built based on A4 data, and we can choose at which SUVr threshold configuration the A4-based model may achieve the best performance area under the curve (AUC) when applied to the random-split half ADNI or J-ADNI subset. We then evaluated whether the selected model may also achieve better performance in the remaining ADNI or J-ADNI subsets. RESULT: When compared to the results without optimization, this procedure showed efficacy of AUC improvement of up to approximately 0.10 when applied to the models "without APOE;" the degree of AUC improvement was larger in the ADNI cohort than in the J-ADNI cohort. CONCLUSIONS: The obtained AUC had improved mildly when compared to the AUC in case of literature-based predetermined SUVr threshold configuration. This means our procedure allowed us to predict preclinical AD among ADNI or J-ADNI second-half samples with slightly better predictive performance. Our optimizing method may be practically useful in the middle of the ongoing clinical study of preclinical AD, as a screening to further increase the prior probability of preclinical AD before amyloid testing.

Rationale for Early Diagnosis of Mild Cognitive Impairment (MCI) Supported by Emerging Digital Technologies.

Disease-modifying pharmacotherapies for Alzheimer's Disease (AD) are currently in late-stage clinical development; once approved, new healthcare infrastructures and services, including primary healthcare, will be necessary to accommodate a huge demand for early and large-scale detection of AD. The increasing global accessibility of digital consumer electronics has opened up new prospects for early diagnosis and management of mild cognitive impairment (MCI) with particular regard to AD. This new wave of innovation has spurred research in both academia and industry, aimed at developing and validating a new "digital generation" of tools for the assessment of the cognitive performance. In light of this paradigm shift, an international working group (the Global Advisory Group on Future MCI Care Pathways) convened to elaborate on how digital tools may be optimally integrated in screening-diagnostic pathways of AD The working group developed consensus perspectives on new algorithms for large-scale screening, detection, and diagnosis of individuals with MCI within primary medical care delivery. In addition, the expert panel addressed operational aspects concerning the implementation of unsupervised at-home testing of cognitive performance. The ultimate intent of the working group's consensus perspectives is to provide guidance to developers of cognitive tests and tools to facilitate the transition toward globally accessible cognitive screening aimed at the early detection, diagnosis, and management of MCI due to AD.

Early Detection of Mild Cognitive Impairment (MCI) in Primary Care.

Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals' cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation.

Early Detection of Mild Cognitive Impairment (MCI) in an At-Home Setting.

Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user's behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.

Application of portable near-infrared spectrometer to Heliotron J plasma diagnostics.

A simple near-infrared (NIR) spectrometer with a wavelength range of 898-2130 nm has recently been applied to diagnose Heliotron J plasmas. It adopts a symmetrical crossed Czerny-Turner mount equipped with a thermoelectrically cooled 512 channel InGaAs linear sensor. Reciprocal linear dispersion was deduced to 96.37 nm/mm at the center of the detector. External filters can be inserted into the path of the collection optics to reject second-order spectra, as needed. Absolute intensity calibration was performed together with a visible spectrometer using a tungsten halogen lamp, and the effect of the transmittance fringe in the visible region of the applied long-pass filter on the NIR calibration was investigated. The intended application of the NIR spectrometer includes extending the wavelength region of a spectral monitor to less contaminated regions for Heliotron J plasma studies. In preliminary measurements, we observed the Paschen series for the hydrogen pellet injection plasma and two atomic helium lines, i.e., 2S-2P singlet and triplet lines, in helium gas puffing experiments. A continuum spectrum in this regime that is attributable to black-body radiation from hot spots on the plasma-facing components was identified. In addition, this may also be used to monitor background radiation in the YAG-Thomson scattering signals near 1064 nm.

An electrically resistive sheet of glial cells for amplifying signals of neuronal extracellular recordings.

Electrical signals of neuronal cells can be recorded non-invasively and with a high degree of temporal resolution using multielectrode arrays (MEAs). However, signals that are recorded with these devices are small, usually 0.01%-0.1% of intracellular recordings. Here, we show that the amplitude of neuronal signals recorded with MEA devices can be amplified by covering neuronal networks with an electrically resistive sheet. The resistive sheet used in this study is a monolayer of glial cells, supportive cells in the brain. The glial cells were grown on a collagen-gel film that is permeable to oxygen and other nutrients. The impedance of the glial sheet was measured by electrochemical impedance spectroscopy, and equivalent circuit simulations were performed to theoretically investigate the effect of covering the neurons with such a resistive sheet. Finally, the effect of the resistive glial sheet was confirmed experimentally, showing a 6-fold increase in neuronal signals. This technique feasibly amplifies signals of MEA recordings.

Unidirectional signal propagation in primary neurons micropatterned at a single-cell resolution.

The structure and connectivity of cultured neuronal networks can be controlled by using micropatterned surfaces. Here, we demonstrate that the direction of signal propagation can be precisely controlled at a single-cell resolution by growing primary neurons on micropatterns. To achieve this, we first examined the process by which axons develop and how synapses form in micropatterned primary neurons using immunocytochemistry. By aligning asymmetric micropatterns with a marginal gap, it was possible to pattern primary neurons with a directed polarization axis at the single-cell level. We then examined how synapses develop on micropatterned hippocampal neurons. Three types of micropatterns with different numbers of short paths for dendrite growth were compared. A normal development in synapse density was observed when micropatterns with three or more short paths were used. Finally, we performed double patch clamp recordings on micropatterned neurons to confirm that these synapses are indeed functional, and that the neuronal signal is transmitted unidirectionally in the intended orientation. This work provides a practical guideline for patterning single neurons to design functional neuronal networks in vitro with the direction of signal propagation being controlled.

Temporomandibular joint articulations on working side during chewing in adult females with cross-bite and mandibular asymmetry.

Influence of mandibular asymmetry and cross-bite on temporomandibular joint (TMJ) articulation remained unknown. This study aimed to investigate whether/how the working-side condylar movement irregularity and articular spaces during chewing differ between patients with mandibular asymmetry/cross-bite and control subjects. The cross-bite group and the control group consisted of 10 adult female patients and 10 adult female subjects, respectively. They performed unilateral gum-chewing. The mandibular movements were recorded using a video-based opto-electronic system. The 3D articular surface of the TMJ for each individual was reconstructed using CT/MRI data. For local condylar points, the normalised jerk cost (NJC) towards normal direction to the condylar surface, the angle between tangential velocity vector and condylar long axis and intra-articular space were measured. Three rotatory angles at centre of the condyle were also measured. During closing and intercuspation, (i) movements of posterior portion of the deviated side condyle showed significantly less smoothness as compared with those for the non-deviated side and control subjects, (ii) the rotations of the condyle on the deviated side induced greater intra-articular space at posterior and lateral portions. These findings suggest that chewing on the side of mandibular deviation/cross-bite may cause irregular movement and enlarged intra-articular space at posterior portion of the deviated side condyle.

Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells.

Statins are 3-hydroxy-3-methylglutaryl-co-enzyme A reductase inhibitors of cholesterol biosynthesis, and have been reported to exert pleiotropic effects on cellular signalling and cellular functions involved in inflammation. Recent reports have demonstrated that previous statin therapy reduced the risk of pneumonia or increased survival in patients with community-acquired pneumonia. However, the precise mechanisms responsible for these effects are unclear. In the present study, we examined the effects of statins on cytokine production from lipopolysaccharide (LPS)-stimulated human bronchial epithelial cells (BEAS-2B). Interleukin (IL)-6 and IL-8 mRNA expression and protein secretion in LPS-stimulated cells were inhibited significantly by the lipophilic statin pitavastatin and the hydrophilic statin pravastatin. As these inhibitory effects of statin were negated by adding mevalonate, the anti-inflammatory effects of statins appear to be exerted via the mevalonic cascade. In addition, the activation levels of Ras homologue gene family A (RhoA) in BEAS-2B cells cultured with pitavastatin were significantly lower than those without the statin. These results suggest that statins have anti-inflammatory effects by reducing cytokine production through inhibition of the mevalonic cascade followed by RhoA activation in the lung.

Occupational and environmental cancer incidence and mortality in China.

BACKGROUND: Most cancers are due to environmental, occupational or other non-genetic factors and are potentially preventable. AIMS: To provide an evidence-based assessment of the burden of occupational and environmental-related cancers in China in 2005. METHODS: The population attributable fraction (PAF) was calculated based on the assumption of no occupational agent exposure. Relative risk estimates for specific cancers of interest and prevalence of exposure were mainly derived from large-scale studies. Data on cancer incidence and mortality was obtained from the Third National Death Cause Survey and cancer registries in China. RESULTS: We estimated that a total of 48,511 deaths of cancer were attributable to occupational agents in China in 2005, with 34,975 among men (3.1% of all cancer deaths) and 13,536 among women (2.1%). A total of 59,410 incident cases of cancer were attributable to occupational agents in China in 2005, with 42,724 among men (2.8% of all cancer incident cases) and 16,686 among women (1.6%). The highest PAF was observed for mesothelioma with asbestos, followed by leukaemia, bladder and lung cancers. Indoor radon was responsible for 0.2% of lung cancer-related deaths among men and women. CONCLUSIONS: Occupational agents represent an important cause of cancer, but indoor radon plays a relatively limited role in cancer causes in China. Our report provides strong evidence of the need for policy makers to develop strategies to reduce the risk of occupational cancers.

IFNß-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum.

BACKGROUND: Interferon-ß-1b (IFNß-1b) has been used to prevent exacerbation of relapsing-remitting multiple sclerosis (RRMS) including optic-spinal multiple sclerosis (OSMS) in Japan. We encountered 2 patients with OSMS with unexpectedly severe exacerbation soon after the initiation of IFNß-1b therapy. The experience urged us to retrospectively review the patients with RRMS who had been treated with IFNß-1b to identify similar cases. METHODS: At neurologic departments of 9 hospitals, the medical records of 56 patients with RRMS were reviewed to identify those who showed severe exacerbation soon after the initiation of IFNß-1b therapy. RESULTS: Of 56 patients with RRMS, we identified 7 who experienced severe exacerbation (exacerbation with increased scores of Expanded Disability Status Scale ≧7.0) within 90 days of the initiation of IFNß-1b therapy. In all 7 patients, the exacerbations after the initiation of IFNß-1b therapy were more severe than those experienced by the individual patients before the use of IFNß-1b, and seemed to have occurred unexpectedly in a short time after the initiation of INFß-1b therapy. A retrospective analysis revealed that all 7 patients had antibodies toward aquaporin 4, and the clinical features of all 7 patients after the exacerbation were consistent with those of neuromyelitis optica (NMO) spectrum. CONCLUSIONS: Our study suggests that IFNß-1b may trigger severe exacerbation in patients with the NMO spectrum. In INFß-1b therapy, cases in NMO spectrum should be carefully excluded.

Structural analyses of high-pressure and high-temperature treated double-walled carbon nanotubes.

This paper reports the structural properties of the high-pressure and high-temperature (HPHT) treated double-walled carbon nanotubes (DWCNTs) based on Raman, XRD and TEM experiments. It was found that the DWCNTs are more stable toward HPHT treatment than the single-walled carbon nanotubes (SWCNTs). We propose that this is probably because the DWCNTs tend not to be deformed by compression and thereby they are less reactive under pressure compared to SWCNTs.