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.

Simplifying Alzheimer's Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire.

Background: Primary outcome measure in the clinical trials of disease modifying therapy (DMT) drugs for Alzheimer's disease (AD) has often been evaluated by Clinical Dementia Rating sum of boxes (CDRSB). However, CDR testing requires specialized training and 30-50 minutes to complete, not being suitable for daily clinical practice. Objective: Herein, we proposed a machine-learning method to estimate CDRSB changes using simpler cognitive/functional batteries (Mini-Mental State Examination [MMSE] and Functional Activities Questionnaire [FAQ]), to replace CDR testing. Methods: Baseline data from 944 ADNI and 171 J-ADNI amyloid-positive participants were used to build machine-learning models predicting annualized CDRSB changes between visits, based on MMSE and FAQ scores. Prediction performance was evaluated with mean absolute error (MAE) and R2 comparing predicted to actual rmDeltaCDRSB/rmDeltayear. We further assessed whether decline in cognitive function surpassing particular thresholds could be identified using the predicted rmDeltaCDRSB/rmDeltayear. RESULTS: The models achieved the minimum required prediction errors (MAE <  1.0) and satisfactory prediction accuracy (R2>0.5) for mild cognitive impairment (MCI) patients for changes in CDRSB over periods of 18 months or longer. Predictions of annualized CDRSB progression>0.5, >1.0, or >1.5 demonstrated a consistent performance (i.e., Matthews correlation coefficient>0.5). These results were largely replicated in the J-ADNI case predictions. CONCLUSIONS: Our method effectively predicted MCI patient deterioration in the CDRSB based solely on MMSE and FAQ scores. It may aid routine practice for disease-modifying therapy drug efficacy evaluation, without necessitating CDR testing at every visit.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Advertisement by medical facilities as an opportunity route of APOE genetic testing in Japan: a website analysis.

The APOE-ε4 allele(s) is a strong risk factor for Alzheimer's disease (AD). A significant point of access for this allele testing is through services provided by medical facilities in Japan, which advertise out-of-insurance APOE testing on their websites. There is a concern that website advertisements for APOE testing may influence the ability for individuals to adequately self-determine whether to undergo APOE testing. We conducted a cross-sectional survey on medical facility websites in Japan advertising APOE genetic testing. We predefined desirable features for advertisement descriptions based on legal regulations and guidelines published by relevant professional societies and evaluated each website according to these features. We identified 220 medical facilities that had posted advertisements on their websites for the provision of APOE genetic testing, of which 85% were small clinics. Contact information, details, and costs of testing were described in most of the websites. Meanwhile, features such as "explaining APOE as a risk gene," "notes on interpreting APOE results," or "explaining examination methods" (e.g., blood sampling) were described to a variable degree depending on individual facilities. "Notes on genetic testing" or "referring to genetic counseling" were hardly referred to, and specialists with appropriate expertise were considered to participate in clinical practice in approximately one-third of these facilities providing APOE testing services. These website evaluation results showed moderate to substantial reliability between independent raters. These results suggest that self-determination of pursuing out-of-insurance APOE testing at some medical facilities in Japan may possibly be influenced in an inappropriate manner, at least in its entry route of taking the test.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease.

BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-ß-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE Îµ4 carrier status, sex, and education. RESULTS: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. CONCLUSIONS: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

[Survey on the Current Advertising and Sales of Mucuna pruriens in Consumer-to-consumer Internet Trading in Japan].

Mucuna pruriens (MP) is leguminous plant which contains 5% of L-3,4-dihydroxyphenylalanine (levodopa) in its seeds. It may have a potential to be used as an alternative therapy for Parkinson's disease (PD). Meanwhile, there is a concern in terms of public health that MP products can be overused by patients with PD. As an entry for patients with PD to acquire MP products in Japan, they are often purchased via internet auctions or free markets. MP products are not reagrded as 'pharmatheutical' by Japanese law as long as the specific legal requirements on advertisements are met, so that the MP products can be advertised or sold without any permission from the authorities. In this study, we aimed to conduct internet survey as to the complianse status of these legal requirements. Several major internet auction or free market websites in Japan were surveyed in May-June 2023 by the authors, and 1157 MP product pages were examined. We found approximately 30-40% of the MP products were suspected to have potential legal risks in terms of their advertisements in their website descriptions, such as claiming pharmatheutical efficacy or describing pharmatheutical-like dosages. In addition, approximately 30-40% of the MP products also did not refer to cautions not to take MP products excessively because of the levodopa ingredients. Current study suggested the need of careful description of the MP products in the auction or free market websites for the MP products exhibitors or sellers, in order to fullfill legal requirements as well as to prevent MP abuse.

Sphingolipid abnormalities in encephalomyeloradiculoneuropathy (EMRN) are associated with an anti-neutral glycolipid antibody.

Accumulating evidence suggests that various sphingolipids and glycosphingolipids can act as mediators for inflammation or signaling molecules in the nervous system. In this article, we explore the molecular basis of a new neuroinflammatory disorder called encephalomyeloradiculoneuropathy (EMRN), which affects the brain, spinal cord, and peripheral nerves; in particular, we discuss whether glycolipid and sphingolipid dysmetabolism is present in patients with this disorder. This review will focus on the pathognomonic significance of sphingolipid and glycolipid dysmetabolism for the development of EMRN and the possible involvement of inflammation in the nervous system.

A pilot study assessing sphingolipids and glycolipids dysmetabolism in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus usually exhibits triad of symptoms including gait disturbance, urinary incontinence, and dementia with ventriculomegaly. Currently, its pathogenesis remains to be fully elucidated. To provide a better understanding of this order, we examined whether dysmetabolism of sphingolipids as major lipid components in the brain present in cerebrospinal fluid (CSF) of the patients. Here, we measured various sphingolipidsincluding ceramide and sphingomyelin and glycolipids by electrospray ionization-tandem mass spectrometry in the cerebrospinal fluid of 19 consecutive idiopathic normal pressure hydrocephalus patients, 49 Parkinson's disease patients, and 17 neurologically normal controls. The data showed that there was a significant and specific reduction of all galactosylceramide subspecies levels in idiopathic normal pressure hydrocephalus patients compared with other groups, whereas ceramide and sphingomyelin levels as well as other neutral glycolipids such as glucosylceramide and lactosylceramide were similar in both disease states. Multiple regression analysis of sex and age did not show any correlation with galactosylceramide levels. We also examined whether MMSE scores are correlated with sphingolipid levels in iNPH patients. A specific subspecies of sphingomyelin (d18:1/18:0) only exhibited a statistically significant negative correlation (p = 0.0473, R = -0.4604) with MMSE scores but no other sphingolipids in iNPH patients. These data strongly suggest that myelin-rich galactosylceramide metabolism is severely impaired in idiopathic normal pressure hydrocephalus patients and might serve as the basis of biomarker for this disorder.

Change in long-term care service usage in Japan following the COVID-19 pandemic: A survey using a nationwide statistical summary in 2018-2021.

AIM: Social restrictions due to the coronavirus disease (COVID-19) pandemic forced many long-term care (LTC) service-users to refrain from using services. We aimed to evaluate the degree of change in the use of LTC services. METHODS: We retrospectively analyzed data from the publicly distributed nationwide statistics summarizing the monthly number of public LTC insurance users in Japan between April 2018 and March 2021. The degree of decline was quantified as a ratio, where the ratio of a certain month to the reference month was divided by the ratio in the previous year. RESULTS: The use of LTC services started to decline in March 2020 and reached its largest decline in May 2020. Thereafter, it recovered but insufficiently, even as of late 2020. The degree of decline was particularly large for services provided in facilities for community-dwelling elderly individuals [Ratio to the previous year = 0.717 (95% CI: 0.645-0.796) in short-stay services, and Ratio = 0.876 (95% CI: 0.802-0.957) in outpatient services], but was non-significant in other types of services, including those provided for elderly individuals living in nursing homes. CONCLUSIONS: Community-dwelling elderly individuals who had used outpatient or short-stay services were especially affected by the COVID-19 pandemic in 2020. This underlines the need for further investigation of the medium- or long-term influence of the decline in service usage on the mental and physical health of the LTC service-users and their caregivers. Geriatr Gerontol Int 2022; 22: 803-809.

Multi-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer's disease.

Understanding Alzheimer's disease (AD) heterogeneity is important for understanding the underlying pathophysiological mechanisms of AD. However, AD atrophy subtypes may reflect different disease stages or biologically distinct subtypes. Here we use longitudinal magnetic resonance imaging data (891 participants with AD dementia, 305 healthy control participants) from four international cohorts, and longitudinal clustering to estimate differential atrophy trajectories from the age of clinical disease onset. Our findings (in amyloid-ß positive AD patients) show five distinct longitudinal patterns of atrophy with different demographical and cognitive characteristics. Some previously reported atrophy subtypes may reflect disease stages rather than distinct subtypes. The heterogeneity in atrophy rates and cognitive decline within the five longitudinal atrophy patterns, potentially expresses a complex combination of protective/risk factors and concomitant non-AD pathologies. By alternating between the cross-sectional and longitudinal understanding of AD subtypes these analyses may allow better understanding of disease heterogeneity.

Automated Evaluation of Conventional Clock-Drawing Test Using Deep Neural Network: Potential as a Mass Screening Tool to Detect Individuals With Cognitive Decline.

Introduction: The Clock-Drawing Test (CDT) is a simple cognitive tool to examine multiple domains of cognition including executive function. We aimed to build a CDT-based deep neural network (DNN) model using data from a large cohort of older adults, to automatically detect cognitive decline, and explore its potential as a mass screening tool. Methods: Over 40,000 CDT images were obtained from the National Health and Aging Trends Study (NHATS) database, which collects the annual surveys of nationally representative community-dwelling older adults in the United States. A convolutional neural network was utilized in deep learning architecture to predict the cognitive status of participants based on drawn clock images. Results: The trained DNN model achieved balanced accuracy of 90.1 ± 0.6% in identifying those with a decline in executive function compared to those without [positive likelihood ratio (PLH) = 16.3 ± 6.8, negative likelihood ratio (NLH) = 0.14 ± 0.03], and 77.2 ± 2.7 % balanced accuracy for identifying those with probable dementia from those without (PLH = 5.1 ± 0.5, NLH = 0.37 ± 0.07). Conclusions: This study demonstrated the feasibility of implementing conventional CDT to be automatically evaluated by DNN with a fair performance in a larger scale than ever, suggesting its potential as a mass screening test for ruling-in or ruling-out those with executive dysfunction or with probable dementia.

Time to onset of drug-induced parkinsonism: Analysis using a large Japanese adverse event self-reporting database.

Whether there are differences in the time to onset of drug-induced parkinsonism (DIP) depending on the type of drugs causing DIP remains uncertain, so that question was investigated here using a large real-world database. Fourteen DIP-related drug categories were defined to perform a disproportionality analysis using a large Japanese pharmacovigilance database containing more than 600,000 self-reported adverse events (AEs) recorded between April 2004 and September 2021 to identify AEs indicating "parkinsonism" in association with the defined drug categories. The time from drug administration to the onset of DIP was comparatively analyzed. Results indicated that the median time to onset was shorter than 1 month in more than half of the cases of DIP; it was shortest with peripheral dopamine antagonists (median: 0.1 weeks), followed by benzodiazepine (median: 0.5 weeks), butyrophenone (median: 0.7 weeks), novel antidepressants (median: 2.5 weeks), atypical antipsychotics (median: 3.3 weeks), other antidepressants (e.g., lithium, median: 3.7 weeks), and benzamide (median: 4.5 weeks). In contrast, anti-dementia drugs, tricyclic antidepressants, and antiepileptic drugs resulted in a relatively longer time to onset (median: 9.9, 17.2, and 28.4 weeks, respectively). In addition, a maximum delay of even longer than 2 years was reported for benzamide (846 weeks), anti-Parkinsonism drugs (382 weeks), phenothiazine (232 weeks), atypical antipsychotics (167 weeks), anti-dementia drugs (161 weeks), and benzodiazepines (120 weeks). The current results suggested that the characteristics of the time to onset of DIP may substantially differ depending on the type of drug causing that DIP. This finding may help when diagnosing patients with parkinsonism.

Species-specific accumulation of ceramides in cerebrospinal fluid from encephalomyeloradiculoneurpathy patients associated with peripheral complement activation: A pilot study.

Glycolipids are now known to be rapidly converted to mediators for inflammatory reactions or to signaling molecules that control inflammatory events in the nervous system. The present study aimed to explore whether disturbed glycolipids metabolism in the nervous system is present in patients with a neuroinflammatory disorder, encephalo-myelo-radiculo-neuropathy (EMRN), because most EMRN patients have been reported to exhibit autoantibodies against neutral glycolipids. Although molecular pathogenesis of this disorder remains unknown, we tried to search the immunochemical abnormalities in this disorder. ELISA for activated peripheral C5 complement and mass spectrometry analysis of cerebrospinal fluid clearly disclosed a significant upregulation of active C5 complement, C5a levels in sera as well as a significant accumulation of species-specific ceramides but not sphingomyelin in cerebrospinal fluid from EMRN patients. Furthermore, we confirmed the occurrence of anti-neutral glycolipids antibodies in all EMRN patients. Thus, the present study might indicate the pathophysiology of this disorder is the dysregulation of glycolipids metabolism and abnormal production of autoantibodies against neutral glycolipids resulting in the abnormal complement activation, although molecular basis for these sphingolipids dysregulation and the occurrence of autoantibodies against glycolipids remains to be elucidated at present. The present study implicates a new therapeutic strategy employing anti-ceramide and/or anti-complement therapy for this disorder.

Facial nerve palsy following the administration of COVID-19 mRNA vaccines: analysis of a self-reporting database.

OBJECTIVES: Facial nerve palsy (or Bell's palsy) has occasionally been reported following the administration of coronavirus disease 2019 (COVID-19) mRNA vaccines (BNT162b2 and mRNA-1273). Our study investigated such cases using a large self-reporting database from the USA (Vaccine Adverse Event Reporting System [VAERS]). METHODS: A disproportionality analysis, adjusted for age and sex, was conducted for VAERS reports from individuals who were vaccinated at the age of 18 years or over, between January 2010 and April 2021. RESULTS: The analysis revealed that the adverse events following immunization (AEFI) of facial nerve palsy, after administration of COVID-19 mRNA vaccines, was significantly highly reported, both for BNT162b2 (reporting odds ratio [ROR] 1.84; 95% confidence interval [CI] 1.65-2.06) and mRNA-1273 (ROR 1.54; 95% CI 1.39-1.70). These levels were comparable to that following influenza vaccination reported before the COVID-19 pandemic (ROR 2.04; 95% CI 1.76-2.36). CONCLUSIONS: Our pharmacovigilance study results suggest that the incidence of facial nerve palsy as a non-serious AEFI may be lower than, or equivalent to, that for influenza vaccines. This information might be of value in the context of promoting worldwide vaccination, but needs to be validated in future observational studies.

The impact of COVID-19 pandemic on the utilization of ambulatory care for patients with chronic neurological diseases in Japan: Evaluation of an administrative claims database.

The COVID-19 pandemic has affected not only the emergency medical system, but also patients' regular ambulatory care, as such decrease in the number of patients visiting outpatient clinics decreased in 2020 than in 2019, or the ban lifting of subsequent visits by telephone for outpatient clinics since March 2020 in lieu of ambulatory care for chronic diseases. In this context, we investigate the impact of the COVID-19 pandemic on ambulatory care at Japanese outpatient clinics for patients with chronic neurological diseases during 2020. We collected data from the administrative claims database (DeSC database) covering more than 1 million individuals. Serial changes in the frequency of subsequent outpatient visits to clinics or hospitals (excluding large hospitals) for chronic ambulatory care of epilepsy, migraine, Parkinson's disease (PD), and Alzheimer's disease (AD) in 2020 were measured. As a result, since April 2020, the monthly outpatient visits for epilepsy, PD, and AD decreased slightly but significantly (approximately 0.90 in relative risk [RR]) but visits for migraine increased (RR = 1.15). Telephone visit was most frequently used in April-May, in less than 5% of monthly outpatient clinic visits for the examined neurological diseases. Outpatient visits for migraine treatment were more likely to be done by telephone than in case of other diseases (adjusted Odds ratio = 2.08). These results suggest that the impact of COVID-19 pandemic on regular ambulatory care for several chronic neurological diseases yielded different effect depending on the disease, in terms of the frequency or type of outpatient visits.

Efficacy and Cost-effectiveness of Promotion Methods to Recruit Participants to an Online Screening Registry for Alzheimer Disease Prevention Trials: Observational Study.

BACKGROUND: Web-based screening may be suitable for identifying individuals with presymptomatic latent diseases for recruitment to clinical studies, as such people do not often visit hospitals in the presymptomatic stage. The promotion of such online screening studies is critical to their success, although it remains uncertain how the effectiveness of such promotion can differ, depending on the different promotion methods, domains of interest, or countries of implementation. OBJECTIVE: The Japanese Trial-Ready Cohort (J-TRC) web study is our ongoing online screening registry to identify individuals with presymptomatic Alzheimer disease (AD), aimed at facilitating the clinical trials for AD prevention. Within the first 9 months of its 2019 launch, the J-TRC web study recruited thousands of online participants via multiple methods of promotion, including press releases, newspaper advertisements, web advertisements, or direct email invitations. Here, we aimed to quantitatively evaluate efficacy and cost-effectiveness of each of these multimodal promotion methods. METHODS: We applied the vector-autoregression model to assess the degree of contribution of each type of promotion to the following target metrics: number of daily visitors to the J-TRC website, number of daily registrants to the J-TRC web study, daily rate of registration among visitors, daily rate of eligible participants among registrants, and median age of daily registrants. The average cost-effectiveness for each promotion method was also calculated using the total cost and the coefficients in the vector-autoregression model. RESULTS: During the first 9 months of the reviewed period from October 31, 2019 to June 17, 2020, there were 48,334 website visitors and 4429 registrations (9.16% of 48,334 visitors), of which 3081 (69.56%) were eligible registrations. Initial press release reports and newspaper advertisements had a marked effect on increasing the number of daily visitors and daily registrants. Web advertisements significantly contributed to the increase in daily visitors (P<.001) but not to the daily registrants, and it also lowered the rate of registrations and the median age of daily registrants. Website visitors from the direct email invitation sent to other cognitive registries seem to have registered with the highest reliability. The calculated average cost-effectiveness for the initial press release was US $24.60 per visitor and US $96.10 per registrant, while the calculated average cost-effectiveness for the newspaper advertisements was US $28.60 per visitor and US $227.90 per registrant. CONCLUSIONS: Our multivariate time-series analysis showed that each promotion method had different features in their effect of recruiting participants to the J-TRC web study. Under the advertisement condition settings thus far, newspaper advertisements and initial press releases were the most effective promotion methods, with fair cost-effectiveness that was equivalent to earlier online studies. These results can provide important suggestions for future promotions for the recruitment of presymptomatic participants to AD clinical trials in Japan.

Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease. METHODS: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid ß (Aß1-40, Aß1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. FINDINGS: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aß1-42 to Aß1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aß and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms). FUNDING: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.

Predicting amyloid risk by machine learning algorithms based on the A4 screen data: Application to the Japanese Trial-Ready Cohort study.

BACKGROUND: Selecting cognitively normal elderly individuals with higher risk of brain amyloid deposition is critical to the success of prevention trials for Alzheimer's disease (AD). METHODS: Based on the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study data, we built machine-learning models and applied them to our ongoing Japanese Trial-Ready Cohort (J-TRC) webstudy participants registered within the first 9 months (n = 3081) of launch to predict standard uptake value ratio (SUVr) of amyloid positron emission tomography. RESULTS: Age, family history, online Cognitive Function Instrument and CogState scores were important predictors. In a subgroup of J-TRC webstudy participants with known amyloid status (n = 37), the predicted SUVr corresponded well with the self-reported amyloid test results (area under the curve = 0.806 [0.619-0.992]). DISCUSSION: Our algorithms may be usable for automatic prioritization of candidate participants with higher amyloid risks to be preferentially recruited from the J-TRC webstudy to in-person study, maximizing efficiency for the identification of preclinical AD participants.

Cerebrospinal Fluid Profiles in Parkinson's Disease: No Accumulation of Glucosylceramide, but Significant Downregulation of Active Complement C5 Fragment.

BACKGROUND: As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson's disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. OBJECTIVE: We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. METHODS: We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured. RESULTS: C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. CONCLUSION: Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.