bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1b open label study of sodium selenate as a disease‐modifying treatment for behavioural variant fronto‐temporal dementia
Authors: Vivash Lucy E , Malpas Charles B , Hovens Christopher M , Velakoulis Dennis , O’Brien Terence 
Published: December 2021

AbstractBackgroundHyperphosphorylated tau is a pathological hallmark of ∼45% of behavioural variant frontotemporal dementia (bvFTD). For this reason, hyperphosphorylated tau represents a promising treatment target for this population. Sodium selenate stimulates the PP2A enzyme, which directly dephosphorylates hyperphosphorylated tau. This Phase 1b, open‐labelled, study investigated sodium selenate as a disease‐modifying treatment for patients with bvFTD.MethodTwelve patients with bvFTD were treated with sodium selenate (15mg tds) for twelve months. Participants underwent a cognitive and behavioural battery, MRI, lumbar puncture and safety assessments at screening, baseline, and at regular intervals following treatment commencement. Adverse events were monitored via diary cards between clinic visits.ResultAll 12 patients completed the study. Safety analysis found that sodium selenate was safe and well tolerated, with no study withdrawals. Commonly reported mild‐moderate adverse events were nail changes (n=6), muscles aches (n=4), headache, fatigue, hair loss and fall (n=3). Five patients reduced their dose to 10mg tds due to adverse events. No treatment‐related serious adverse events occurred. Analyses of efficacy data are ongoing. A mixed‐effects analysis showed an overall small but significant decline on cognition and behaviour, including total NUCOG score (b=‐0.18, 95% CI=‐0.28–0.08) Cambridge Behavioural Index (b=0.32, 95% CI=0.18‐0.46) and Carer Burden Scale score (b=0.1, 95% CI = 0.02‐0.18). Percentage change in whole‐brain volume from baseline to week 52 ranged from ‐0.26% to ‐6.51% (n=7 >‐1.8%, n=4 <‐1.8%). Plasma tau levels (n=6) did not change from baseline (3.73±0.26pg/mL) to week 52 (4.66±0.24pg/mL). CSF tau also showed no change from baseline (167.8±11.2pg/mL) to week 52 (156.1±2.49pg/mL). Although not significant, the directional changes are in line with the proposed mechanism of sodium selenate.Exploratory analyses of “responders” (brain volume change >‐1.8%, n=7) found no change in NUCOG total score (b=‐0.03, 95% CI ‐0.14‐0.07) or CBS score (b=‐0.05, 95% CI ‐0.04‐0.13) over time.ConclusionSodium selenate is safe and well tolerated in patients with bvFTD. Exploratory analyses indicate it may reduce atrophy and halt cognitive decline in a subset of bvFTD patients. Sodium selenate should be further investigated as a potential treatment for bvFTD, and biomarkers to identify the subset of “responder” patients explored.
Health care utilization patterns in early symptomatic AD prior to enrollment into Phase 2/3 clinical trial AMARANTH
Authors: Chandler Julie , Zimmer Jennifer A , Kubisiak Emily , Kubisiak Joanna 
Published: December 2021

AbstractBackgroundIn Alzheimer’s disease (AD), pathogenic changes occur decades before clinical symptoms and diagnosis. Pre‐diagnostic medical history and healthcare resource utilization (HCRU) patterns of patients with early symptomatic AD may aid patient identification earlier in the disease. This study examined HCRU in a subgroup of clinical trial patients to detect early indicators of cognitive, functional and/or behavioral decline.MethodsAMARANTH (NCT02245737) was a double‐blind, placebo‐controlled multi‐center trial that enrolled amyloid‐positive patients with early symptomatic AD (mild cognitive impairment (MCI) due to AD or mild AD dementia). This addendum study analyzed baseline characteristics and Medicare claims of a subgroup of participants compared to two larger age‐matched cohorts of Medicare beneficiaries (Cognitive impairment (CI)/AD and non‐CI/AD matched controls) (Figure 1). AMARANTH participants consented to access of 8 years of prior Medicare claims data and had baseline data available from the parent study. Participants were stratified by APOE4 carrier status, disease, and gender. Descriptive statistics and regression models assessed differences in participant costs across strata and the diagnostic histories between participants and controls. Variables considered in stepwise selection of model covariates included observation months, age, frailty, geography, and comorbidities.ResultsAddendum participants were representative of the AMARANTH cohort but were older and less functionally and cognitively impaired at study entry. Medicare costs did not differ across APOE4 or disease status, but costs for men were lower. Pre‐diagnosis, participant and control costs were comparable, while an increase at diagnosis was observed in the CI/AD controls. A summary of diagnostic histories between participants and controls is shown in Table 1. Post‐diagnostic drug utilization was higher in participants. They were more likely than CI/AD controls to have used psychotherapeutic and neurological agents, and more likely than non‐CI/AD controls to have used antidepressants/anticonvulsants and analgesics/anti‐inflammatory/genitourinary agents.ConclusionsPost‐diagnostic HCRU patterns and costs were higher in CI/AD controls than participants, who did not differ from non‐CI/AD controls; however, participants may not be representative of the broader Medicare CI/AD population. This study provides descriptive HCRU patterns of participants years prior to diagnosis; future analysis with larger cohorts may refine and better identify diagnostic indicators in early symptomatic AD patients.
A network‐based drug‐screening platform for Alzheimer’s disease by integrating mathematical modeling and pathological features of human brain organoids
Authors: Park Jong‐Chan , Jang So‐Young , Lee Dongjoon , Lee Jeongha , Kang Uiryong , Chang Hongjun , Kim Haeng Jun , Han Sun‐Ho , Seo Jinsoo , Choi Murim , Lee Dong Young , Byun Min Soo , Yi Dahyun , Cho Kwang‐Hyun , Mook‐Jung Inhee 
Published: December 2021

AbstractBackgroundDeveloping effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. The difficulty of acquiring human brain samples and the lack of a disease model that adequately recapitulates the pathological hallmarks pose significant challenges in the field.MethodHere, we report an efficient, network‐based drug‐screening platform developed by integrating mathematical modelling and the pathological features of AD with human iPSC‐derived cerebral organoids (iCOs), including CRISPR‐Cas9‐edited isogenic lines. We use 1,300 organoids from 11 participants to build a high‐ content screening (HCS) system and test blood‐brain barrier‐permeable FDA‐approved drugs.ResultOur results confirmed that our iCOs had pathological features of AD, and thus could be an appropriate model reflecting characteristics of the actual disease‐related human brain lesions. Also, We completed the construction and validation of the molecular regulatory network model for AD. We proposed candidate drugs based on systems analysis of the dynamical network model with detailed regulatory mechanisms. We found that all of the candidate drugs were effective to some degree in reducing Aβ or tau deposition and enhancing or maintaining neuronal cell viability.ConclusionOur study provides a strategy for precision medicine through the convergence of mathematical modelling and a miniature pathological brain model using iCOs. With further generation of the iCOs or iPSC‐derived microglia (iMG) from various types of AD patients, our approach may propose strategies for the precision medicine therapy.
Traditional healing and medicine in dementia care for indigenous populations in North America, Australia, and New Zealand: A scoping review protocol
Authors: Shrestha Hom Lal , McArthur Michael , Rowe Robyn L , Wabie Joey‐Lynn , Maar Marion , Walker Jennifer D 
Published: December 2021

AbstractObjectiveIn this scoping review we aim to explore approaches to the integration of traditional healing and medicine in dementia care for Indigenous communities in North America, Australia, and New Zealand. We aim to understand the roles and experiences of traditional healers, strategies and their evaluation, and the barriers and opportunities for integration of Indigenous and western dementia care approaches. Introduction: Access to culturally safe geriatric care and dementia assessment, diagnosis, and care in Indigenous populations worldwide is an emerging challenge. The World Health Organization recognizes traditional healers as stakeholders in dementia care. Traditional healers can provide dementia assessment and care in unique ways and play a catalytic role in the process of dementia care planning. This scoping review will inform Indigenous health service providers about the potential integration of traditional healing and medicine into dementia care and support systems. Inclusion criteria: This review will include all types of study designs, that examine the integration of Indigenous approaches and traditional healers in dementia care in Indigenous communities in North America (Canada and U.S.), Australia and New Zealand.MethodsIn close collaboration with Indigenous community advisors, we will search for OVID MEDLINE, PsycINFO, CINAHL and EMBASE include English literature from 1990 to 2020. After two independent screens of title and abstract, and then full text, we will extract the study population, participants, intervention type, aims, methods, key findings, and knowledge gaps. The results will be summarized and presented to Indigenous community advisors for contextual interpretation and validation prior to being finalized.ResultsOur initial search of CINAHL, Embase, Medline and PsycINFO identified 516 records published between 2000 and 2020 that met our search criteria. After 164 duplicates were removed, we screened 352 titles and abstracts and excluded 209 that did not meet inclusion criteria. Our second stage review of 143 full text studies resulted in the further exclusion of 113 studies. Of these, 84 studies did not include traditional medicine and 13 did not involve Indigenous populations or meet our study design criteria. Results were extracted from the 30 eligible and relevant studies that were included in the final scoping review.
Identifying and triangulating all available evidence on the effect of blood lipids and statins on dementia outcomes
Authors: McGuinness Luke A , Higgins Julian PT , Ben‐Shlomo Yoav 
Published: December 2021

AbstractBackgroundMuch published literature exists on the effect of blood lipid levels, and lipid‐regulating agents (LRA) such as statins, on the risk of dementia and related outcomes. Several approaches, including observational studies, randomised controlled trials (RCTs) and Mendelian randomisation (MR) studies (which uses genetic variants as proxies for the risk factor of interest) have been used to try and address this question, each with distinct assumptions and limitations. However, no previous review has sought to systematically identify and integrate these distinct study designs as part of a single synthesis exercise. This comprehensive systematic review and qualitative triangulation of the evidence aims to address this.MethodFollowing standard systematic review methods, 16109 potentially eligible records were identified by a systematic search and screened as part of the review. Of these, 127 records reporting 105 primary studies were included, the majority of which (n=92; ∼88%) were observational studies. Data were extracted using a piloted form, and the risk of bias in included studies was assessed using the appropriate domain‐based tool (e.g. ROBINS‐I for non‐randomised studies of interventions).ResultDistinct study designs were only available for some exposure (lipids/statins) and outcome (all‐cause dementia, Alzheimer’s disease, vascular dementia) pairs. A common theme across study designs was the absence of vascular dementia outcomes.A key example of the triangulation approach if the results for the effect of statins on all‐cause dementia. Evidence from the meta‐analysis of observational studies found a protective effect (HR: 0.78, 95%CI: 0.69‐0.89), in contrast to both the RCT (OR:1, 95%CI: 0.60‐1.65) and MR (RR:0.9, 95%CI: 0.29‐2.83) approaches. This discrepancy could potentially be explained by immortal time bias, which typically increases the observed protective effect of the intervention, as several observational studies were found to suffer from this bias.ConclusionEvidence on the effect of blood lipid levels, and lipid modifying agents, is available from study with distinct methodological designs. By identifying and integrating this evidence as part of a single synthesis exercise, the strength of the conclusions can be increased. Future research should specifically focus on vascular dementia as an outcome, as there is a lack of evidence on this condition.
Mindfulness is associated with amyloid, tau and cognition in preclinical AD
Authors: Strikwerda‐Brown Cherie , Ozlen Hazal , Binette Alexa Pichet , Chapleau Marianne , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: December 2021

AbstractBackgroundMindfulness refers to the ability to engage in non‐judgmental awareness of the present moment. This psychological trait is gaining increased attention in both scientific and general public settings, given its association with an array of health benefits. While psychological traits such as depression, anxiety, and neuroticism have been associated with increased risk for Alzheimer’s disease (AD), the potential protective benefit of ‘positive’ psychological factors, such as mindfulness, remains to be explored. Here, we examined the relationship between mindfulness and AD markers in the preclinical phase of the disease.MethodTwo hundred and sixty cognitively normal older adults, including 124 with amyloid and tau‐PET scans, were included from the PREVENT‐AD cohort. All participants completed the Five Facet Mindfulness Questionnaire and a comprehensive neuropsychological battery. Multivariate partial least squares (PLS) analyses were used to examine the relationships between different facets of mindfulness (Observing, Describing, Acting with Awareness, Nonjudgment, and Nonreactivity), AD pathology, and cognition.ResultHigher levels of mindful nonjudgment and nonreactivity were associated with less amyloid deposition in bilateral temporoparietal and frontal cortices (p = .003; Figure 1A). Higher levels of mindful acting with awareness, nonjudgment, nonreactivity, and describing were also related to less tau deposition in bilateral medial and lateral temporal regions (p < .006; Figure 1B). Finally, higher levels of mindful nonjudgment and describing were associated with better performance on measures of global cognition, immediate and delayed memory, and attention (p = .002; Figure 2). These relationships remained significant when additional psychological (depression, anxiety, stress, perseverative thinking and personality traits) and demographic (age, sex, education and APOE status) variables were included in analyses.ConclusionHigher trait mindfulness was associated with less amyloid and tau pathology and better cognition in the preclinical phase of AD, with distinct combinations of mindfulness facets differentially related to each of the AD markers. These findings suggest that, in addition to its other established health benefits, mindfulness may also represent an independent psychological protective factor for AD. Moreover, this study provides empirical support for the potential utility of mindfulness interventions in early AD, which represents an area of significant ongoing international research interest.
Examining the impact of sleep apnea on the ability to participate in cognitive testing among older adults
Authors: O'Leary Kimberly , Kiselica Andrew M 
Published: December 2021

AbstractBackgroundAlthough neuropsychological evaluations are indicated for older adults with suspected cognitive impairments, some patients cannot participate meaningfully in testing due to significant cognitive impairments or impacts from health conditions. One condition that may affect the ability to participate in testing is sleep apnea. Sleep apnea is a risk factor for cognitive problems. It can cause deficits in motivation, attention, and arousal, which may hinder the ability to participate meaningfully in an evaluation.MethodWe assessed whether individuals with self‐reported sleep apnea were more likely than individuals without sleep apnea to demonstrate inability to meaningfully provide test results (i.e., a futile testing profile). The sample included 9,263 older adults from the National Alzheimer’s Coordinating Center Uniform Data Set (1608 with self‐reported sleep apnea and 7393 without). Individuals were considered to demonstrate a futile testing profile if ≥75% of cognitive tests met at least one of the following criteria: 1. Unable to be completed due to a cognitive/behavioral problem; 2. A score at the floor of the range of possible scores (score of 0 for most tests); 3. Performance below the second percentile based on demographically adjusted norms, corresponding to an extremely low score.ResultsIndividuals with sleep apnea (6.60%) were no more likely than individuals without sleep apnea (7.7%) to demonstrate a futile testing profile, X
2(1) = 2.404. This finding held, even when evaluating the rate of futile testing profiles by cognitive severity status.ConclusionsResults suggest that those with sleep apnea are not more likely than those without to demonstrate a futile testing profile. Although sleep apnea is a significant predictor and complicator of cognitive impairment, individuals with sleep apnea still appear to be able to complete cognitive testing and deliver meaningful findings.
Utilizing study and site performance metrics to improve efficiency of clinical trials: An initiative of the Alzheimer’s Clinical Trials Consortium (ACTC)
Authors: Walter Sarah , Craft Suzanne , Geldmacher David S. , Menard William , Sano Mary , Obisesan Thomas O , Combs Martha , Gessert Devon , Shaffer‐Bacareza Elizabeth , Miller Garrett , Donohue Michael C , Rafii Michael S , Aisen Paul S ,   Alzheimer's Clinical Trials Consortium (ACTC)
Published: December 2021

AbstractBackgroundThe Alzheimer's Clinical Trials Consortium (ACTC) aims to provide an optimal infrastructure, utilizing centralized resources and shared expertise, to accelerate the development of effective interventions for Alzheimer’s disease and related disorders (ADRD). Metrics help clinical research sites understand where they stand relative to other sites and share best practices. For ACTC and study leaders, metrics aid in tracking the progress towards established goals, assessing performance of the sites and of the coordinating center in supporting site efforts, and may identify areas where additional development is needed.MethodThis initiative is led by an ACTC committee, comprised of member site PIs, research staff, and ACTC’s coordinating center. Proposed metrics were approved by the ACTC Steering Committee, and include those typically used to assess performance of a clinical trial (i.e., screening and randomization totals) as well as information not typically quantified (e.g. PI oversight and responsiveness). Reports are generated by extracting data from the ACTC data system, which ensures accuracy and minimizes site burden. A key element of this initiative is feedback from sites, obtained ad hoc and semiannually. Surveys were also used to understand the impact of COVID‐19 pandemic and other barriers to study startup. Interactive reports are distributed quarterly, facilitating both high level and detailed review. Site‐specific anonymized reports allow sites to see how they are performing relative to other sites.Result5 surveys were distributed with response rates between 50% and 82%. Quarterly reports, including summaries of site activation and screening performance, were distributed to 75 sites. Results obtained will be in our presentation.ConclusionWe established procedures to collect, report and disseminate metrics, providing the foundation for a strong connection between sites and study teams. Our next steps are to develop additional summaries, maximize survey responses, improve the efficiency of report dissemination, as well as to explore the utility of metrics in measuring efficiency of trial conduct. This initiative will inform the development and implementation of additional ACTC trials, as well as tracking ACTC progress in building a consortium responsive to a changing landscape of clinical trials.
Task switching challenge to reveal abnormal brain‐heart signatures in cognitively healthy individuals with abnormal CSF amyloid/tau
Authors: Arechavala Rebecca Johnson , Liu Anqi , Rochart Roger , Kloner Robert , Fonteh Alfred N. , Kleinman Michael T. , Harrington Michael G. , Arakaki Xianghong 
Published: December 2021

AbstractBackgroundAlpha oscillations during task switching reveals general attention (low alpha) and higher executive attentional control (high alpha). Alpha oscillations have been related to heart rate variability (HRV), both change in Alzheimer’s disease (AD). We aim to explore if task switching challenge with quantitative electroencephalography (qEEG) can reveal abnormal alpha power and HRV in individuals with high risk of AD, and we predict HRV improves qEEG’s detection of high AD risk.MethodWe compared alpha power during task switching testing between two groups of cognitively healthy participants (52‐91 years) based on different cerebrospinal fluid (CSF) amyloid/tau ratio: normal (CH‐NAT, n=19) or pathological amyloid/tau ratio (CH‐PAT, n=27). Participants were required to name the color or word of a colored word for each stimulus, with two sequential stimuli per trial. Alpha event‐related desynchronization (ERD) was analyzed during low load, repeat trials (color‐color or word‐word) and high load, switch trials (color‐word or word‐color). HRV was assessed from 5‐minute ECG recording during rest or task, including: standard deviation of RR‐intervals (SDNN), root mean squared of successive differences (RMSSD) in the time domain, as well as high (HF) and low frequency (LF) in the frequency domain. We trained a binary classifier to predict the CH‐PATs using a 30 random split of training (80%) and testing (20%) data and two‐layer, fully connected neural network after identifying significant qEEG and HRV features.ResultWe found that low alpha power was less negative in CH‐PATs than CH‐NATs (Central: ‐0.18±0.66 vs. ‐0.72±0.72, p=0.011, Cohen’s d=0.79; Parietal: ‐0.25±0.75 vs. ‐0.83±0.92, p=0.024, Cohen’s d=0.70) (Fig. 1). Furthermore, we observed significant HR and LF changes from resting to task state only in CH‐PATs, but not in CH‐NATs (Fig. 2). After identifying brain features and heart features, we explored the HRV effect on brain features’ test accuracy.ConclusionThese results suggest: 1) low alpha power during task switching challenge differs between CH‐PATs and CH‐NATs; 2) HRV suggests hyperactive autonomic regulations from resting to task in CH‐PATs, but not CH‐NATs. qEEG reveals interaction of brain and heart features in early AD pathology that may help early diagnosis and monitoring of novel therapies.