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BACKGROUND: Unsupervised online cognitive assessments have demonstrated promise as an efficient and scalable approach for evaluating cognition in aging, and Alzheimers disease and related dementias. OBJECTIVES: The aim of this study was to evaluate the feasibility, usability, and construct validity of the Paired Associates Learning task from the Cambridge Neuropsychological Test Automated Battery® in adults enrolled in the Brain Health Registry. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: The Paired Associates Learning task was administered to Brain Health Registry participants in a remote, unsupervised, online setting. In this cross-sectional analysis, we 1) evaluated construct validity by analyzing associations between Paired Associates Learning performance and additional participant registry data, including demographics, self- and study partner-reported subjective cognitive change (Everyday Cognition scale), self-reported memory concern, and depressive symptom severity (Patient Health Questionnaire-9) using multivariable linear regression models; 2) determined the predictive value of Paired Associates Learning and other registry variables for identifying participants who self-report Mild Cognitive Impairment by employing multivariable binomial logistic regressions and calculating the area under the receiver operator curve; 3) investigated feasibility by looking at task completion rates and statistically comparing characteristics of task completers and non-completers; and 4) evaluated usability in terms of participant requests for support from BHR related to the assessment. RESULTS: In terms of construct validity, in participants who took the Paired Associates Learning for the first time (N=14,528), worse performance was associated with being older, being male, lower educational attainment, higher levels of self- and study partner-reported decline, more self-reported memory concerns, greater depressive symptom severity, and self-report of Mild Cognitive Impairment. Paired Associates Learning performance and Brain Health Registry variables together identified those with self-reported Mild Cognitive Impairment with moderate accuracy (areas under the curve: 0.66-0.68). In terms of feasibility, in a sub-sample of 29,176 participants who had the opportunity to complete Paired Associates Learning for the first time in the registry, 14,417 started the task. 11,647 (80.9% of those who started) completed the task. Compared to those who did not complete the task at their first opportunity, those who completed were older, had more years of education, more likely to self-identify as White, less likely to self-identify as Latino, less likely to have a subjective memory concern, and more likely to report a family history of Alzheimers disease. In terms of usability, out of 8,395 received requests for support from BHR staff via email, 4.4% (n=374) were related to PAL. Of those, 82% were related to technical difficulties. CONCLUSIONS: Our findings support moderate feasibility, good usability, and construct validity of cross-sectional Paired Associates Learning in an unsupervised online registry, but also highlight the need to make the assessment more inclusive and accessible to individuals from ethnoculturally and socioeconomically diverse communities. A future, improved version could be a scalable, efficient method to assess cognition in many different settings, including clinical trials, observational studies, healthcare, and public health.

BackgroundAlthough Black/African American older adults bear significant inequities in prevalence, incidence, and outcomes of Alzheimer's disease and related dementias, they are profoundly under-included in Alzheimer's Disease research. Community-Engaged Research (e.g., equitable community/science partnerships) is an evidence-based approach for improving engagement of underrepresented populations into Alzheimer's Disease research, but has lacked scalability to the national level. As internet use among older adults from underrepresented populations continues to grow, internet-based research shows promise as a feasible, valid approach to engagement and longitudinal assessment. The Community Engaged Digital Alzheimer's Research (CEDAR) study utilizes a community-engaged research approach to increase the engagement and research participation of Black/African American adults in the Brain Health Registry (BHR) and Alzheimer Disease clinical research.ObjectivesTo describe the methods and evaluate the feasibility of the CEDAR culturally-informed digital platform within BHR.DesignAll Black/African American participants in BHR were invited to enroll in CEDAR and to consider serving on a newly convened Community-Scientific Partnership Board to guide the study. The community board guided the development a culturally-informed cadre of engagement materials and strategies to increase research participation. Engagement strategies included incentives for study task completion, culturally-informed communications (e.g., landing page, emails and social media), resources about brain health, and video and written testimonials by CEDAR participants.SettingBHR, an Internet-based registry and cohort.ParticipantsBHR participants self-identifying as Black/African American were invited to enroll. All participants who signed an online informed consent document were enrolled.MeasurementsWe report the number of participants invited, enrolled, completed tasks, and volunteered to join the community board. We compared the demographics, cognitive profile, and baseline BHR task completion rates between CEDAR participants and all those invited to join the study.ResultsOf 3738 invited, 349 (9.34%) enrolled in CEDAR. 134 (37% of CEDAR participants) volunteered to join the community board, of which 19 were selected for the community board. Compared to those invited, the CEDAR cohort had a higher percentage of female participants (84.5%) and a lower percentage of participants who identify as belonging to more than one ethnocultural group (21.8%). Compared to those did not enroll in CEDAR, those enrolled in CEDAR had a higher percentage of participants completing all BHR tasks (22%) and a higher percentage of participants completing at least one cognitive test (76%). Those enrolled in CEDAR also had a higher percentage of participants having an enrolled study partner (18%).ConclusionsA culturally-informed Community-Engaged Research approach, including a remotely-convened community board, to engagement of Black/African American participants in an online research registry is feasible. This approach can be adapted for use in various clinical studies and other settings. Future studies will evaluate the effectiveness of the engagement strategies.

BackgroundFailure of Alzheimer's disease and related diseases (ADRD) research studies to include and engage Black participants is a major issue, which limits the impact and generalizability of research findings. Little is known about participation of Black adults in online ADRD-related research registries.ObjectivesAs part of the Community Engaged Digital Alzheimer's Research (CEDAR) Study, this study aims to increase our understanding of facilitators and barriers of Black adults to participating in ADRD-related online registries, as well as to understand their preferences for communication channels.Design, setting, participants, measurementsWe invited all Black participants enrolled in the Brain Health Registry (BHR) to complete a cross-sectional online survey. The survey consisted of rating scales and open-text questions asking about their attitudes towards brain health research, reasons for joining and continuing to participate in BHR, difficulties with participating, and preferences for modes of contact and website usage.ResultsOf all invited Black BHR participants (N=3,636), 198 (5.5%) completed the survey. The mean age was 58.4 (SD=11.3), mean years of education were 16.3 (SD=2.4), and 85.5% identified as female. Reported facilitators for joining and continuing to participate in BHR were personal interest (e.g., learning more about own brain health) and altruism (e.g., helping research). Among additional registry features which could encourage return, receiving feedback or scores about BHR tasks was rated the highest. Of those who found BHR participation difficult (21%), the most frequent reason was time burden. The most preferred way of receiving study information was via email. Participants reported that the websites that they used the most were YouTube and Facebook.DiscussionThe results of our study can inform the development of culturally-responsive registry features and engagement efforts to improve inclusion and participation of Black adults in online ADRD research. Providing participants with feedback about their registry performance and reducing the number of registry tasks are among the recommended strategies.

BackgroundThis study aims to understand whether and how participant characteristics (age, gender, education, ethnocultural identity) are related to their feedback about taking a remote, unsupervised, online cognitive assessment.MethodsThe Brain Health Registry is a public online registry which includes cognitive assessments. Multivariable ordinal regressions assessed associations between participant characteristics and feedback responses of older (55+) participants (N=11,553) regarding their Cogstate Brief Battery assessment experience.ResultsHigher age, secondary education or less, Latino identity, and female gender were associated with a poorer assessment experience; higher age and a non-White identity were associated with experiencing the assessment instructions as less clear; and higher age, non-White identity, and secondary education or less were associated with rating additional human support with the assessment as more useful.DiscussionOur findings highlight the importance of improving the design and instructions of unsupervised, remote, online cognitive assessments to better suit the needs of diverse communities.

A previous study (Haley RW, Marshall WW, McDonald GG, Daugherty MA, Petty F, Fleckenstein JL: Brain abnormalities in Gulf War syndrome: evaluation with 1H MR spectroscopy. Radiology 2000; 215: 807-817) suggested that individuals with Gulf War Illness (GWI) had reduced quantities of the neuronal marker N-acetylaspartate (NAA) in the basal ganglia and pons. This study aimed to determine whether NAA is reduced in these regions and to investigate correlations with other possible causes of GWI, such as psychological response to stress in a large cohort of Gulf War veterans. Individuals underwent tests to determine their physical and psychological health and to identify veterans with (n=81) and without (n=97) GWI. When concentrations of NAA and ratios of NAA to creatine- and choline-containing metabolites were measured in the basal ganglia and pons, no significant differences were found between veterans with or without GWI, suggesting that GWI is not associated with reduced NAA in these regions. Veterans with GWI had significantly higher rates of post-traumatic stress disorder, supporting the idea that GWI symptoms are stress related. [ABSTRACT FROM AUTHOR]

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Administrative Core oversees and coordinates all ADNI activities, to ensure the success and maximize the impact of ADNI in advancing Alzheimer's disease (AD) research and clinical trials. It manages finances and develops policies for data sharing, publications using ADNI data, and access to ADNI biospecimens. The Core develops and executes pilot projects to guide future ADNI activities and identifies key innovative methods for inclusion in ADNI. For ADNI4, the Administrative Core collaborates with the Engagement, Clinical, and Biomarker Cores to develop and evaluate novel, digital methods and infrastructure for participant recruitment, screening, and assessment of participants. The goal of these efforts is to enroll 500 participants, including > 50% from underrepresented populations, 40% with mild cognitive impairment, and 80% with elevated AD biomarkers. This new approach also provides a unique opportunity to validate novel methods. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Administrative Core oversees and coordinates all ADNI activities. The overall goal is to ensure ADNI's success and help design future Alzheimer's disease (AD) clinical trials. A key innovation is data sharing without embargo to maximize scientific impact. For ADNI4, novel, digital methods for recruitment and assessment were developed. New methods are designed to improve the participation of underrepresented populations., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Early identification of deficits in our ability to perceive odors is important as many normal (i.e., aging) and pathological (i.e., sinusitis, viral, neurodegeneration) processes can result in diminished olfactory function. To realistically enable population-level measurements of olfaction, validated olfaction tests must be capable of being administered outside the research laboratory and clinical setting., Aim: The purpose of this study was to determine the feasibility of remotely testing olfactory performance using a test that was developed with funding from the National Institutes of Health as part of a ready-to-use, non-proprietary set of measurements useful for epidemiologic studies (NIH Toolbox Odor ID Test)., Materials and Methods: Eligible participants older than 39 years and active (within 6 months) in the Brain Health Registry (BHR), an online cognitive assessment platform which connects participants with researchers, were recruited for this study. Interested participants were mailed the NIH Toolbox Odor ID Test along with instructions on accessing a website to record their responses. Data obtained from subjects who performed the test at home was compared to the normative data collected when the NIH Toolbox Odor ID Test was administered by a tester in a research setting and validated against the Smell Identification Test. The age-range and composition of the population ensured we had the ability to observe both age-related decline and gender-related deficits in olfactory ability, as shown in the experimental setting., Results: We observed that age-associated olfactory decline and gender-associated performance was comparable to performance on the administered test. Self-administration of this test showed the age-related loss in olfactory acuity, F(4, 1156)=14.564, p<.0001 as well as higher accuracy for women compared to men after controlling for participants' age, F(1, 1160) = 22.953, p <.0001. The effect size calculated as Hedge's g, was 0.41., Conclusion: These results indicate that the NIH Toolbox Odor ID Test is an appropriate instrument for self-administered assessment of olfactory performance. The ability to self-administer an inexpensive olfactory test increases its utility for inclusion in longitudinal epidemiological studies and when in-person testing is not feasible., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jaén et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In Alzheimer's disease (AD) research, subjective reports of cognitive and functional decline from participant-study partner dyads is an efficient method of assessing cognitive impairment and clinical progression., Methods: Demographics and subjective cognitive/functional decline (Everyday Cognition Scale [ECog]) scores from dyads enrolled in the Brain Health Registry (BHR) Study Partner Portal were analyzed. Associations between dyad characteristics and both ECog scores and study engagement were investigated., Results: A total of 10,494 BHR participants (mean age = 66.9 ± 12.16 standard deviations, 67.4% female) have enrolled study partners (mean age = 64.3 ± 14.3 standard deviations, 49.3% female), including 8987 dyads with a participant 55 years of age or older. Older and more educated study partners were more likely to complete tasks and return for follow-up. Twenty-five percent to 27% of older adult participants had self and study partner-report ECog scores indicating a possible cognitive impairment., Discussion: The BHR Study Partner Portal is a unique digital tool for capturing dyadic data, with high impact applications in the clinical neuroscience and AD fields. Highlights The Brain Health Registry (BHR) Study Partner Portal is a novel, digital platform of >10,000 dyads. Collection of dyadic online subjective cognitive and functional data is feasible. The portal has good usability as evidenced by positive study partner feedback. The portal is a potential scalable strategy for cognitive impairment screening in older adults., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Healthcare data is a scarce resource and access is often cumbersome. While medical software development would benefit from real datasets, the privacy of the patients is held at a higher priority. Realistic synthetic healthcare data can fill this gap by providing a dataset for quality control while at the same time preserving the patient's anonymity and privacy. Existing methods focus on American or European patient healthcare data but none is exclusively focused on the Australian population. Australia is a highly diverse country that has a unique healthcare system. To overcome this problem, we used a popular publicly available tool, Synthea, to generate disease progressions based on the Australian population. With this approach, we were able to generate 100,000 patients following Queensland (Australia) demographics.

Introduction: This study aimed to understand whether older adults' longitudinal completion of assessments in an online Alzheimer's disease and related dementias (ADRD)-related registry is influenced by self-reported medical conditions., Methods: Brain Health Registry (BHR) is an online cognitive aging and ADRD-related research registry that includes longitudinal health and cognitive assessments. Using logistic regressions, we examined associations between longitudinal registry completion outcomes and self-reported (1) number of medical conditions and (2) eight defined medical condition groups (cardiovascular, metabolic, immune system, ADRD, current psychiatric, substance use/abuse, acquired, other specified conditions) in adults aged 55+ ( N = 23,888). Longitudinal registry completion outcomes were assessed by the completion of the BHR initial questionnaire (first questionnaire participants see at each visit) at least twice and completion of a cognitive assessment (Cogstate Brief Battery) at least twice. Models included ethnocultural identity, education, age, and subjective memory concern as covariates., Results: We found that the likelihood of longitudinally completing the initial questionnaire was negatively associated with reporting a diagnosis of ADRD and current psychiatric conditions but was positively associated with reporting substance use/abuse and acquired medical conditions. The likelihood of longitudinally completing the cognitive assessment task was negatively associated with number of reported medical conditions, as well as with reporting cardiovascular conditions, ADRD, and current psychiatric conditions. Previously identified associations between ethnocultural identity and longitudinal assessment completion in BHR remained after accounting for the presence of medical conditions., Discussion: This post hoc analysis provides novel, initial evidence that older adults' completion of longitudinal assessments in an online registry is associated with the number and types of participant-reported medical conditions. Our findings can inform future efforts to make online studies with longitudinal health and cognitive assessments more usable for older adults with medical conditions. The results need to be interpreted with caution due to selection biases, and the under-inclusion of minoritized communities., Competing Interests: Chengshi Jin, Anna Aaronson, Joseph Eichenbaum, Adam Diaz, Rachana Tank, Monica Camacho, Derek Flenniken, Juliet Fockler, Diana Truran‐Sacrey, and Aaron Ulbricht report no potential conflict of interest. Miriam Ashford receives support from the National Institutes of Health's (NIH) National Institute on Aging (NIA), grant F32AG072730‐01 (made to institution) and declares no potential conflicts of interest. John Neuhaus declares to have grant funding from the NIH.R. Scott Mackin declares to have grants from the following entities: NIH and Janssen Research and Development LLC, with all grant payments made to university. Michael W. Weiner receives support for his work from the following funding sources: NIH, grants from Department of Defense (DOD), grants from Patient‐Centered Outcomes Research Institute (PCORI), grants from California Department of Public Health (CDPH), grants from University of Michigan, grants from Siemens, grants from Biogen, grants from Hillblom Foundation, grants from the Alzheimer's Association, grants from the state of California, grants from Johnson & Johnson, grants from Kevin and Connie Shanahan, grants from GE, grants from VUmc, grants from Australian Catholic University (HBI‐BHR), grants from The Stroke Foundation, grants from the Veterans Administration, personal fees from Acumen Pharmaceutical, personal fees from Cerecin, personal fees from Dolby Family Ventures, personal fees from Eli Lilly, personal fees from Merck Sharp & Dohme Corp., personal fees from the NIA, personal fees from Nestle/Nestec, personal fees from PCORI/PPRN, personal fees from Roche, personal fees from University of Southern California (USC), personal fees from NervGen, personal fees from Baird Equity Capital, personal fees from BioClinica, personal fees from Cytox, personal fees from Duke University, personal fees from Eisai, personal fees from FUJIFILM‐Toyama Chemical (Japan), personal fees from Garfield Weston, personal fees from Genentech, personal fees from Guidepoint Global, personal fees from Indiana University, personal fees from Japanese Organization for Medical Device Development, Inc. (JOMDD), personal fees from Medscape, personal fees from Peerview Internal Medicine, personal fees from Roche, personal fees from T3D Therapeutics, personal fees from WebMD, personal fees from Vida Ventures, personal fees from The Buck Institute for Research on Aging, personal fees from China Association for Alzheimer's Disease (CAAD), personal fees from Japan Society for Dementia Research, personal fees from Korean Dementia Society, outside the submitted work; and I hold stocks or options with Alzheon Inc., Alzeca, and Anven. Monica Rivera Mindt declares to have grants from the following entities (NIH/NIA 2U19AG024904‐16, NIH/NIA R01AG065110‐01A1, NIH/NIA #R56AG075744, NIH/NIA R01AG066471‐01A1, NIH/NIA #U19AG078109‐01), with all grant payments made to university. Rachel L Nosheny has received support from NIA (support to institution) for the present manuscript and grants from NIA (grant to institution), California Department of Public Health (grant to institution) Genentech, Inc., Health Equity Innovations Fund (grant to institution), Alzheimer's Association (grant to institution), and Genentech Charitable Foundation (grant to institution). Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: The Clinical Dementia Rating (CDR) is a well-validated instrument widely used to detect and stage dementia due to Alzheimer disease. The digital Electronic Clinical Dementia Rating (eCDR) can be remotely self-administered and automatically scored, with potential to facilitate efficient dementia screening and staging., Objective: To evaluate the association of the eCDR with the CDR and other in-clinic assessments for screening older adults for cognitive impairment., Design, Setting, and Participants: This multisite, cross-sectional study used baseline data from a longitudinal, observational study from 2020 to 2023, including up to 3 years of follow-up. Participants were enrolled from 3 Alzheimer Disease Research Centers and the Brain Health Registry. Participants (aged ≥55 years, with a study partner, and no acute or unstable major medical conditions) were recruited during in-clinic visits or by automated emails., Exposures: Participants completed the Uniform Data Set Version 3 (UDS; including the CDR) in supervised clinical research settings, and then completed the eCDR remotely, online and unsupervised, using their own device., Main Outcomes and Measures: The primary outcomes were eCDR scores (item; categorical box and global; continuous box and global), CDR scores (item; categorical box and global), and UDS assessment scores. Associations were evaluated using linear and logistic regressions., Results: A total of 3565 participants were contacted, and 288 were enrolled. Among 173 participants with item-level data (mean [SD] age, 70.84 [7.65] years; 76 women [43.9%]), eCDR to CDR concordance was 90% or higher for 33 items (63%) and 70% to 89% for 13 items (25%). Box (domain) level concordance ranged from 80% (memory) to 99% (personal care). The global score concordance rate was 81%. κ statistics were fair to moderate. Among 206 participants with box and global scores (mean [SD] age, 71.34 [7.68] years; 95 women [46.1%]), eCDR continuous global score was associated with CDR global (categorical) score with an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.70-0.87). Correlations between eCDR and in-clinic UDS assessments were similar to those between CDR sum of box scores and the same in-clinic assessments., Conclusions and Relevance: These findings suggest that the eCDR is valid and has potential use for screening and assessment of older adults for cognitive and functional decline related to Alzheimer disease. Instrument optimization and validation in diverse cohorts in remote settings are crucial for evaluating scalability and eCDR utility in clinical research, trials, and health care settings.

Introduction: This culturally tailored enrollment effort aims to determine the feasibility of enrolling 5000 older Latino adults from California into the Brain Health Registries (BHR) over 2.25 years., Methods: This paper describes (1) the development and deployment of culturally tailored BHR websites and digital ads, in collaboration with a Latino community science partnership board and a marketing company; (2) an interim feasibility analysis of the enrollment efforts and numbers, and participant characteristics (primary aim); as well as (3) an exploration of module completion and a preliminary efficacy evaluation of the culturally tailored digital efforts compared to BHR's standard non-culturally tailored efforts (secondary aim)., Results: In 12.5 months, 3603 older Latino adults were enrolled (71% of the total California Latino BHR initiative enrollment goal). Completion of all BHR modules was low (6%)., Discussion: Targeted ad placement, culturally tailored enrollment messaging, and culturally tailored BHR websites increased enrollment of Latino participants in BHR, but did not translate to increased module completion., Highlights: Culturally tailored social marketing and website improvements were implemented. The efforts enrolled 5662 Latino individuals in 12.5 months. The number of Latino Brain Health Registry (BHR) participants increased by 122.7%. We failed to adequately enroll female Latinos and Latinos with lower education. Future work will evaluate effects of a newly released Spanish-language BHR website., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Major depressive disorder (MDD) has increasing prevalence with age. Both objective measures of cognitive dysfunction and subjective report of cognitive difficulties related to MDD are often thought to worsen with increasing age. However, few studies have directly evaluated these characteristics across the adult lifespan., Methods: Participants included 23,594 adults completing objective and subjective measures of cognition on an online research registry. Linear regression including interactions of age group with depression was used to evaluate the association of self-reported MDD with measures of cognition in three age groups: 21-40 years; 41-60 years; 61+ years., Results: MDD (n = 2127) demonstrated poorer objective cognitive performance and greater subjective ratings of cognitive difficulties across all domains assessed compared to non-depressed individuals (ND; n = 21,467). Significant interactions of age group and MDD status with objective and subjective measures of cognition were observed for both middle age and older adults when compared to young adults but few significant differences between middle-aged and older adults were evident., Limitations: This study relied on self-report of MDD diagnosis, utilized remotely administered and unsupervised measures of cognition, and the sample was not diverse., Conclusions: The magnitude of association between MDD and cognitive correlates appears to plateau in middle age. Our results suggest that increased rates of dementia are not due to greater cognitive consequence of MDD in older adults and that age effects, and not greater effects of depression, may lead to increased diagnosis of MDD based on subjective report of cognitive symptoms., Competing Interests: Conflict of interest During the past three years, Dr. Mackin has received research support from The National Institute of Mental Health and Janssen Research and Development, LLC. Dr. Weiner has served on the Scientific Advisory Boards for Pfizer, BOLT International, Neurotrope Bioscience, Alzheon, Inc., Alzheimer's Therapeutic Research Institute (ATRI), Eli Lilly, U. of Penn's Neuroscience of Behavior Initiative, National Brain Research Centre (NBRC), India, Dolby Family Ventures, LP, and ADNI. Dr. Neuhaus has received research support from The National Institute on Aging. Dr. Nosheny has received research support from The National Institute on Aging; the California Department of Public Health; Genentech, Inc.; and the Alzheimer's Association. Dr. Ashford has received research support from the National Institute of Aging. Drs. Rhodes, Kassel, Knight, Banh, Ashford, and Tank, and Emily Burns, Monica R. Camacho, Diana Truran, Chengshi Jin, and Joseph Eichenbaum reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Use of online registries to efficiently identify older adults with cognitive decline and Alzheimer's disease (AD) is an approach with growing evidence for feasibility and validity. Linked biomarker and registry data can facilitate AD clinical research., Methods: We collected blood for plasma biomarker and genetic analysis from older adult Brain Health Registry (BHR) participants, evaluated feasibility, and estimated associations between demographic variables and study participation., Results: Of 7150 participants invited to the study, 864 (12%) enrolled and 629 (73%) completed remote blood draws. Participants reported high study acceptability. Those from underrepresented ethnocultural and educational groups were less likely to participate., Discussion: This study demonstrates the challenges of remote blood collection from a large representative sample of older adults. Remote blood collection from > 600 participants within a short timeframe demonstrates the feasibility of our approach, which can be expanded for efficient collection of plasma AD biomarker and genetic data., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The objective of this study is to evaluate the reliability and validity of the ReVeRe TM word list recall test (RWLRT), which uses speech recognition, when administered remotely and unsupervised., Methods: Prospective cohort study. Participants included 249 cognitively intact community dwelling older adults. Measures included clinician administered neuropsychological assessments at baseline and unsupervised remotely administered tests of cognition from six time-points over six months., Results: The RWLRT showed acceptable validity. Reliability coefficients varied across time points, with poor reliability between times 1 and 2 and fair-to-good reliability across the remaining five testing sessions. Practice effects were observed with repeated administration as expected., Discussion: Unsupervised computerized tests of cognition, particularly word list learning and memory tests that use speech recognition, have significant potential for large scale early detection and long-term tracking of cognitive decline due to AD.

Finding concepts in large clinical ontologies can be challenging when queries use different vocabularies. A search algorithm that overcomes this problem is useful in applications such as concept normalisation and ontology matching, where concepts can be referred to in different ways, using different synonyms. In this paper, we present a deep learning based approach to build a semantic search system for large clinical ontologies. We propose a Triplet-BERT model and a method that generates training data directly from the ontologies. The model is evaluated using five real benchmark data sets and the results show that our approach achieves high results on both free text to concept and concept to concept searching tasks, and outperforms all baseline methods., (©2021 AMIA - All rights reserved.)

Background: The goal of a clinical quality registry is to deliver immediate gains in survival and quality of life by delivering timely feedback to practitioners, thereby ensuring every patient receives the best existing treatment. We are developing an Australian Brain Cancer Registry (ABCR) to identify, describe, and measure the impact of the variation and gaps in brain cancer care from the time of diagnosis to the end of life., Methods: To determine a set of clinical quality indicators (CQIs) for the ABCR, a database and internet search were used to identify relevant guidelines, which were then assessed for quality using the AGREE II Global Rating Scale. Potential indicators were extracted from 21 clinical guidelines, ranked using a modified Delphi process completed in 2 rounds by a panel of experts and other stakeholders, and refined by a multidisciplinary Working Group., Results: Nineteen key quality reporting domains were chosen, specified by 57 CQIs detailing the specific inclusion and outcome characteristics to be reported., Conclusion: The selected CQIs will form the basis for the ABCR, provide a framework for achievable data collection, and specify best practices for patients and health care providers, with a view to improving care for brain cancer patients. To our knowledge, the systematic and comprehensive approach we have taken is a world first in selecting the reporting specifications for a brain cancer clinical registry., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: This study investigated the extent to which subjective and objective data from an online registry can be analyzed using machine learning methodologies to predict the current brain amyloid beta (Aβ) status of registry participants., Methods: We developed and optimized machine learning models using data from up to 664 registry participants. Models were assessed on their ability to predict Aβ positivity using the results of positron emission tomography as ground truth., Results: Study partner-assessed Everyday Cognition score was preferentially selected for inclusion in the models by a feature selection algorithm during optimization., Discussion: Our results suggest that inclusion of study partner assessments would increase the ability of machine learning models to predict Aβ positivity., Competing Interests: JA, MTA, CJ, JN, DT, and RLN have no interests to declare. RSM has received grant funding from the National Institute of Mental Health and has received research support from Johnson & Johnson. PM is an employee of Cogstate, Ltd. GDR is Study Chair for the IDEAS study and has received additional research support from National Institutes of Health (NIH), Alzheimer's Association, Tau Consortium, Avid Radiopharmaceuticals, and Eli Lilly. He is a consultant for Axon Neurosciences, General Electric (GE) Healthcare, Eisai, and Merck, and he is an associate editor for JAMA Neurology. MWW receives support for his work from the following funding sources: NIH, Department of Defense, Patient Centered Outcomes Research Institute (PCORI), California Department of Public Health, University of Michigan, Siemens, Biogen, Larry L. Hillblom Foundation, Alzheimer's Association, and the State of California. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, Vrije Universiteit Medical Center Amsterdam, Australian Catholic University, The Stroke Foundation, and the Veterans Administration. He has served on Advisory Boards for Eli Lilly, Cerecin/Accera, Roche, Alzheon, Inc., Merck Sharp & Dohme Corp., Nestle/Nestec, PCORI, Dolby Family Ventures, National Institute on Aging (NIA), Brain Health Registry, and ADNI. He serves on the editorial boards for Alzheimer's & Dementia, Topics in Magnetic Resonance Imaging, and Magnetic Resonance Imaging. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera, Inc., Alzheimer's Drug Discovery Foundation (ADDF), Merck, BioClinica, Eli Lilly, Indiana University, Howard University, Nestle/Nestec, Roche, Genentech, NIH, Lynch Group GLC, Health & Wellness Partners, Bionest Partners, American Academy of Neurology (AAN), New York University, Japanese Government Alliance, National Center for Geriatrics and Gerontology (Japan), US Against Alzheimer's, Society for Nuclear Medicine and Molecular Imaging (SNMMI), The Buck Institute for Research on Aging, and FUJIFILM‐Toyama Chemical (Japan). He holds stock options with Alzheon, Inc., Alzeca, and Anven., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Remote data collection, including the establishment of online registries, is a novel approach to efficiently identify risk for cognitive decline and Alzheimer's disease (AD) in older adults, with growing evidence for feasibility and validity. Addition of genetic data to online registries has the potential to facilitate identification of older adults at risk and to advance the understanding of genetic contributions to AD., Methods: 573 older adult participants with longitudinal online Brain Health Registry (BHR) data underwent apolipoprotein E (APOE) genotyping using remotely collected saliva samples and a novel, automated Biofluid Collection Management Portal. We evaluated acceptability of genetic sample collection and estimated associations between (1) sociodemographic variables and willingness to participate in genetics research and (2) APOE results and online cognitive and functional assessments. We also assessed acceptance of hypothetical genetics research participation by surveying a larger sample of 25,888 BHR participants., Results: 51% of invited participants enrolled in the BHR genetics study, BHR-GenePool Study (BHR-GPS); 27% of participants had at least one APOE ε4 allele. Older participants and those with higher educational attainment were more likely to participate. In the remotely administered Cogstate Brief Battery, APOE ε4/ε4 homozygotes (HM) had worse online learning scores, and greater decline in processing speed and attention, compared to ε3/ε4 heterozygotes (HT) and ε4 non-carriers (NC)., Discussion: APOE genotyping of more than 500 older adults enrolled in BHR supports the feasibility and validity of a novel, remote biofluids collection approach from a large cohort of older adults, with data linkage to longitudinal online cognitive data. This approach can be expanded for efficient collection of genetic data and other information from biofluids in the future., Competing Interests: Juliet Fockler, Winnie Kwang, Miriam T. Ashford, Derek Flenniken, Joshua Hwang, Diana Truran, Chengshi Jin, Ruth O'Hara, Joachim F. Hallmayer, Jerome A. Yesavage, and Rachel L. Nosheny have no interests to declare. R. Scott Mackin has received research support from The National Institute of Mental Health and Johnson and Johnson. Michael W. Weiner receives support for his work from the following funding sources: NIH: 5U19AG024904‐14; 1R01AG053798‐01A1; R01 MH098062; U24 AG057437‐01; 1U2CA060426‐01; 1R01AG058676‐01A1; and 1RF1AG059009‐01, DOD: W81XWH‐15‐2‐0070; 0W81XWH‐12‐2‐0012; W81XWH‐14‐1‐0462; W81XWH‐13‐1‐0259, PCORI: PPRN‐1501‐26817, California Dept. of Public Health: 16‐10054, U. Michigan: 18‐PAF01312, Siemens: 444951‐54249, Biogen: 174552, Hillblom Foundation: 2015‐A‐011‐NET, Alzheimer's Association: BHR‐16‐459161; The State of California: 18‐109929. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, and the Veterans Administration. He has served on advisory boards for Eli Lilly, Cerecin/Accera, Roche, Alzheon, Inc., Merck Sharp & Dohme Corp., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Brain Health Registry, and ADNI. He serves on the editorial boards for Alzheimer's & Dementia, TMRI, and MRI. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera Inc., Alzheimer's Drug Discovery Foundation (ADDF), Merck, BioClinica, Eli Lilly, Indiana University, Howard University, Nestle/Nestec, Roche, Genentech, NIH, Lynch Group GLC, Health & Wellness Partners, Bionest Partners, American Academy of Neurology (AAN), NYU, Japanese Government Alliance, National Center for Geriatrics and Gerontology (Japan), US Against Alzheimer's, Society for Nuclear Medicine and Molecular Imaging (SNMMI), The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, and T3D Therapeutics. He holds stock options with Alzheon Inc., Alzeca, and Anven. The following entities have provided funding for academic travel: Kenes Intl., Merck, ADCS, ATRI, Eli Lilly, The Alzheimer's Association, Merck, Tokyo University, Kyoto University, AAN, AC Immune, CHU Toulouse, St. George Hospital University, Indiana U., U. Melbourne, Australian Catholic University, Japanese Government Alliance, National Center for Geriatrics and Gerontology (Japan), US Against Alzheimer's, NYU, USC, and SNMMI., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: Assessment of functional status is associated with risk of cognitive decline and diagnosis of dementia, and can be assessed by participants and study partners (SPs)., Methods: In 770 older adults enrolled in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and the online Brain Health Registry (BHR), we estimated associations between online assessments and clinical variables related to Alzheimer's disease (AD) risk., Results: Worse online learning scores and SP-reported functional decline were associated with higher probability of AD dementia diagnosis and poor in-clinic cognitive assessment, and with higher odds of amyloid beta (Aβ) positivity when combined with participants' report of less decline. SP report of functional decline conferred predictive value independent of online cognitive assessments. Participants underreported decline compared to SPs., Discussion: The results support the validity of online assessments and their greater utilization in healthcare and research settings. Online SP-reported functional decline is an indicator of dementia and AD risk., (© 2020 the Alzheimer's Association.)

Introduction: This study aimed to predict brain amyloid beta (Aβ) status in older adults using collected information from an online registry focused on cognitive aging., Methods: Aβ positron emission tomography (PET) was obtained from multiple in-clinic studies. Using logistic regression, we predicted Aβ using self-report variables collected in the Brain Health Registry in 634 participants, as well as a subsample (N = 533) identified as either cognitively unimpaired (CU) or mild cognitive impairment (MCI). Cross-validated area under the curve (cAUC) evaluated the predictive performance., Results: The best prediction model included age, sex, education, subjective memory concern, family history of Alzheimer's disease, Geriatric Depression Scale Short-Form, self-reported Everyday Cognition, and self-reported cognitive impairment. The cross-validated AUCs ranged from 0.62 to 0.66. This online model could help reduce between 15.2% and 23.7% of unnecessary Aβ PET scans in CU and MCI populations., Disucssion: The findings suggest that a novel, online approach could aid in Aβ prediction., Competing Interests: Miriam T. Ashford, John Neuhaus, Chengshi Jin, Monica R. Camacho, Juliet Fockler, Diana Truran, and R. Scott Mackin have no interests to declare., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: This study aimed to identify the relationship of sociodemographic variables with older adults participation in an online registry for recruitment and longitudinal assessment in cognitive aging., Methods: Using Brain Health Registry (BHR) data, associations between sociodemographic variables (sex, race, ethnicity, education) and registry participation outcomes (task completion, willingness to participate in future studies, referral/enrollment in other studies) were examined in adults aged 55+ (N = 35,919) using logistic regression. All models included sex, race, ethnicity, education, age, and subjective memory concern., Results: Non-white race, being Latino, and lower educational attainment were associated with decreased task completion and enrollment in additional studies. Results for sex were mixed., Discussion: The findings provide novel information about engagement in online aging-related registries, and highlight a need to develop improved engagement strategies targeting underrepresented sociodemographic groups. Increasing registry diversity will allow researchers to refer more representative populations to Alzheimer's and related dementias prevention and treatment trials., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, APOE ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ+ versus Aβ- participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Clinical terminologies play an essential role in enabling semantic interoperability between medical records. However, existing terminologies have several issues that impact data quality, such as content gaps and slow updates. In this study we explore the suitability of existing, community-driven resources, specifically Wikipedia, as a potential source to bootstrap an open clinical terminology, in terms of content coverage. In order to establish the extent of the coverage, a team of expert clinical terminologists manually mapped a clinically-relevant subset of SNOMED CT to Wikipedia articles. The results show that approximately 80% of the concepts are covered by Wikipedia. Most concepts that do not have a direct match in Wikipedia are composable from multiple articles. These findings are encouraging and suggest that it should be possible to bootstrap an open clinical terminology from Wikipedia.

Computer-assisted (diagnostic) coding (CAC) aims to improve the operational productivity and accuracy of clinical coders. The level of accuracy, especially for a wide range of complex and less prevalent clinical cases, remains an open research problem. This study investigates this problem on a broad spectrum of diagnostic codes and, in particular, investigates the effectiveness of utilising SNOMED CT for ICD-10 diagnosis coding. Hospital progress notes were used to provide the narrative rich electronic patient records for the investigation. A natural language processing (NLP) approach using mappings between SNOMED CT and ICD-10-AM (Australian Modification) was used to guide the coding. The proposed approach achieved 54.1% sensitivity and 70.2% positive predictive value. Given the complexity of the task, this was encouraging given the simplicity of the approach and what was projected as possible from a manual diagnosis code validation study (76.3% sensitivity). The results show the potential for advanced NLP-based approaches that leverage SNOMED CT to ICD-10 mapping for hospital in-patient coding.

Introduction: Methods for efficiently identifying cognitive decline and Alzheimer's disease (AD) are a critical unmet need. The goal of this work was to validate novel online study partner (SP)-reported outcomes to identify cognitive decline in older adults., Methods: In older adults enrolled in the Brain Health Registry, we analyzed associations between SP-reported cognitive decline, measured by the Everyday Cognition Scale, and either (1) participant cognition, assessed by Cogstate Brief Battery or (2) participant-reported diagnosis of mild cognitive impairment or AD., Results: We found strong associations between SP-reported Everyday Cognition Scale and both Cogstate scores and participant diagnosis. The associations were cognitive domain specific, dependant on participant diagnosis, and were stronger in spouse dyads and those who knew each other longer., Discussion: Collecting SP-reported data online from a large cohort is feasible. Results support the construct validity of our approach, which has the potential to facilitate clinical AD and aging research.

Introduction: The purpose of this study is to compare online neuropsychological test performance of older adults across self-reported diagnoses of being cognitively normal, mild cognitive impairment, and dementia due to Alzheimer's disease and to determine the association of memory concerns and family history of dementia on cognitive performance., Methods: Participants completed the Cogstate Brief Battery unsupervised at home., Results: Data from 6463 participants over the age of 55 years were analyzed. Adults with the diagnosis of mild cognitive impairment and Alzheimer's disease were associated with poorer performance on all cognitive tests than cognitively normal adults ( P  < .05 for all), and online cognitive test performance significantly improved diagnostic classification ( P  < .001). Poorer performance on all cognitive measures was associated with memory concern ( P  < .001 for all) but not family history of dementia., Discussion: Our results provide preliminary support for the use of cognitive tests taken online without supervision as a means to improve the efficiency of participant screening and recruitment for clinical trials.

The increasing demand for healthcare and the static resources available necessitate data driven improvements in healthcare at large scale. The SnoMAP tool was rapidly developed to provide an automated solution that transforms and maps clinician-entered data to provide data which is fit for both administrative and clinical purposes. Accuracy of data mapping was maintained.

Background: Death certificates provide an invaluable source for mortality statistics which can be used for surveillance and early warnings of increases in disease activity and to support the development and monitoring of prevention or response strategies. However, their value can be realised only if accurate, quantitative data can be extracted from death certificates, an aim hampered by both the volume and variable nature of certificates written in natural language. This study aims to develop a set of machine learning and rule-based methods to automatically classify death certificates according to four high impact diseases of interest: diabetes, influenza, pneumonia and HIV., Methods: Two classification methods are presented: i) a machine learning approach, where detailed features (terms, term n-grams and SNOMED CT concepts) are extracted from death certificates and used to train a set of supervised machine learning models (Support Vector Machines); and ii) a set of keyword-matching rules. These methods were used to identify the presence of diabetes, influenza, pneumonia and HIV in a death certificate. An empirical evaluation was conducted using 340,142 death certificates, divided between training and test sets, covering deaths from 2000-2007 in New South Wales, Australia. Precision and recall (positive predictive value and sensitivity) were used as evaluation measures, with F-measure providing a single, overall measure of effectiveness. A detailed error analysis was performed on classification errors., Results: Classification of diabetes, influenza, pneumonia and HIV was highly accurate (F-measure 0.96). More fine-grained ICD-10 classification effectiveness was more variable but still high (F-measure 0.80). The error analysis revealed that word variations as well as certain word combinations adversely affected classification. In addition, anomalies in the ground truth likely led to an underestimation of the effectiveness., Conclusions: The high accuracy and low cost of the classification methods allow for an effective means for automatic and real-time surveillance of diabetes, influenza, pneumonia and HIV deaths. In addition, the methods are generally applicable to other diseases of interest and to other sources of medical free-text besides death certificates.

The goal of this study was to identify factors contributing to hippocampal atrophy rate (HAR) in clinically normal older adults (NC) and participants with mild cognitive impairment (MCI). Longitudinal HAR was measured on T1-weighted magnetic resonance imaging, and the contribution of age, gender, apolipoprotein E (ApoE) ε4 status, intracranial volume, white matter lesions, and β-amyloid (Aβ) levels to HAR was determined using linear regression. Age-related effects of HAR were compared in Aβ positive (Aβ+) and Aβ negative (Aβ-) participants. Age and Aβ levels had independent effects on HAR in NC, whereas gender, ApoE ε4 status, and Aβ levels were associated with HAR in MCI. In multivariable models, Aβ levels were associated with HAR in NC; ApoE ε4 and Aβ levels were associated with HAR in MCI. In MCI, age was a stronger predictor of HAR in Aβ- versus Aβ+ participants. HAR was higher in Aβ+ participants, but most of the HAR was because of factors other than Aβ status. Age-related effects on HAR did not differ between NC versus MCI participants with the same Aβ status. Therefore, we conclude that even when accounting for other covariates, Aβ status, and not age, is a significant predictor of HAR; and that most of the HAR is not accounted for by Aβ status in either NC or MCI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alcohol-dependent individuals (ALC) have smaller hippocampi and poorer neurocognition than healthy controls. Results from studies on the association between alcohol consumption and hippocampal volume have been mixed, suggesting that comorbid or premorbid factors (i.e., those present prior to the initiation of alcohol dependence) determine hippocampal volume in ALC. We aimed to characterize the effects of select comorbid (i.e., cigarette smoking) and premorbid factors (brain-derived neurotrophic factor [BDNF] genotype [Val66Met rs6265]) on hippocampal volume in an ALC cohort followed longitudinally into extended abstinence. One hundred twenty-one adult ALC in treatment (76 smokers, 45 non-smokers) and 35 non-smoking light-drinking controls underwent quantitative magnetic resonance imaging, BDNF genotyping, and neurocognitive assessments. Representative subgroups were studied at 1 week, 1 month, and at an average of 7 months of abstinence. ALC had smaller hippocampi than healthy controls at all time points. Hippocampal volume at 1 month of abstinence correlated with lower visuospatial function. Smoking status did not influence hippocampal volume or hippocampal volume recovery during abstinence. However, only BDNF Val homozygotes tended to have hippocampal volume increases over 7 months of abstinence, and Val homozygotes had significantly larger hippocampi than Met carriers at 7 months of abstinence. These findings suggest that BDNF genotype, but not smoking status or measures of drinking severity, regulate functionally relevant hippocampal volume recovery in abstinent ALC. Future studies aimed at exploring genetic determinants of brain morphometry in ALC may need to evaluate individuals during extended abstinence after the acute environmental effects of chronic alcohol consumption have waned., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study was conducted to determine the relationship of frontal lobe cortical thickness and basal ganglia volumes to measures of cognition in adults with sickle cell anemia (SCA)., Methods: Participants included 120 adults with SCA with no history of neurologic dysfunction and 33 healthy controls (HCs). Participants were enrolled at 12 medical center sites, and raters were blinded to diagnostic group. We hypothesized that individuals with SCA would exhibit reductions in frontal lobe cortex thickness and reduced basal ganglia and thalamus volumes compared with HCs and that these structural brain abnormalities would be associated with measures of cognitive functioning (Wechsler Adult Intelligence Scale, 3rd edition)., Results: After adjusting for age, sex, education level, and intracranial volume, participants with SCA exhibited thinner frontal lobe cortex (t = -2.99, p = 0.003) and reduced basal ganglia and thalamus volumes compared with HCs (t = -3.95, p < 0.001). Reduced volume of the basal ganglia and thalamus was significantly associated with lower Performance IQ (model estimate = 3.75, p = 0.004) as well as lower Perceptual Organization (model estimate = 1.44, p = 0.007) and Working Memory scores (model estimate = 1.37, p = 0.015). Frontal lobe cortex thickness was not significantly associated with any cognitive measures., Conclusions: Our findings suggest that basal ganglia and thalamus abnormalities may represent a particularly salient contributor to cognitive dysfunction in adults with SCA.

The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0-0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.

The goal was to elucidate the time course of regional brain atrophy rates relative to age in cognitively normal (CN) aging, mild cognitively impairment (MCI), and Alzheimer's disease (AD), without a priori models for atrophy progression. Regional brain volumes from 147 cognitively normal subjects, 164 stable MCI, 93 MCI-to-AD converters and 111 ad patients, between 51 and 91 years old and who had repeated 1.5 T magnetic resonance imaging (MRI) scans over 30 months, were analyzed. Relations between regional brain volume change and age were determined using generalized additive models, an established nonparametric concept for approximating nonlinear relations. Brain atrophy rates varied nonlinearly with age, predominantly in regions of the temporal lobe. Moreover, the atrophy rates of some regions leveled off with increasing age in control and stable MCI subjects whereas those rates progressed further in MCI-to-AD converters and AD patients. The approach has potential uses for early detection of AD and differentiation between stable and progressing MCI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Prolonged disruption of sleep in animal studies is associated with decreased neurogenesis in the dentate gyrus. Our objective was to determine whether insomnia severity in a sample of posttraumatic stress disorder (PTSD) patients and control subjects was associated with decreased volume in the CA3/dentate hippocampal subfield., Methods: Volumes of hippocampal subfields in 17 veteran men positive for PTSD (41 +/- 12 years) and 19 age-matched male veterans negative for PTSD were measured with 4-T magnetic resonance imaging. Subjective sleep quality was measured by the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index., Results: Higher scores on the ISI, indicating worse insomnia, were associated with smaller volumes of the CA3/dentate subfields (r = -.48, p < .01) in the combined sample. Adding the ISI score as a predictor for CA3/dentate volume to a hierarchical linear regression model after first controlling for age and PTSD symptoms accounted for a 13% increase in incremental variance (t = -2.47, p = .02)., Conclusions: The findings indicate for the first time in humans that insomnia severity is associated with volume loss of the CA3/dentate subfields. This is consistent with animal studies showing that chronic sleep disruption is associated with decreased neurogenesis and dendritic branching in these structures., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease., Objective: To measure neurocognitive dysfunction in neurologically asymptomatic adults with SCA vs healthy control individuals., Design, Setting, and Participants: Cross-sectional study comparing neuropsychological function and neuroimaging findings in neurologically asymptomatic adults with SCA and controls from 12 SCA centers, conducted between December 2004 and May 2008. Participants were patients with SCA (hemoglobin [Hb] SS and hemoglobin level < or = 10 mg/dL) aged 19 to 55 years and of African descent (n = 149) or community controls (Hb AA and normal hemoglobin level) (n = 47). Participants were stratified on age, sex, and education., Main Outcome Measures: The primary outcome measure was nonverbal function assessed by the Wechsler Adult Intelligence Scale, third edition (WAIS-III) Performance IQ Index. Secondary exploratory outcomes included performance on neurocognitive tests of executive function, memory, attention, and language and magnetic resonance imaging measurement of total intracranial and hippocampal volume, cortical gray and white matter, and lacunae., Results: The mean WAIS-III Performance IQ score of patients with SCA was significantly lower than that of controls (adjusted mean, 86.69 for patients with SCA vs 95.19 for controls [mean difference, -5.50; 95% confidence interval {CI}, -9.55 to -1.44]; P = .008), with 33% performing more than 1 SD (<85) below the population mean. Among secondary measures, differences were observed in adjusted mean values for global cognitive function (full-scale IQ) (90.47 for patients with SCA vs 95.66 for controls [mean difference, -5.19; 95% CI, -9.24 to -1.13]; P = .01), working memory (90.75 vs 95.25 [mean difference, -4.50; 95% CI, -8.55 to -0.45]; P = .03), processing speed (86.50 vs 97.95 [mean difference, -11.46; 95% CI, -15.51 to -7.40]; P < .001), and measures of executive function. Anemia was associated with poorer neurocognitive function in older patients. No differences in total gray matter or hippocampal volume were observed. Lacunae were more frequent in patients with SCA but not independently related to neurocognitive function., Conclusion: Compared with healthy controls, adults with SCA had poorer cognitive performance, which was associated with anemia and age.

Context: Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD., Objective: To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus., Design: Case-control study., Participants: A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41 [12] years) and 19 age-matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community., Interventions: High-resolution magnetic resonance imaging at 4 T., Main Outcome Measure: Volumes of hippocampal subfields., Results: Posttraumatic stress disorder was associated with 11.4% (1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5% (0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields., Conclusions: The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures.

The objectives of this study were to (1) compare atrophy rates associated with normal aging and Alzheimer disease (AD) using the semi-automated Boundary Shift Integral (BSI) method and manual tracing of the entorhinal cortex (ERC) and hippocampus and (2) calculate power of BSI vs. ERC and hippocampal volume changes for clinical trials in AD. We quantified whole brain and ventricular BSI atrophy rates and ERC and hippocampal atrophy rates from longitudinal MRI data in 20 AD patients and 22 age-matched healthy controls. All methods revealed significant brain atrophy in controls and AD patients. AD patients had approximately 2.5 times greater whole brain BSI atrophy rates and more than 5 times greater ERC and hippocampal atrophy rates than controls. ERC and hippocampal atrophy rates were higher in both groups than whole brain BSI atrophy rates, but lower than ventricular BSI atrophy rates. Effect size and power calculations suggest that ERC and hippocampal measurements may be more sensitive than ventricular or whole brain BSI for detecting AD progression and the potential effects of disease modifying agents. Logistic regression analysis revealed that combined rates of ERC and ventricular BSI were the best explanatory variables for classifying AD from controls.