New Commuting Zone delineation for the U.S. based on 2020 data.

This paper documents the creation of new 'commuting zones' for the United States based on 2020 geographies and data. Commuting zones originated in the late 1980's as the result of an effort by the Economic Research Service of the U.S. Department of Agriculture to provide a county-based delineation of functional regions that covered the entire U.S. and linked rural areas to their nearest economic center. The commuting zones presented here update the 2010 era definitions. Additionally, this new delineation incorporates measures of quality to facilitate comparison with earlier decades and to account for the fact that the quality of commuting-based delineations may have been substantially affected by changing patterns of work and residence during and after the covid-19 pandemic. The methodology used here seeks to replicate as nearly as possible the method employed in earlier versions of this delineation using hierarchical clustering on a proportional flows matrix generated from county to county commuting flows. The data and all scripts used to generate them and this paper are available at https://github.com/csfowler/CommutingZones2020.git .

Mars's induced magnetosphere can degenerate.

The interaction between planets and stellar winds can lead to atmospheric loss and is, thus, important for the evolution of planetary atmospheres1. The planets in our Solar System typically interact with the solar wind, whose velocity is at a large angle to the embedded stellar magnetic field. For planets without an intrinsic magnetic field, this interaction creates an induced magnetosphere and a bow shock in front of the planet2. However, when the angle between the solar wind velocity and the solar wind magnetic field (cone angle) is small, the interaction is very different3. Here we show that when the cone angle is small at Mars, the induced magnetosphere degenerates. There is no shock on the dayside, only weak flank shocks. A cross-flow plume appears and the ambipolar field drives planetary ions upstream. Hybrid simulations with a 4° cone angle show agreement with observations by the Mars Atmosphere and Volatile Evolution mission4 and Mars Express5. Degenerate, induced magnetospheres are complex and not yet explored objects. It remains to be studied what the secondary effects are on processes like atmospheric loss through ion escape.

A Comparison of an Australian Observational Longitudinal Alzheimer's Disease Cohort to Community-Based Australian Data.

Background: Observational Alzheimer's disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied. Objective: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia. Methods: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities. Results: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation - AIBL 79±7 years, PBS/census 81±7, p < 0.001, dementia/census 83±8, p < 0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, p = 0.020, dementia/census 29%, p < 0.001; CALD - AIBL 3%, PBS/census 20%, p < 0.001, dementia/census 22%, p < 0.001). Conclusions: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD.

Stable potassium isotope ratios in human blood serum towards biomarker development in Alzheimer's disease.

The Alzheimer's disease (AD)-affected brain purges K with concurrently increasing serum K, suggesting brain-blood K transferal. Here, natural stable K isotope ratios-δ41K-of human serum samples were characterized in an AD biomarker pilot study (plus two paired Li-heparin and potassium ethylenediaminetetraacetic acid [K-EDTA] plasma samples). AD serum was found to have a significantly lower mean δ41K relative to controls. To mechanistically explore this change, novel ab initio calculations (density functional theory) of relative K isotope compositions between hydrated K+ and organically bound K were performed, identifying hydrated K+ as isotopically light (lower δ41K) compared to organically bound K. Taken together with literature, serum δ41K and density functional theory results are consistent with efflux of hydrated K+ from the brain to the bloodstream, manifesting a measurable decrease in serum δ41K. These data introduce serum δ41K for further investigation as a minimally invasive AD biomarker, with cost, scalability, and stability advantages over current techniques.

Association of Basal Forebrain Atrophy With Cognitive Decline in Early Alzheimer Disease.

BACKGROUND AND OBJECTIVES: In early Alzheimer disease (AD), ß-amyloid (Aß) deposition is associated with volume loss in the basal forebrain (BF) and cognitive decline. However, the extent to which Aß-related BF atrophy manifests as cognitive decline is not understood. This study sought to characterize the relationship between BF atrophy and the decline in memory and attention in patients with early AD. METHODS: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who completed Aß-PET imaging and repeated MRI and cognitive assessments were included. At baseline, participants were classified based on their clinical dementia stage and Aß status, yielding groups that were cognitively unimpaired (CU) Aß-, CU Aß+, and mild cognitive impairment (MCI) Aß+. Linear mixed-effects models were used to assess changes in volumetric measures of BF subregions and the hippocampus and changes in AIBL memory and attention composite scores for each group compared with CU Aß- participants. Associations between Aß burden, brain atrophy, and cognitive decline were evaluated and explored further using mediation analyses. RESULTS: The cohort included 476 participants (72.6 ± 5.9 years, 55.0% female) with longitudinal data from a median follow-up period of 6.1 years. Compared with the CU Aß- group (n = 308), both CU Aß+ (n = 107) and MCI Aß+ (n = 61) adults showed faster decline in BF and hippocampal volumes and in memory and attention (Cohen d = 0.73-1.74). Rates of atrophy in BF subregions and the hippocampus correlated with cognitive decline, and each individually mediated the impact of Aß burden on memory and attention decline. When all mediators were considered simultaneously, hippocampal atrophy primarily influenced the effect of Aß burden on memory decline (ß [SE] = -0.139 [0.032], proportion mediated [PM] = 28.0%) while the atrophy of the posterior nucleus basalis of Meynert in the BF (ß [SE] = -0.068 [0.029], PM = 13.1%) and hippocampus (ß [SE] = -0.121 [0.033], PM = 23.4%) distinctively influenced Aß-related attention decline. DISCUSSION: These findings highlight the significant role of BF atrophy in the complex pathway linking Aß to cognitive impairment in early stages of AD. Volumetric assessment of BF subregions could be essential in elucidating the relationships between the brain structure and behavior in AD.

Exploring the link between comorbidities and Alzheimer's dementia in the Australian Imaging, Biomarker & Lifestyle (AIBL) study.

INTRODUCTION: Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD). METHODS: We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross-sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD. RESULTS: A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. DISCUSSION: This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity-MCI/AD associations and underlying mechanisms of these associations. Highlights: Comorbidities that significantly increased AD odds included anxiety and other neurological disorders.Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.Alcohol consumption had the most significant confounding effect in the study.Visual-AD association was modified by age, sex, and APOE ε4 allele status.Anxiety-AD and depression-AD associations were modified by sex.

Benchmark findings from a veteran electronic patient-reported outcomes evaluation from a chronic pain management telehealth program.

BACKGROUND: Chronic pain is a leading cause of disability and negatively impacts biological/physical, psychological, and social aspects of life resulting in significant pain interference or disability. This project was part of a longitudinal mixed-methods implementation evaluation of the TelePain-Empower Veterans Program (EVP), a non-pharmacological chronic pain intervention. The purpose of this quality management project was to examine electronic patient-reported outcome measures (ePROs) including primary pain-related (intensity, interference, catastrophizing, kinesiophobia) and secondary outcomes (physical, psychological, acceptance, social) to determine TelePain-EVP effectiveness. Secondary purpose was to examine dosing effects to better understand potential dose relationships between EVP use and ePROs. METHODS: Standardized ePRO measures were examined at week 1 (baseline), week 10 (post-EVP), and week 26 (follow-up). Qualtrics, a cloud-based platform was used to collect ePRO data at each time point. Veterans that completed at-least one survey at any specified time point were categorized as responders (n = 221). Linear-mixed models (LMMs) were fit to assess changes for each primary and secondary ePRO. RESULTS: Participants ranged from 24 to 81 years old; veterans were typically male (65.16%), black or African American (76.47%), married or partnered (41.63%), attended at-least some college or vocational school (67.87%), and reported low back as their primary pain location (29.41%). There was a significant decrease in pain catastrophizing from baseline to post-TelePain-EVP (p < .001). However, pain catastrophizing improvement from baseline was not present at week 26 (p = .116). Pain interference also decreased from baseline to post-treatment (p = .05), but this improvement did not exceed the adjusted significance threshold. Additional pre-post improvements were also observed for certain secondary ePROs: psychological (anxiety, depression), acceptance (activities engagement). Only the activities engagement effect remained 26 weeks from baseline. Mixed results were observed for EVP dose across primary and secondary outcomes. CONCLUSIONS: Evidence from this evaluation indicate that TelePain-EVP has positive outcomes for certain pain (catastrophizing), psychological (anxiety, depression), and acceptance (activities engagement) for veterans with chronic pain. More TelePain related studies and enterprise-wide evaluations are needed along with comparative and cost effectiveness methods to determine patient benefits and the economic value gained of treatment options such as TelePain-EVP.

Qualitative Evaluation Informs the Implementation of a Telehealth Program to Manage Chronic Pain.

In response to the opioid epidemic and high rates of chronic pain among the veteran population, the U.S. Department of Veterans Affairs implemented the TelePain-Empower Veterans Program (EVP), a nonpharmacological pain management program for veterans. Delivered virtually, TelePain-EVP incorporates integrated health components (Whole Health, Acceptance and Commitment Therapy, and Mindful Movement) through interdisciplinary personalized coaching. The objective of this quality improvement project was to evaluate the implementation of TelePain-EVP to identify determinants to implementation, benefits and challenges to participation, and recommendations for future direction. We used a qualitative descriptive design to conduct semistructured telephone interviews with TelePain-EVP leaders (n = 3), staff (n = 10), and veterans (n = 22). The interview guides aligned with the Consolidated Framework for Implementation Research (CFIR). Thematic content analysis organized and characterized findings. Several CFIR domains emerged as determinants relevant to program implementation, including innovation (eg, design); individuals (eg, deliverers, recipients); inner (eg, communications) and outer settings (eg, local conditions); and implementation process (eg, reflecting and evaluating). Identified determinants included facilitators (eg, virtual delivery) and barriers (eg, staff shortages). Participants reported improvements in pain management coping skills, interpersonal relationships, and sense of community, but no self-reported reductions in pain or medication use. Program improvement recommendations included using centralized staff to address vacancies, collecting electronic data, offering structured training, and providing course materials to veteran participants. Qualitative data can inform the sustained implementation of TelePain-EVP and other similar telehealth pain management programs. These descriptive data should be triangulated with quantitative data to objectively assess participant TelePain-EVP outcomes and associated participant characteristics. PERSPECTIVE: A qualitative evaluation of a telehealth program to manage chronic pain, guided by the CFIR framework, identified determinants of program implementation. Additionally, participants reported improvements in pain management coping skills, interpersonal relationships, and sense of community, but no self-reported reductions in pain or medication use.

Exploring the association between cancer and cognitive impairment in the Australian Imaging Biomarkers and Lifestyle (AIBL) study.

An inverse association between cancer and Alzheimer's disease (AD) has been demonstrated; however, the association between cancer and mild cognitive impairment (MCI), and the association between cancer and cognitive decline are yet to be clarified. The AIBL dataset was used to address these knowledge gaps. The crude and adjusted odds ratios for MCI/AD and cognitive decline were compared between participants with/without cancer (referred to as C+ and C- participants). A 37% reduction in odds for AD was observed in C+ participants compared to C- participants after adjusting for all confounders. The overall risk for MCI and AD in C+ participants was reduced by 27% and 31%, respectively. The odds of cognitive decline from MCI to AD was reduced by 59% in C+ participants after adjusting for all confounders. The risk of cognitive decline from MCI to AD was halved in C+ participants. The estimated mean change in Clinical Dementia Rating-Sum of boxes (CDR-SOB) score per year was 0.23 units/year higher in C- participants than in C+ participants. Overall, an inverse association between cancer and MCI/AD was observed in AIBL, which is in line with previous reports. Importantly, an inverse association between cancer and cognitive decline has also been identified.

Optimized spatial information for 1990, 2000, and 2010 U.S. census microdata.

We report on the successful completion of a project to upgrade the positional accuracy of every response to the 1990, 2000, and 2010 U.S. decennial censuses. The resulting data set, called Optimized Spatial Census Information Linked Across Time (OSCILAT), resides within the restricted-access data warehouse of the Federal Statistical Research Data Center (FSRDC) system where it is available for use with approval from the U.S. Census Bureau. OSCILAT greatly improves the accuracy and completeness of spatial information for older censuses conducted prior to major quality improvements undertaken by the Bureau. Our work enables more precise spatial and longitudinal analysis of census data and supports exact tabulations of census responses for arbitrary spatial units, including tabulating responses from 1990, 2000, and 2010 within 2020 block boundaries for precise measures of change over time for small geographic areas.

Mobile and Web-Based Partnered Intervention to Improve Remote Access to Pain and Posttraumatic Stress Disorder Symptom Management: Recruitment and Attrition in a Randomized Controlled Trial.

BACKGROUND: Increasing access to nonpharmacological interventions to manage pain and posttraumatic stress disorder (PTSD) is essential for veterans. Complementary and integrative health (CIH) interventions can help individuals manage symptom burden with enhanced accessibility via remotely delivered health care. Mission Reconnect (MR) is a partnered, self-directed intervention that remotely teaches CIH skills. OBJECTIVE: The purpose of this paper is to describe the recruitment, onboarding phase, and attrition of a fully remote randomized controlled trial (RCT) assessing the efficacy of a self-directed mobile and web-based intervention for veterans with comorbid chronic pain and PTSD and their partners. METHODS: A total of 364 veteran-partner dyads were recruited to participate in a mixed methods multisite waitlist control RCT. Qualitative attrition interviews were conducted with 10 veterans with chronic pain and PTSD, and their self-elected partners (eg, spouse) who consented but did not begin the program. RESULTS: At the point of completing onboarding and being randomized to the 2 treatment arms, of the 364 recruited dyads, 97 (26.6%) failed to complete onboarding activities. Reported reasons for failure to complete onboarding include loss of self-elected partner buy-in (n=8, 8%), difficulties with using remote data collection methods and interventions (n=30, 31%), and adverse health experiences unrelated to study activities (n=23, 24%). Enrolled veterans presented at baseline with significant PTSD symptom burden and moderate-to-severe pain severity, and represented a geographically and demographically diverse population. Attrition interviews (n=10) indicated that misunderstanding MR including the intent of the intervention or mistaking the surveys as the actual intervention was a reason for not completing the MR registration process. Another barrier to MR registration was that interviewees described the mailed study information and registration packets as too confusing and excessive. Competing personal circumstances including health concerns that required attention interfered with MR registration. Common reasons for attrition following successful MR registration included partner withdrawal, adverse health issues, and technological challenges relating to the MR and electronic data collection platform (Qualtrics). Participant recommendations for reducing attrition included switching to digital forms to reduce participant burden and increasing human interaction throughout the registration and baseline data collection processes. CONCLUSIONS: Challenges, solutions, and lessons learned for study recruitment and intervention delivery inform best practices of delivering remote self-directed CIH interventions when addressing the unique needs of this medically complex population. Successful recruitment and enrollment of veterans with chronic pain and PTSD, and their partners, to remote CIH programs and research studies requires future examination of demographic and symptom-associated access barriers. Accommodating the unique needs of this medically complex population is essential for improving the effectiveness of CIH programs. Disseminating lessons learned and improving access to remotely delivered research studies and CIH programs is paramount in the post-COVID-19 climate. TRIAL REGISTRATION: ClinicalTrials.gov NCT03593772; https://clinicaltrials.gov/ct2/show/NCT03593772.

Remotely Delivered Psychologically Informed Mindful Movement Physical Therapy for Pain Care: A Framework for Operationalization.

Background: While there is recognition by the greater medical community and physical therapists to address the biopsychosocial needs of people with chronic, persistent pain, there are challenges in implementation and delivery including wide variability in interventions, lack of clear rationale, and absence of clinical models that are feasible and acceptable on a large scale. Important components for psychologically informed physical therapy (PiPT) for pain care include behavioral approaches (e.g., Acceptance and Commitment Therapy), mindfulness, pain neuroscience education, motivational interviewing (MI), and interoceptive skills-building. The Empower Veterans Program (EVP) Mindful Movement framework blends these components and emphasizes a mindfulness and self-compassion approach with MI and body-based experiential learning. This program was offered in-person at the Atlanta and Maryland VA Health Care Centers with published positive Patient Reported Outcomes (PRO) pre-COVID 19 crisis and shifted to entirely remote delivery in March 2020. Objective: This paper offers an evidence-based and theory driven framework to operationalize a remotely delivered group-based psychologically informed mindful movement physical therapy intervention as part of an interdisciplinary pain care program. Methods: Since 2021 PRO and demographics are collected using a survey administered through Qualtrics over a 12-month period at baseline, immediately post TelePain EVP, at 6 months, and at 12 months, with findings forthcoming. Discussion/Results: Tele-pain EVP offers 6-9 groups a week with 7-9 veterans from Atlanta based team and 3-4 groups a week with 5-9 veterans from Maryland based team. Adaptations for remote delivery optimized mindfulness and active learning strategies including interoceptive skills-building and use of MI to support self-efficacy to trust, restore a sense of safety in the body, and explore adaptations for safe movement. Conclusion: TelePain-EVP Mindful Movement provides a framework for other programs to translate for their populations and systems to further develop best practices in PiPT for pain care and integration into interdisciplinary care.

Longitudinal trajectories of basal forebrain volume in normal aging and Alzheimer's disease.

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid-ß (Aß) deposition are early pathological features in Alzheimer's disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed Aß-PET and serial magnetic resonance imaging scans. Individuals were grouped at baseline according to the presence of cognitive impairment (CU, CI) and Aß status (Aß-, Aß+). Longitudinal volumetric changes in the BF and hippocampus were assessed across groups. The results indicated that high Aß levels correlated with faster volume loss in the BF and hippocampus, and the effect of Aß varied within BF subregions. Compared to CU Aß+ individuals, Aß-related loss among CI Aß+ adults was much greater in the predominantly cholinergic subregion of Ch4p, whereas no difference was observed for the Ch1/Ch2 region. The findings support early and substantial vulnerability of the BF and further reveal distinctive degeneration of BF subregions during early AD.

CSF Aß42 and tau biomarkers in cognitively unimpaired Aß- middle-aged and older APOE ε4 carriers.

This study aimed to determine the relationship between the apolipoprotein E (APOE) ε4 allele and cerebrospinal fluid (CSF) and neuroimaging biomarkers of Alzheimer's disease, and cognition in cognitively unimpaired (CU) middle-aged adults (n = 82; Mage = 58.2), and in Aß- CU older adults (n = 71; Mage = 71.8). Aß- CU middle-aged ε4 carriers showed lower CSF Aß42 levels, higher levels of CSF total tau (t-tau) and neurofilament light (NfL), and poorer cognitive performance compared to noncarriers (Cohen's d: 0.30-0.56). In Aß- CU older adults, ε4 carriers also had lower CSF Aß42 levels and higher levels of CSF t-tau and p-tau181, compared to noncarriers (Cohen's d: 0.65-0.74). In both Aß- middle-aged and older adults, hippocampal and total brain volume were equivalent between ε4 carriers and noncarriers. In Aß- CU middle-aged adults, APOE ε4 is associated with decreased levels of Aß, increased tau and NfL, and poorer cognition. Similar relationships were observed in Aß- CU older adults. These results have implications for understanding clinicopathological relationships between APOE ε4 and the emergence of cognitive and biomarker abnormalities in Aß- adults.

Empower Veterans Program (EVP): a chronic pain management program demonstrates positive outcomes among veterans.

BACKGROUND: Chronic pain is a highly prevalent health condition among veterans. Traditional pharmacological interventions present unique challenges for chronic pain management including prescription opioid addiction and overdose. In alignment with the 2016 Comprehensive Addiction and Recovery Act and VA's Stepped Care Model to meet veterans' pain management needs, the Offices of Rural Health and Pain Management, Opioid Safety, and Prescription Drug Monitoring Program (PMOP) funded an enterprise-wide initiative to implement a Step 3 integrated tele-pain program: Empower Veterans Program (EVP). EVP provides veterans with chronic pain self-care skills using a whole health driven approach to pain management. OBJECTIVES: The Comprehensive Addiction and Recovery Act prompted the strategic approach to offer non-pharmacological options to meet veterans' pain management needs. EVP, a 10-week interdisciplinary group medical appointment, leverages Acceptance and Commitment Therapy, Mindful Movement, and Whole Health to provide veterans with chronic pain self-care skills. This evaluation was conducted to describe participant characteristics, graduation, and satisfaction rates; and assess pre-post patient-reported outcomes (PRO) associated with EVP participation. METHODS: A sample of 639 veterans enrolled in EVP between May, 2015 and December, 2017 provided data to conduct descriptive analyses to assess participant demographics, graduation, and satisfaction rates. PRO data were analyzed using a within-participants pre-post design, and linear mixed-effects models were used to examine pre-post changes in PRO. RESULTS: Of 639 participants, 444 (69.48%) graduated EVP. Participant median program satisfaction rating was 8.41 (Interquartile Range: 8.20-9.20). Results indicate pre-post EVP improvements (Bonferroni-adjusted p < .003) in the three primary pain outcomes (intensity, interference, catastrophizing), and 12 of 17 secondary outcomes, including physical, psychological, health-related quality of life (HRQoL), acceptance, and mindfulness measures. DISCUSSION: Data suggest that EVP has significant positive outcomes in pain, psychological, physical, HRQoL, acceptance, and mindfulness measures for veterans with chronic pain through non-pharmacological means. Future evaluations of intervention dosing effect and long-term effectiveness of the program is needed.

User Testing of the Veteran Delegation Tool: Qualitative Inquiry.

BACKGROUND: Informal caregivers, or care partners, provide critical support to care recipients when managing health care. Veterans Health Administration (VHA) priorities identify care partners as vital in supporting veterans' care management. The Veteran Delegation Tool (VDT) is VHA's Health Insurance Portability and Accountability Act-compliant solution for care partners to comanage veterans' care through VHA's electronic health portal. Human-centered design approaches in VDT development are needed to inform enhancements aimed at promoting uptake and sustained use. OBJECTIVE: The objective of this prospective descriptive quality improvement project was to use a human-centered design approach to examine VDT use perceptions and practical experiences. METHODS: This project was conducted using a 4-phase approach: frame, discover, design, and deliver. The frame phase designed the protocol and prepared the VDT system for testing. This paper reports on the discover phase, which used semistructured and follow-up interviews and user testing to examine VDT's benefits, facilitators, and barriers. The discover phase data informed the design and deliver phases, which are underway. RESULTS: Veterans (24/54, 44%), care partners (21/54, 39%), and individuals who represented dual roles (9/54, 17%)-namely veteran care partner (4/54, 7%), veteran clinical provider (2/54, 4%), and care partner provider (3/54, 6%)-participated in semistructured interviews in the discover phase. A subsample of these participants (3/54, 6%) participated in the follow-up interviews and user testing. Analysis of the semistructured interviews indicated convergence on the respondents' perceptions of VDT's benefits, facilitators, and barriers and recommendations for improving VDT. The perceived benefits were authorized access, comanagement of care needs on the web, communication with the clinical team, access to resources, and ease of burden. Perceived barriers were nonrecognition of the benefits of VDT, technical literacy access issues, increased stress in or burden on care partners, and personal health information security. Participant experiences across 4 VDT activity domains were upgrade to My HealtheVet Premium account, registration, sign-in, and use. User testing demonstrated users' challenges to register, navigate, and use VDT. Findings informed VDT development enhancements and recommendations. CONCLUSIONS: Care partners need Health Insurance Portability and Accountability Act-compliant access to electronic health portals to assist with care management. VDT is VHA's solution, allowing communication among delegates, veterans, and clinical care teams. Users value VDT's potential use and benefits, while access and navigation improvements to ensure uptake and sustained use are needed. Future efforts need to iteratively evaluate the human-centered phases, design and deliver, of VDT to target audiences. Continued efforts to understand and respond to care partners' needs are warranted.

Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease.

The most frequently utilized biomarkers to support a pre-mortem clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) include concentrations of the 14-3-3 and total tau (T-tau) proteins, as well as the application of protein amplification techniques, such as the real time quaking-induced conversion (RT-QuIC) assay, in cerebrospinal fluid (CSF). Utilizing CSF from a cohort of neuropathologically confirmed (definite) sCJD (n = 50) and non-CJD controls (n = 48), we established the optimal cutpoints for the fully automated Roche Elecsys® immunoassay for T-tau and the CircuLexTM 14-3-3 Gamma ELISA and compared these to T-tau protein measured using a commercially available assay (INNOTEST hTAU Ag) and 14-3-3 protein detection by western immunoblot (WB). These CSF specimens were also assessed for presence of misfolded prion protein using the RT-QuIC assay. T-tau showed similar diagnostic performance irrespective of the assay utilized, with ~90% sensitivity and specificity. The 14-3-3 protein detection by western blot (WB) has 87.5% sensitivity and 66.7% specificity. The 14-3-3 ELISA demonstrated 81.3% sensitivity and 84.4% specificity. RT-QuIC was the single best performing assay, with a sensitivity of 92.7% and 100% specificity. Our study indicates that a combination of all three CSF biomarkers increases sensitivity and offers the best chance of case detection pre-mortem. Only a single sCJD case in our cohort was negative across the three biomarkers, emphasizing the value of autopsy brain examination on all suspected CJD cases to ensure maximal case ascertainment.

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer's Disease.

BACKGROUND: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. OBJECTIVE: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. METHODS: Plasma GFAP and Aß were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aß-PET imaging, comprising 54 healthy control (13 Aß-PET+ and 41 Aß-PET-), 11 mild cognitively impaired (3 Aß-PET+ and 8 Aß-PET-) and 6 probable AD (5 Aß-PET+ and 1 Aß-PET-) individuals. Linear regressions were used to assess associations of interest. RESULTS: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aß deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aß (plasma Aß42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aß (Aß-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. CONCLUSION: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aß load.

Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: an AIBL 18F-MK6240 PET study.

BACKGROUND: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). 18F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change. METHODS: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aß-), 44 CU Aß+, 51 cognitively impaired Aß+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up 18F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter. FINDINGS: CU Aß- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aß+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aß+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aß+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels. INTERPRETATION: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD. FUNDING: NHMRC; Cerveau Technologies.

Leukocyte surface biomarkers implicate deficits of innate immunity in sporadic Alzheimer's disease.

INTRODUCTION: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions. METHODS: In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aß clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aß status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts. CONCLUSION: Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.