bluuebunny/crossref_metadata_2025_split huggingface dataset:
S‐Cysteinylated Transthyretin in Cerebrospinal Fluid as a Biomarker of Specimen Integrity
Authors: Kremer Schuyler Phillip , Borges Chad 
Published: January 2025

AbstractBackgroundCurrently there is no way to determine if archived cerebrospinal fluid (CSF) specimens have been properly handled and can be considered suitable for research purposes. Transthyretin (TTR) is abundant in CSF and undergoes a redox reaction that shifts its native proteoform into an S‐cysteinylated form. This reaction proceeds spontaneously ex vivo when CSF is thawed, but ceases at storage temperatures of ‐80°C. The relative abundance of these TTR proteoforms can be measured using dilute‐and‐shoot, intact protein liquid chromatography/mass spectrometry (LC/MS). Here we report that the spontaneous ex vivo changes in TTR S‐cysteinylation that occur when CSF is in the thawed state are systematic and substantial enough to potentially qualify the relative abundance of S‐cysteinylated TTR as an endogenous marker capable of tracking specimen integrity.MethodTwelve CSF samples that were recovered postmortem were provided by Banner Sun Health Research Institute. The specimens were from patients diagnosed with Alzheimer’s or Parkinson’s disease or deemed by a pathologist as neurologically normal. A 1:2 dilution of 10 µL of CSF with 0.1% trifluoroacetic acid was directly injected onto a capillary LC system through a protein captrap (via a 10‐minute run), then into a time‐of‐flight mass spectrometer. Raw mass spectra were averaged over the TTR elution period. Following charge state deconvolution, the peak heights representing S‐cysteinylated TTR and native TTR were determined. Specimens were then incubated at 37°C for 24 hours to drive the ex vivo oxidation process to its conclusion and the LC/MS measurement process was repeated.ResultThe mean relative percentage of all initially measured CSF specimens was 23.1% (± 20% SD). Following 24 hours of incubation at 37°C, the mean relative percentage of S‐cysteinylated TTR increased to 86.0% (± 5.3% SD); paired t‐test p<0.0001 and ROC c‐statistic=0.99.ConclusionThe dynamic range observed in the relative percentage of S‐cysteinylated TTR between nominally fresh and fully ex vivo‐oxidized CSF specimens was substantially greater than that observed in our previously developed ΔS‐Cys‐Albumin assay, which is used to forensically track the exposure of blood plasma and serum to thawed conditions. This suggests that a ΔS‐Cys‐TTR assay could find similar utility for archived CSF specimens.
Is the US infusion capacity sufficient for the expected demand with the emergence of disease‐modifying Alzheimer’s treatments?
Authors: Mattke Soeren , Chen Jiahe , Hanson Mark 
Published: January 2025

AbstractBackgroundDisease‐modifying treatments for Alzheimer’s disease (AD) are becoming available. To date, all current treatments require intravenous infusion, and concerns have emerged that lack of infusion capacity may limit access to treatment. We predict supply and demand for infusions for AD treatment in the US under different assumptions over a 10‐year period.MethodWe use a Markov model to predict the number of individuals identified as eligible for AD treatment from 2023 to 2032, taking into account constrained capacity for AD specialist visits and confirmatory biomarker testing. We analyze chronic treatment starting at mild cognitive impairment (70% of patients) and mild dementia (30%) until transition to moderate dementia with infusions every two and four weeks for an estimated duration of 5.7 years, and time‐limited treatment every four weeks for 52 weeks as a lower bound estimate. National historic trends of infusion capacity were obtained from the CDC’s Ambulatory Health Care Data surveys and projected forward. Estimates for excess capacity and future growth of capacity for AD treatment were obtained from a survey covering 404 US infusion centers.ResultThe model predicts that 370,527 patients would be eligible to start treatment in 2023, increasing by 1% per year. Based on the CDC data, around 21 million infusions across therapeutic areas would be provided in 2023 with a projected annual growth rate of 3%. The survey of infusion centers suggests that 3% of capacity is currently devoted to AD with that share growing 1% per year, as well as up to 17% average unused capacity. Figure 1 shows the projected supply and demand. The solid lines show demand for the three types of treatment, the green and black dashed lines the projected supply and the maximum projected supply, if all unused capacity were devoted to AD infusions.ConclusionProjected US infusion capacity would be insufficient for all three treatment types, and even the maximum projected capacity would only be sufficient for time‐limited treatments. Expansion of capacity and introduction of treatments that do not require intravenous infusions will be necessary to ensure timely access to treatment.
Feasibility of detecting Amyloid burden in preclinical Alzheimer’s disease with quantitative magnetization transfer MRI
Authors: Mao Andrew , Flassbeck Sebastian , Marchetto Elisa , Rusinek Henry , Assländer Jakob 
Published: January 2025

AbstractBackgroundMagnetization transfer (MT) MRI is sensitive to the presence of macromolecules, including amyloid‐beta, and previous work suggests that it may be useful for discriminating patients with Alzheimer's disease (AD) from healthy controls. In this study, we investigated if quantitative MT (qMT) is capable of detecting the amyloid concentration in a preclinical cohort.MethodWe recruited 14 subjects with a clinical dementia rating of 0 from NYU's ADRC cohort (7 male, mean age 74, 6 amyloid‐negative). An experimental 12 min qMT technique with an effective 1.24 mm isotropic resolution was used to obtain 6 parameter maps describing an unconstrained 2‐pool qMT model (Figure 1). MPRAGE and FLAIR images were acquired at 1 mm isotropic, rigid‐body registered to the qMT maps and used to perform Freesurfer‐based cortical parcellation. [18F]Florbetaben (FBB) images acquired within the preceding 24 months were rigid‐body registered to the qMT maps and used to compute average measurements across each cortical lobe for each hemisphere at 50% of the cortical thickness. Pearson's correlation coefficients were computed for all 6 qMT parameters with respect to FBB SUVR values. Amyloid‐positive and negative groups were compared using one‐way ANOVA tests. 5 Desikan‐Killiany ROIs containing substantial artifacts in the qMT maps were excluded from all analyses, though some imaging artifacts remain.ResultThe exchange rate between the two spin pools and the macromolecular pool's longitudinal relaxation rate were found to be both negatively correlated with amyloid concentration and significantly decreased in amyloid‐positive subjects most prominently within the temporal lobe (Figures 2–3). The former is consistent with previous reports in more advanced AD stages, but the latter has not previously been reported as its value is fixed in most qMT methods. However, we observed no significant changes in the macromolecular pool size—which encompasses both myelin and amyloid‐beta—with increasing amyloid burden.ConclusionMT MRI may be a promising tool for monitoring amyloid accumulation without the need for contrast agents or radiotracers. A larger cohort and a further optimized qMT sequence are needed to validate these preliminary findings.
Leveraging WeChat for Dementia Caregiver Support: Insights from a Process Evaluation
Authors: Hong Y. Alicia , Shen Kang , Chang Wei‐Hsuan 
Published: January 2025

AbstractBackgroundThe evaluation of mHealth interventions often lacks detailed process evaluation data. This study presents the design and results of a process evaluation for the Wellness Enhancement for Caregivers (WECARE) program, an mHealth intervention designed to improve caregiving skills and psychosocial wellbeing of Chinese American dementia caregivers. This evaluation focused on understanding the acceptance, engagement, and the barriers and facilitators influencing behavioral changes among participants, offering valuable feedback for program refinement and dissemination.MethodA group of 23 Chinese American family caregivers for persons with dementia participated in the WECARE, delivered via WeChat, a widely used social media platform in Mandarin‐speaking communities. WECHAT sent multimedia materials for psychoeducation and skills enhancement six days per week over a seven‐week period. In addition, weekly surveys were distributed via WeChat to gather participants' experiences and suggestions regarding the program.ResultResponse rates to the weekly assessments ranged from 40% to 80%. The study found a higher level of participant interaction with private messaging as opposed to links to external surveys. WeChat’s text and audio message features enriched the quantitative survey data, yielding deeper qualitative insights. The analysis indicated a positive correlation between the applicability of the content and participants' implementation of the intervention strategies in their daily routines, as well as noticeable behavioral improvements. Suggestions from participants were also collected for future enhancements of the program.ConclusionThe process evaluation data provided critical insights into the implementation and effectiveness of mHealth initiatives, particularly for minority groups such as Chinese American dementia caregivers. The use of short interactive surveys incorporating open‐ended questions on preferred social media platforms proved to be an efficient method for both process evaluation and increasing participant engagement. This study highlights the importance of continued research into process evaluations to refine and improve mHealth interventions for marginalized groups.
Dementia Mortality in the United States, 2020‐2022
Authors: Kramarow Ellen A. , Tejada‐Vera Betzaida 
Published: January 2025

AbstractBackgroundDementia‐related mortality increased significantly in the first year of the COVID‐19 pandemic in the United States. Explanations for the rise in dementia‐related death rates are complex and multi‐factorial. Older adults with dementia often have other chronic conditions that result in increased risk of death. Residence in institutional settings, more common among older adults and those with dementia, was associated with COVID‐19 mortality, particularly at the beginning of the pandemic. Death rates for both COVID‐19 and dementia among the older population have declined since 2020. However, dementia‐related death rates remain higher than pre‐pandemic levels. This research describes the changing contribution of COVID‐19 deaths to overall dementia mortality.MethodsThis analysis uses mortality data from the 2020‐2022 National Center for Health Statistics multiple cause‐of‐death files. Dementia‐related deaths are those with International Classification of Diseases, 10th Revision cause‐of‐death codes F01 (vascular dementia), F03 (unspecified dementia), G30 (Alzheimer disease), or G31 (other degenerative diseases of nervous system) reported anywhere on the death certificate. For adults age 65 and older, we describe the underlying and contributing causes of death associated with dementia mortality by sex, age group, race and Hispanic origin, and place of death.ResultsIn 2022, 6.7% of death certificates for adults age 65 and older with dementia recorded anywhere on the death certificate also mentioned COVID‐19, a decline from 7.9% in 2021 and 12.0% in 2020 (Figure 1). Declines in the percentage with COVID‐19 mentioned were similar for older Black non‐Hispanic, White non‐Hispanic, and Hispanic decedents. From 2020 to 2022, the percentage of dementia‐related deaths with COVID‐19 mentioned declined for deaths in nursing homes or hospice facilities (from 13.8% to 6.8%) and increased for deaths at home (from 2.2% to 4.3%). In 2022, for all dementia‐related deaths among adults age 65 and older, the leading causes reported as underlying causes of death were dementia (64.6%), heart disease (9.1%), stroke (4.6%), COVID‐19 (3.9%), cancer (2.9%), and Parkinson disease (2.4%) (Figure 2).ConclusionsDementia‐related mortality in the United States increased during the COVID‐19 pandemic. To date, dementia‐related death rates remain above pre‐pandemic levels, but the contribution of COVID‐19 to dementia‐related deaths has declined.
Combined population attributable fractions for dementia are dependent on strong assumptions of the form of interactions between risk factors: an analysis of data from the Canadian Longitudinal Study on Aging
Authors: Jones Aaron , Dolatshahi Yasaman 
Published: January 2025

AbstractBackgroundSeveral recent studies have used communality weights to calculate a combined population attributable fraction (PAF) of modifiable risks factors for dementia. Other research has suggested this method may be underestimating the true PAF. We applied multiple methods to calculate the combined PAF of 12 modifiable risk factors using record‐level, national Canadian data.MethodWe used baseline data (2011‐2015) from the comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA). We measured the 12 risk factors identified in the Lancet Commission on dementia prevention, intervention, and care. We calculated a combined PAF of these risk factors using the independent multiplicative method of Barnes and Yaffe (BY‐M), the additive and multiplicative methods of Welberry (W‐A and W‐M), and communality‐adjusted multiplicative method of Norton (N‐M). We also implemented a novel method (J‐MA) to mix multiplicative and additive interactivity based on the number of risk factors present. All methods incorporated sample weights and used the risk ratios from the Lancet Commission.ResultThere were 30,097 baseline participants in the CLSA ranging in age from 45 to 85 years (median 62). Combined PAFs varied widely: 78.5%(W‐M), 75.9% (BY‐M), 59.8% (J‐MA), 58.2% (W‐A), and 43.3% (N‐M). The BY‐M and W‐M methods resulted in unrealistically high combined risk ratios (RR >90) in individuals with many risk factors. The other methods produced broadly realistic results. Despite a nominally multiplicative form, N‐M produced results consistent with sub‐additive interactivity and makes arbitrary analytic choices. The J‐MA method also uses an arbitrary function to blend multiplicative and additive interactions. The W‐A approach made no assumption other than additive interactivity.ConclusionAssumptions regarding how risk factors for dementia interact highly influence combined PAFs. All multiplicative methods produce either unrealistic results or require arbitrary analytic choices. The additive method makes no arbitrary assumptions but may not reflect the actual form of interactions between risk factors. Not enough is known on how modifiable risk factors for dementia interact to estimate combined PAFs with confidence. When reporting PAFs for dementia a range of possible values, including one assuming additive interactions, should be provided and the assumptions behind each value clearly stated.
Care negotiation between people living alone with dementia in the United States and non‐kin caregivers
Authors: Lowers Jane , Smith Colby , Brus Kaitlyn , Perkins Molly , Hepburn Kenneth 
Published: January 2025

AbstractBackgroundOne in five people with cognitive impairment or dementia lacks family caregivers. People aging alone receive care from non‐family sources, including friends and neighbors, but the dynamics of these relationships are unexplored.MethodThematic analysis of qualitative interviews with 15 people with cognitive impairment or early dementia without close family and 14 non‐family caregiversResultWe identified five themes that shape non‐family dementia caregiving dynamics: 1) establishing a relationship of trust, 2) personal motivations for seeking/providing care, 3) negotiating caregiving etiquette, 4) establishing caregiving boundaries, 5) the role of distant family.ConclusionDementia caregiving by non‐family involves ongoing interpersonal negotiation of trust, roles, and boundaries.
Alzheimer’s Disease and related dementias prevalence higher in Appalachian counties within Central Appalachia
Authors: Wing Jeffrey , Rajczyk Jenna , Burke James 
Published: January 2025

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) prevalence varies geographically in the US. The Appalachian region has lower educational attainment and health care access barriers compared to non‐Appalachian regions. The objective of this proposal is to assess whether the geographic variation of ADRD in Central Appalachia is explained by county‐level sociodemographic factors or access to care.MethodsCenters for Medicare and Medicaid Services Public Use Files from 2015‐2018 were used to estimate county‐level ADRD prevalence among all fee‐for‐service beneficiaries in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia). Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission’s Appalachian/non‐Appalachian designation, and by rural/urban (Rural‐Urban Continuum Codes) classification. Models were then adjusted for: (1) county‐level demographics including age, gender, Medicaid eligibility, and comorbidities (atrial fibrillation, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, ischemic heart disease, schizophrenia/other psychotic disorders, and stroke); (2) sociodemographics (race/ethnic distribution, education, aging population distribution, and renter‐occupied housing); and (3) diagnostic access (PCP visits, neurology visits, and imaging scans).ResultsA total of 592 counties comprise the Central Appalachian region where 43% (n = 255) are Appalachian and 45% (n = 267) are rural counties. The prevalence of ADRD did not vary over the time period but was higher for Appalachian counties both overall (PR: 1.03; 95% CI: 1.02, 1.04) and after adjustment (PR: 1.02; 95% CI: 1.00, 1.03) compared to non‐Appalachian counties. This difference was similar among rural and urban counties (p = 0.326). These differences did vary across the states in the region (p = 0.0040). In North Carolina and Tennessee, Appalachian counties had higher ADRD prevalence, while in Ohio and Tennessee, rural counties have lower ADRD prevalence.ConclusionThere is a consistent difference between Appalachian and non‐Appalachian counties, with Appalachian counties having relatively higher ADRD prevalence (in the range of 2.0‐3.0% times higher) than non‐Appalachian counties. These differences persisted even after considering age, education, other sociodemographic factors and access to care measures.
Characterizing Disease Modifying Effects Using Overall Treatment Effect Across all Post‐Baseline Visits
Authors: O'Gorman John , Chen Tianle , Wang Guoqiao 
Published: January 2025

AbstractBackgroundThe well‐accepted statistical efficacy inference approach for Alzheimer’s disease (AD) clinical trials compares the absolute difference in change from baseline at the last study visit using MMRM (henceforth referred to as MMRM‐Last‐Visit). Recent AD clinical trials have shown that treatment effects may be manifested prior to 18 months. The objective is to evaluate models estimating an overall treatment effect across all post‐baseline visits that may characterize disease modifying effects in contemporary early AD clinical trials.MethodWe will evaluate the performance of: (1) MMRM‐Last‐Visit, (2) MMRM‐All‐Visits, estimating an overall treatment effect across all post‐baseline visits, (3) Linear mixed effects (LME) model with time being continuous, comparing the slopes across treatment groups, (4) Constrained LME, comparing the slopes which constraining the treatment groups to have the same mean baseline, (5) Longitudinal data analysis model with natural cubic spline in time (LDA‐NCS), modeling the raw data and comparing the absolute difference in change from baseline at the last visit (LDA‐NCS ‐Last‐Visit), (6) Constrained LDA‐NCS, similar to LDA‐NCS while constraining treatment groups to have the same mean baseline, and (7) proportional/percentage MMRM (pMMRM), which models the percentage reduction across all post‐baseline visits. Simulated data mimicking disease modifying effect in contemporary early AD trials were used for the evaluation. Subsequently, we evaluate the performance using bootstrapping techniques.ResultWe will present simulation results that mimic a range of assumptions from contemporary early AD trials, including sample size, power, and type I error results.ConclusionModels estimating an overall treatment effect across all post‐baseline visits have shown promise in characterizing disease modifying effects seen in contemporary early AD clinical trials and may help accelerating drug development.This study was funded by Biogen, JO and TC are employees and shareholders of BIogen.
Priorities to Support Care Partners of People Living with Dementia: Results of a Modified Delphi Process
Authors: Dawson Walter D , Gelmon Sherril B , Reed Jenn Hollandsworth 
Published: January 2025

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) place substantial burdens on care partners. The need to better support ADRD care partners through policy actions is high, specifically to enhance existing services and reduce inequities experienced by historically underserved communities.MethodBetween July and September 2023, a modified Delphi process was employed to determine policy and program priorities for supporting Oregon‐based care partners. Representatives of organizations serving people living with ADRD and their care partners, as well as organizations serving selected historically and currently underrepresented communities, were invited to participate (N = 40). Prospective participants created and categorized a preliminary list of ideas during an initial meeting. The eight thematic categories (Care Partner Supports, Programs/Services, Information Resources, Care Coordination, Data Systems/Technology, Policy, Funding/Financing, and Professional Education/Workforce Development) framed the three surveys for the Delphi process. In survey 1, respondents received the list of ideas and were invited to generate up to five additional priority ideas per category. In survey 2, participants reviewed the revised list and rated each idea on a five‐point scale of importance. In survey 3, participants were presented with the mean importance score for each idea and then indicated five top priorities for each thematic category.ResultThe 15 ideas with the highest weighted scores were each endorsed by at least 60% of survey 3 respondents, and were arrayed across six of the thematic areas: Care Partner Supports = 4, Programs/Services = 3, Funding/Financing = 3, Information Resources = 2, Care Coordination = 2, and Professional Education/Workforce Development = 1.ConclusionThe use of the Delphi process facilitated input from individuals with different perspectives, and gave all participants’ contributions equal weight, achieving a balance of power and minimization of bias that might not have occurred through methods such as in‐person discussion and debate. This process identified specific and actionable priorities to better support Oregon care partners through program development and policy action, and may have applicability elsewhere.