bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between dual‐decline in cognition and gait speed with risk of dementia – results from the ASPREE trial cohort
Authors: Collyer Taya , Murray Anne , Woods Robyn , Storey Elsdon , Chong Trevor , Ryan Joanne , Orchard Suzanne , Brodtmann Amy , Srikanth Velandai K , Shah Raj C , Callisaya Michele L 
Published: December 2022

AbstractBackgroundDual decline in gait speed and cognition is associated with an increased risk of dementia. However, it is unclear if risks are conferred by decline in domain‐specific cognition and gait. We aimed to examine associations between dual decline in gait speed and cognition (global cognition, memory, processing speed and verbal fluency) with risk of dementia.MethodsProspective cohort study. Participants were from the ASPREE (ASPirin in Reducing Events in the Elderly) study, a double‐blind, randomized, placebo‐controlled trial of low dose aspirin in older adults (≥70 years; ≥65 if US minority). Of 19,114 randomized participants, 16,855 (88%) had longitudinal gait and cognitive data. Gait speed was measured at 0, 2, 4, 6 years and close‐out. Cognitive measures included Modified Mini‐Mental State examination (3MS, global cognition), Hopkins Verbal Learning Test‐Revised (HVLT‐R, memory), Symbol Digit Modalities (SDMT, processing speed) and Controlled Oral Word Association Test (COWAT‐F, verbal fluency), assessed at years 0, 1, 3, 5, and close‐out. Participants were classified into four groups: 1) dual decline in gait and cognition; 2) gait decline only; 3) cognitive decline only and 4) non‐decliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as decline in gait speed ≥0.05 m/s per year across the study. Dementia (DSM‐IV criteria) was adjudicated by an expert panel using cognitive tests, functional status and clinical records. Cox proportional hazard models were used to estimate risk of dementia adjusting for covariates with death as competing risk.ResultsThe mean age of participants was 75.0 (SD4.4) years. Compared with non‐decliners, risk of dementia was highest in the gait+HVLT‐R decliners (HR 24.7; 95% CI 16.3‐37.3), followed by the gait+3MS (HR 22.2; 95% CI 15.0‐32.9), gait+COWAT‐F (HR 4.66 95%; CI 3.5‐6.3) and gait+SDMT (HR 4.3 95% CI 3.2‐5.8) groups. Dual decliners also had higher risk of dementia than those with either gait or cognitive decline alone for 3MS and HVLT‐R.ConclusionThe combination of decline in gait speed and memory may be the best suited to predict future dementia risk.
A novel episodic memory test optimized for smart phone high‐frequency assessments
Authors: Anwyl‐Irvine Alexander L , Kaula Alexander J , Cashdollar Nathan , Taptiklis Nick , Cormack Francesca K 
Published: December 2022

AbstractBackgroundDecline in episodic memory is a strong marker of neurodegenerative diseases, making it an important target for cognitive assessment. We present a new remote, repeatable, and brief assessment of episodic memory and visual short‐term memory (VSTM) for smart phone deployment. We evaluated this task for sensitivity to age and established cognitive measures of memory and attention.MethodThe task consists of a learning phase where participants see a sequence of items, then are asked to replicate the item order and location by dragging and dropping these items on‐screen. A recall phase follows a minimum 12‐hour delay, with replication of the earlier response. Each session takes less than 2 minutes. The first phase supplies metrics of spatial and order precision VSTM, with the second phase characterising long‐term episodic memory.Experiment 1 (n = 133) compares the task with CANTAB assessments of visuospatial memory. In Experiment 2 (n = 80) the novel task was repeated twice daily for a week, alongside momentary mood ratings, and a more comprehensive battery of CANTAB tasks at baseline.In Experiment 1, multiple regression and dominance analyses explore the independent and shared variance of measures in explaining age. In Experiment 2, clustering and multivariate autoregressive models outline differences in timeseries relationships between mood and memory, and age.ResultExperiment 1 revealed that CANTAB measures and novel spatial and order metrics were correlated with age (r = .20 to r = .37, adjusted P = <.05). Multiple regression showed models with CANTAB Paired Associate Learning (PAL) score, and delayed novel spatial metrics were significantly predictive of age (t = ‐4.08, 3.17, p <.005). The dominance analysis revealed novel immediate precision overlapped with existing measures in predicting Age, while delayed precision had more unique variance (4.6% vs 0.62% unique sample variance explained in Age, accounting for PAL).Experiment 2 characterised variance in individual learning curves over time and differing autoregressive processes associated with age and CANTAB measures.ConclusionWe present a brief novel episodic memory task that can be deployed remotely, with delayed spatial precision significantly predictive of healthy Ageing. Additionally, we show this test’s suitability as a repeated assessment, compatible with high‐frequency study designs in older populations.
Neuropathology in the LifeAfter90 Study: Update on an Ethnically Diverse Cohort Study of Oldest‐Old
Authors: Dugger Brittany N , Jin Lee‐Way , Vargo Veronica , DeCarli Charles S. , Johal Sharan , Gilsanz Paola , Mungas Dan M. , Kawas Claudia H. , Glymour M. Maria , Corrada Maria M. , Whitmer Rachel A. 
Published: December 2022

AbstractBackgroundNeuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life; however, this has been limited to studies of oldest‐old non‐Hispanic white (NHW) decedents. Our goal was to characterize neuropathology in a cohort of diverse oldest‐old decedents.MethodThe Life after 90 study is an ongoing cohort study of members of Kaiser Permanente Northern California, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Participants are examined on average every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v. 10.ResultAs of January 2022, 216 participants (26% of sample) were enrolled in autopsy (autopsy enrollees: 20% Asian, 15% African American, 17% Latino, 9% Multiracial/Other, and 39% NHW) with 25 deceased and neuropathological evaluations completed. Average age of death was 95 years (range 91‐106), 13 (62.5%) were female, 6 Latino, 14 NHW, 3 Multiracial, 1 Asian, and 1 African American. At final clinical exam, 3 participants had dementia (12%), 8 questionable/mild cognitive impairment (32%), and 14 were cognitively normal (56%). With respect to Alzheimer’s disease (AD) neuropathologic diagnosis, 8 met criteria for intermediate likelihood (32%), 11 low (44%), and 6 did not have AD (24%); none had high AD likelihood. All participants had some level of neurofibrillary tangles (NFTs); median Braak NFT stage was II (range I‐V). Six participants lacked plaques, and highest Thal phase was 4. Eleven participants (44%) had Lewy bodies. Hippocampal sclerosis was seen in 1 participant, whereas TDP‐43 inclusions were detected in 5 (20%). Cerebral amyloid angiopathy was seen in 13 participants (25%). The most common assessed pathologies were age related tau astrogliopathy in 19 participants (76%) and some degree of arteriolosclerosis in 24 participants (96%) although only 4 were considered to have severe arteriolosclerosis.ConclusionThis diverse cohort of oldest‐old individuals indicate numerous brain pathologies are present with advanced age, albeit most participants having mild severity and distributions of pathologies providing further evidence of the complex and multifactorial nature of clinic‐pathological correlations.
Ex vivo Expanded Human Regulatory T Cells Modify Neuroinflammation in a Preclinical Model of Alzheimer’s disease
Authors: Faridar Alireza , Vasquez Matthew , Thome Aaron D , Yin Zheng , Xuan Hui , Wang Jing Hong , Thonhoff Jason R , Zhao Weihua , Zhao Hong , Beers David , Wong Stephen T.C. , Masdeu Joseph C. , Appel Stanley 
Published: December 2022

AbstractBackgroundRegulatory T cells (Tregs) play a neuroprotective role by suppressing microglia and macrophage‐mediated inflammation and modulating adaptive immune reactions. We previously documented that Treg immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD). Ex vivo expansion of Tregs restores and amplifies their immunosuppressive functions in vitro. A key question is whether adoptive transfer of ex vivo expanded human Treg can suppress neuroinflammation and amyloid pathology in a preclinical mouse model.MethodAn immunodeficient mouse model of AD was generated by backcrossing the 5xFAD onto Rag2 knockout mice (5xFAD‐Rag2KO). Human Tregs were expanded ex vivo for 24 days and administered to 5xFAD‐Rag2KO. Changes in amyloid burden and microglia characteristics were evaluated using ELISA and confocal microscopy. NanoString Mouse AD multiplex gene expression analysis was applied to explore the impact of ex vivo expanded Tregs on the neuroinflammation transcriptome.ResultElimination of adaptive immune system in 5xFAD‐Rag2KO mice was associated with upregulation of 95 inflammation genes, amplified number of reactive microglia and increased plaque size. Following peripheral administration, ex vivo expanded human Tregs crossed blood‐brain barrier of 5xFAD‐Rag2KO and reduced amyloid burden and reactive microglia. Interrogation of inflammation gene expression documented down‐regulation of pro‐inflammatory cytokines (IL1A&B, IL6, Tnfa, IFNγ), complement cascade (C1qa, C1qb, C1qc, C4a/b), toll‐like receptors (Tlr3, Tlr4 and Tlr7) and microglial activations markers (CD14, Tyrobp,Trem2).Conclusion
Ex vivo expanded human Tregs, with amplified immunomodulatory function, suppressed neuroinflammation and alleviated AD pathology in vivo. Our results provide preclinical evidences for Treg cell therapy as a potential treatment strategy in AD.
Convergent and criterion validity of a computer adaptive self‐administered word list memory test and the Mayo Test Drive composite: correlations with traditional measures and group difference by PET imaging biomarker status in persons without dementia.
Authors: Stricker Nikki H. , Twohy Erin L , Albertson Sabrina M. , Christianson Teresa J. , Stricker John L , Machulda Mary M. , Karstens Aimee J , Kremers Walter K. , Hassenstab Jason J. , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C. 
Published: December 2022

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.MethodsMayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.ResultsConvergent validity was supported through significant correlation (p’s < .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s < .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s<.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.ConclusionsMTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.
Framework for disclosing AD biomarker results following cognitive assessment within a pragmatic, multi‐country implementation evaluation
Authors: MacLeod Tim , Baksh Magda Ruth , Filho Otelo Corrêa dos Santos , Govia Ishtar , Robledo Luis Miguel Gutierrez , Kowa Hisatomo , Ritchie Craig W. , Willis Deanna R , Coppinger Justine , Ball Daniel E , Murray James F , Largent Emily A. 
Published: December 2022

AbstractBackgroundBlood‐based biomarker tests are critical tools with the potential to change pathways for dementia diagnosis and care. These tests are less invasive than PET scan or lumbar puncture, potentially more affordable, and thus more accessible across more care settings and in more countries. Utilization in primary care settings together with brief cognitive assessments provides a compelling use case that could transform diagnosis, assessment and care.A critical challenge to the widespread adoption of blood‐based biomarker testing is the issue of disclosure. To date, Alzheimer’s Disease and Related Dementias (ADRD) biomarker disclosure recommendations have primarily focused on disclosure in research and/or specialized‐care settings. Primary care clinicians are well situated to conduct biomarker testing, but they are likely to need training and support to develop confidence and capacity to communicate results.MethodReview of literature findings involving biomarker disclosure and input from dementia researchers from six countries reflecting diverse health care systems informed development of a disclosure framework to support the inaugural project of the Davos Alzheimer’s Collaborative’s (DAC) Systems Preparedness (DAC‐SP) initiative. This project seeks to promote routine uptake of cognitive screening among people ≥ age 60 and, when cognitive impairment is identified, blood‐based biomarker testing. The biomarker testing is completed using a commercially available, CLIA‐certified test that measures the likelihood of amyloid pathology when cognitive impairment is identified.ResultThe framework recognizes that biomarker disclosure is part of a comprehensive patient evaluation that includes cognitive assessment and a broader discussion of the patient’s health and wellbeing. It divides disclosure into five phases: pre‐test education; consent for and administration of testing; disclosure of results and discussion of treatment plan; provision of educational materials; and follow up (Table 1). This general framework can be adapted for site‐specific factors such as health literacy, health systems operations, legal structures, and cultural relevance.ConclusionAs part of a pragmatic multisite implementation evaluation of a screening and early detection program including high and middle income countries, the authors have developed a framework to guide biomarker disclosure to patients in primary care settings. This provisional framework represents an important first step towards clinical consensus building on biomarker disclosure.
The association of accelerometer‐measured physical activity, white matter hyperintensity volume, and cognition in normal aging
Authors: Calcetas Amanda T. , Bangen Katherine J. , Thomas Kelsey R. , Smith Christine N. , Bordyug Maria , Brenner Einat K , Zlatar Zvinka 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMH) are an indicator of small vessel cerebrovascular disease, which increases the risk of developing Alzheimer’s disease and related dementia (ADRD). Moderate to vigorous intensity physical activity (MVPA), can help maintain brain structure, function, and cognition in aging. However, the mechanisms by which MVPA may preserve cerebrovascular health remain understudied. To help elucidate the cerebrovascular mechanisms by which MVPA preserves cognition, we examined associations of MVPA and WMH volume, MRI markers of neurodegeneration, and cognition.MethodForty‐three adults without cognitive impairment (aged 65–85, 74% female) were recruited from ongoing studies at the University of California, San Diego and underwent MRI exams and comprehensive neuropsychological assessment. Waist‐worn accelerometers objectively measured MVPA for one week. WMH volume was quantified on fluid‐attenuated inversion recovery (FLAIR) scans using semi‐automated procedures and were log transformed and normalized by total intracranial volume (ICV). Hippocampal volume (normalized by ICV) and entorhinal thickness were derived via FreeSurfer. Adjusting for age, sex, and education, ANCOVA models compared participants who had <60 minutes of MVPA per week (n = 18; MVPA<60 group) to those who had ≥60 minutes of MVPA per week (n = 25; MVPA≥60 group) on MRI markers of WMH, hippocampal volume, and entorhinal thickness, and neuropsychological performance on measures of executive function, language, and memory.ResultOlder adults in the MVPA≥60 group had lower WMH volume compared to those in the MVPA<60 group (p = 0.036, ηp
2 = 0.108). There were no significant differences in hippocampal volume (p = 0.157, ηp
2 = 0.052) or entorhinal thickness (p = 0.980, ηp
2 = 0.000) between MVPA groups. The MVPA≥60 group performed better on measures of executive function (Trails B, p = 0.030, ηp
2 = 0.109) and language (category fluency, p = 0.030, ηp
2 = 0.110) than the MVPA<60 group, although the groups did not differ on memory performance (p’s >.05).ConclusionEngaging in 60+ minutes of MVPA week may be beneficial for cerebrovascular health and help preserve some aspects of executive and language function performance in older adults. Future work will determine whether better cognitive performance in the MVPA≥60 group is mediated by lower WMH volume. Furthermore, randomized controlled trials that increase MVPA are needed to elucidate cause‐effect associations between MVPA and cognitive and brain health.
End‐of‐life burdensome interventions among Medicare fee‐for‐service beneficiaries with no dementia, non‐advanced dementia, and advanced dementia
Authors: Zhu Yingying , Olchanski Natalia , Freund Karen M , Faul Jessica D , Fillit Howard M , Breslau Rachel M , Cohen Joshua T , Neumann Peter J , Lin Pei‐Jung 
Published: December 2022

AbstractBackgroundOlder adults with dementia have difficulties communicating their treatment preferences and experience end‐of‐life burdensome interventions with discomfort and limited benefits. This study compared utilization of burdensome interventions during the last 90 days of life among Medicare fee‐for‐service (FFS) beneficiaries with no dementia, non‐advanced dementia, and advanced dementia.MethodThis study utilized data from 2000‐2016 Health and Retirement Study (HRS) linked with Medicare and Medicaid claims, and HRS Exit Interviews. We quantified rates of imaging tests and life‐sustaining treatments during the last 90 days of life among those with no dementia, non‐advanced dementia, and advanced dementia. Life‐sustaining treatments include tube feeding, intensive care unit care, cardiopulmonary resuscitation, and invasive mechanical ventilation. Among patients with a claims‐based diagnosis of dementia, we classified them as having advanced dementia if they had three or more activities of daily living limitations and any diagnosis of malnutrition, pressure ulcer, incontinence, or aspiration pneumonia. We used logistic regression to examine factors associated with end‐of‐life imaging tests and life‐sustaining treatments.ResultA higher proportion of beneficiaries with non‐advanced dementia (68%) and advanced dementia (79%) had end‐of‐life imaging tests, compared to those without dementia (57%) (p<0.01). Beneficiaries with dementia were more likely than non‐dementia beneficiaries to receive these imaging tests, controlling for patient characteristics (non‐advanced dementia: OR = 2.2 [95% CI 2.0‐2.5]; advanced dementia: OR = 5.4 [4.5‐6.5]). The proportion of receiving end‐of‐life life‐sustaining treatments was lower among the non‐advanced dementia cohort (23%), compared to non‐dementia (27%) and advanced‐dementia (27%) individuals (p<0.01). After adjusting for patient characteristics, beneficiaries with dementia were more likely than those without dementia to receive at least one life‐sustaining treatment (non‐advanced dementia: OR = 1.1 [1.0‐1.2]; advanced dementia: OR = 1.9 [1.6‐2.3]). Younger age, survey self‐respondents, beneficiaries with fewer instrumental activities of daily living limitations and no advance care planning were more likely to have end‐of‐life imaging tests and life‐sustaining treatments.ConclusionOur findings suggest that older adults with dementia, especially advanced dementia, are more likely to receive end‐of‐life burdensome interventions compared to individuals without dementia. Advance care planning involving patients with dementia, their families, and physicians about end‐of‐life treatment may improve the quality of care.