bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards clinical implementation: Establishing standardized operating procedures to limit the pre‐analytical sample handling effects on the novel Alzheimer’s disease blood‐based biomarkers
Authors: Gouda Mariam , Teuling Mark M.Den , Hussainali Zulaiga , van Leeuwenstijn Mardou S. S. A. , ’t Veld Sjors G.J.G. in , Pijnenburg Yolande A.L. , Edelmayer Rebecca M. , Teunissen Charlotte E. , Verberk Inge M.W. 
Published: June 2023

AbstractBackgroundClinical implementation of novel blood‐based biomarkers for Alzheimer’s disease (AD) will aid in accurate, less‐invasive diagnosis. However, variation in blood handling may affect the accuracy of biomarker’s measurement. Establishing standardized operating procedures (SOPs) to mitigate these effects is essential for implementing novel blood‐based biomarkers into clinical use. We aim to provide an evidence‐based SOP specific for AD blood‐based biomarkers by studying the effects of multiple pre‐analytical variations in blood samples from AD and healthy controls (HCs). Here, we show the first results obtained, addressing the effect of biomarker’s adsorption to lab plastics, during sample processing.MethodBlood samples are being withdrawn from 150 volunteers (AD and HCs) and treated according to one of ten pre‐analytical experimental protocols. Several aliquots per sample are being obtained, to be shared and analyzed among labs, focusing on labs with novel P‐tau plasma tests. Preliminary results are acquired for the effect of 1x, 2x and 4x tube transfers in fresh polypropylene tubes with fresh pipet tips at every transfer, compared to no tube transfer, as a reference condition. Sample analysis was performed on Simoa using the Simoa neurology 4‐plex E assay (Aβ1‐42, Aβ1‐40, GFAP, NfL), and the P‐tau181 V2 assay. A variation in the median value of one of the measured biomarkers of at least 10% from the reference condition was regarded as a significant change.ResultFormally, medians of all tube transfers for all biomarkers measured (Aβ1‐42, Aβ1‐40, GFAP, NfL and Ptau‐181), stayed within the predefined range, for both AD and HC. However, the levels of Aβ1‐42 and Aβ1‐40 showed an obvious tendency to decrease at the 4th tube transfer. For Aβ1‐40, levels in HCs were more affected compared to those in AD (median 92%; AD: median = 95%). For Aβ1‐42, both AD and HCs showed a similar decrease (median: 91% and 93%). This decrease is not so apparent with the Aβ1‐42/Aβ1‐40 ratio.
ConclusionIn line with the results, 4 tube transfers or less should have no influence on the accuracy of the measured biomarkers. For Aβ peptide measurements, using the Aβ1‐42/Aβ1‐40 ratio appears to stabilize the effect of tube transfer.
Pilot study of social and structural determinants of health (SSDOH) measures in the UPENN Alzheimer’s disease research center
Authors: Stites Shana D. , Midgett Sharnita , Visco Alexis , Mechanic‐Hamilton Dawn 
Published: June 2023

AbstractBackgroundTo mitigate health and healthcare disparities in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) research and care, scientists must be able to characterize and measure social and structural determinants of health (SSDoH) that may help explain heterogeneity in cognitive, functional, and interventional outcomes in AD/ADRD.MethodParticipants (n = 70) were members of the UPENN ADRC clinical cohort with unimpaired cognition who completed the SSDoH measures via an online survey. SSDoH measures were chosen based on content and psychometric properties. Self‐report measures are in the following categories: (1) Education, (2) Occupation, (3) Economic Status and Strain, (4) Stressors and Subjective Stress, (6) Subjective Social Support and Status, and (7) Sociodemographic data, which included self‐report of age, race, language, disability, neighborhood, sex, sexual orientation, and gender identity questions.ResultResults describe piloting the measures, the gaps and strengths of measures, and plans for future collection and analysis. The response rate was 74% (52 out of 70 participants started the survey). Most participants completed the survey within 25 to 30 minutes. Most participants reported being satisfied with the battery, and a few reached out to ADRC staff to express interest in volunteering additional data. Some revision to the longitudinal record of neighborhoods was needed.ConclusionA multidomain battery of SSDoH measures was feasible to implement in the UPENN ADRC clinical cohort. Routine collection of SSDoH may help researchers better understand factors that create disparities in AD/ADRD outcomes and develop interventions to mitigate them.
A prototype robot‐mediated reminiscence therapy (RMRT) for people with dementia
Authors: Yuan Fengpei , Shved Jonathan , Bahour Abdurhman , Crane Monica , Duzan Joshua , Boltz Marie , Bilal Dania , Zhao Xiaopeng 
Published: June 2023

AbstractBackgroundApproximately 6.2 million older Americans are living with Alzheimer’s Disease and Alzheimer’s Disease related dementias (AD/ADRD). Reminiscence therapy (RT) has shown a positive impact on the mood, cognition, communication, and quality of life of people with AD/ADRD (PLWD). Traditional RT is usually delivered by professional facilitators, limiting the accessibility of RT to PLWD. Robotics has the potential to facilitate RT, enabling accessible, home‐based, personalized RT.MethodA prototype of robot‐mediated reminiscence therapy (RMRT) was implemented using a humanoid social robot, Pepper. A multimedia file, including pictures, audio, and video, was created as a source of prompts for memory stimulation. The file consisted of nine topics, including pets, cars, holidays, hobbies, chores, movies, music, sports, and local scenes. In each topic, the robot displayed a memory trigger on the left side of its tablet and engaged in a conversation with PLWD. The robot started the conversation with background information relevant to the memory trigger and then provided appropriate prompts (e.g., questions) to encourage PLWD to talk. The PLWD can control the robot by clicking buttons and using voice input.The prototype RMRT was tested with two female participants (one with mild dementia due to AD, aged 75‐85 and one with mild cognitive impairment, aged above 85). They used the topics, holidays, movies, and music. Questionnaires were used to assess their acceptance and user experience.ResultBoth participants reported a positive user experience with the RMRT. The robot was easy to use, its appearance was pleasing, and talking with the robot was relaxing. Participants preferred to control the robot using both the tablet and voice input. One participant suggested that the user icon should match the user’s gender. Both participants would like to use the RMRT in the future and would recommend it to others.ConclusionThe two participants had a positive experience interacting with the RMRT and made suggestions for improving its design. Our next step is to address the participants’ suggestions for improving the design of the robot and test its usability with a larger sample of PLWD to assess the effectiveness, efficiency, and user experience during RMRT.
Sleep apnea and cognition in older APOE4 carriers and non‐carriers
Authors: Halter Colt M , Woodard John L. 
Published: June 2023

AbstractBackgroundSleep apnea (SA) is common in late life and has received much attention as a possible risk factor for Alzheimer’s disease (AD). However, cross‐sectional findings suggest little, if any, relationship between SA and impaired cognition in Apolipoprotein E ε4 (APOE4) allele carriers and non‐carriers. Preclinical AD detection is essential, and the relationship between SA, APOE4, and cognitive impairment merits further analysis in a large sample. Therefore, we investigated whether SA and APOE4 carrier status were related to neuropsychological functioning using the National Alzheimer’s Coordinating Center (NACC) database. We predicted an interaction between SA and APOE4 carrier status, such that APOE4 carriers with SA would show the most significant impairment in cognition.MethodParticipants were at least 65 years of age with normal cognitive status. Sample sizes ranged from 1902 to 1945, depending on available neuropsychological data. SA presence or absence was clinician‐determined. Participants completed nine cognitive measures, including semantic memory (verbal category fluency), executive functioning (verbal letter fluency), visual scanning and executive functioning (Trails A and Trails B), global cognitive functioning (total Montreal Cognitive Assessment [MoCA]), and memory (MoCA–delayed recall and Benson Complex Figure Copy – delayed). We compared non‐carriers (ε3/ε3) and heterozygous carriers (ε3/ε4) using three‐way ANOVAs and ANCOVAs, while considering sex and age.ResultThere were no main or interaction effects of SA, carrier status, or sex on participant age (p>.05). Therefore, age was used as a covariate in three‐way ANCOVAs to enhance the power to detect a significant effect if present. Contrary to our hypotheses, there were no main or interaction effects involving SA (p>.05) with sex or carrier status. An APOE4 main effect was observed only for MoCA total and delayed recall scores.ConclusionPast cross‐sectional studies report a weak or null relationship between SA and cognitive performance. We found no main or interaction effects involving SA with sex or APOE4 carrier status on neuropsychological functioning in a large sample of older adults. Our large sample size helps provide more evidence for these null relationships and is consistent with other large‐sample studies.
White matter hyperintensity, neurofilament light chain, and cognitive decline
Authors: Dhana Anisa , Decarli Charles , Krueger Kristin R , Dhana Klodian , Desai Pankaja , Evans Denis A , Rajan Kumar B 
Published: June 2023

AbstractBackgroundWhite matter hyperintensity (WMH), assessed by magnetic resonance imaging (MRI), is a marker of cerebrovascular disease. Neurofilament light chain (NFL), assessed in the blood, is a biomarker of neurodegeneration. While both measures, WMH and NFL, are associated with cognitive impairment, we aimed to evaluate which of the two measurements is most advantageous in determining the risk of cognitive impairment.MethodWe conducted this investigation in Chicago Health and Aging Project (CHAP), a prospective population‐based cohort study in the United States. The study included 1,323 participants with data on NFL serum concentrations and 923 who underwent an MRI scan and had data on WMH volumes. NFL was measured using an ultrasensitive immunoassay, single‐molecule array technology. MRI scans of the brain were acquired using 1.5‐T systems. Global cognitive function was created as a composite measure of 4 neuropsychological tests, standardized and averaged to z‐scores. Linear mixed‐effects models were used to examine associations of the NFL, WMH, and cognitive decline adjusting for age, sex, race, education, and APOE e4.ResultOf 1,323 participants, 808 (61%) were African Americans, and 38% were men, with an average age of 78.5 years. WMH and NFL were associated with faster cognitive decline in a multivariable‐adjusted model. Individuals in the third tertile of WMH had a faster cognitive decline by 0.029 (95%CI ‐0.052, ‐0.006) units per year compared to the first tertile. Also, compared to the first tertile of NFL, individuals in the third tertile had a faster cognitive decline by 0.029 (95%CI ‐0.046, ‐0.011) units per year. The stratified analysis by the tertiles of WMH showed that NFL was associated with a cognitive decline only in participants in the lowest tertile of WMH (‐0.089; 95%CI ‐0.159, ‐0.02). Similarly, when we stratified analysis by the tertiles of the NFL, we found a significant association of WMH with cognitive decline only participants in the lowest tertile of the NFL (‐0.052; 95%CI ‐0.008, ‐0.024).ConclusionWhile both biomarkers, NFL and WMH, are associated with cognitive decline, our findings suggest that within individuals with low values of NFL, WMH may identify people with a faster rate of decline in cognitive functioning.
Does informing people about modifiable dementia risk factors lead to improved behavioral risk profiles?
Authors: Bartlett Larissa , Doherty Kathleen , Farrow Maree , Eccleston Claire , Bindoff Aidan D , Kitsos Alex , Vickers James C 
Published: June 2023

AbstractBackgroundThe Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) is a large, online, prospective public health cohort study with nested interventions targeting modifiable dementia risk. The objective of ISLAND is to investigate the effectiveness of public health strategies aimed at increasing knowledge about behavioral and lifestyle factors associated with dementia, and to encourage behavior change to reduce future risk profiles at individual and population level.MethodCommencing October 2019, Tasmanian residents aged 50 and over were invited via a rolling media campaign to join ISLAND. Online surveys administered at baseline were repeated annually to enable tracking of changes in physical and mental health, social functioning, dementia risk knowledge, motivations and behaviors. After each survey wave, participants were provided a personal Dementia Risk Profile (DRP), a traffic‐light style report of their own risk level against nine domains, together with WHO recommendations for achieving ‘low risk’ status. For analyses, the DRP provides individual domain scores and a cumulative risk score, computed by summing domain scores (low = 0, medium = 0.5, high = 1). Newsletters and study information included prompts for participants to join the PD‐MOOC, a free, 4‐week online course about preventing dementia, which runs three times each year.ResultParticipants who provided full data at baseline and the October 2021 annual surveys (n = 2,935) reported a significant and moderate‐sized reduction in their cumulative DRP scores (βs = ‐.36 [95%CI ‐.40, ‐.31]. Within this sample, the participants who engaged with the PD‐MOOC (1,208, 42%) reported a small additional independent benefit (βs = ‐.08 [95%CI‐.11, ‐.05]). General knowledge about dementia risk reduction increased across all respondents (βs = .11 [95%CI .06, .15]) and amongst PD‐MOOC participants, the effect was stronger (βs = .61 [95%CI .53, .70]). The results of mediation models testing the role of knowledge and motivations in observed DRP changes will be presented.ConclusionThese preliminary findings support the core hypothesis of ISLAND, that increasing knowledge about modifiable dementia risk factors is associated with action‐taking to change key risk behaviors. Future work will link dementia‐risk knowledge and behavioral patterns over time with cognitive and blood‐based markers of neurodegeneration, to understand the long‐term effects of this online public health project.
Association of tamoxifen and raloxifene therapy with cognitive performance, odds of mild cognitive impairment, and neuroimaging markers of neurodegeneration
Authors: Kara Firat , Lohse Christine M. , Castillo Anna , Tosakulwong Nirubol , Lesnick Timothy G. , Jack Clifford R. , Petersen Ronald C. , Olson Janet E. , Couch Fergus J. , Ruddy Kathryn J. , Kantarci Kejal , Mielke Michelle M. 
Published: June 2023

AbstractBackgroundTamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone receptor‐positive breast cancer. Raloxifene, another SERM, has been used for the treatment of osteoporosis in post‐menopausal women. The aim of this cross‐sectional study was to examine whether a history of tamoxifen or raloxifene use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or structural neurodegenerative MRI markers.MethodThe study included women with and without a personal history of breast cancer enrolled in the Mayo Clinic Study of Aging (MCSA). A history of breast cancer and use of SERMs before the MCSA enrollment visit was abstracted using the Rochester Epidemiology Project medical‐linkage system. Participants had a diagnosis of MCI (prevalent) at the time of enrollment into the MCSA. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive measures z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), hippocampal volume, and Alzheimer’s disease signature cortical thickness.ResultAmong the women aged ≥ 50 at enrollment in the MCSA, 151 had a history of breast cancer, and 2235 had no prior history of any cancer. Of the 151 women with a history of breast cancer, 42 (28%) had taken tamoxifen and 109 (72%) had not at enrollment in the MCSA; 54 had neuroimaging data (tamoxifen = 16; no tamoxifen = 38). Among the women without prior history of cancer at enrollment in the MCSA, 76 (3%) had taken raloxifene and 2159 (97%) had not; 755 had neuroimaging data (raloxifene = 25; no raloxifene = 730). No significant associations between tamoxifen with global or domain‐specific cognition or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders (Table 1). Likewise raloxifene was not significantly associated with global or domain‐specific cognition or odds of MCI in women without a history of cancer after adjusting for confounders (Table 2). We did not find significant associations between SERMs and any neuroimaging outcome (Table 3).ConclusionOur results suggest use of tamoxifen or raloxifene is not significantly associated with cognition in postmenopausal women.
Differences between healthy adults and mild cognitive impairment patients in Category Fluency performance: A scoring method based on words’ Serial Recall Order and item‐level features
Authors: Marco Matteo De , Blackburn Daniel J , O'Malley Ronan , Venneri Annalena 
Published: June 2023

AbstractBackgroundSemantic Memory (SM) alterations occur very early in preclinical AD. Category Fluency (CF) is the most widely‐used measure of free SM recall but is not effective at detecting subtle SM changes. Its score based on word‐count, in fact, is also influenced by other abilities such as processing speed and executive functioning.We thus designed an alternative, item‐level scoring method less susceptible to these intervenient variables. This quantifies “how difficult” each CF word is based on 9 semantic features. Additionally, the Serial Recall Order (SRO) is established. This is an ordinal variable that tags the position of each word within the recalled list. Participant‐specific correlations are then calculated between SRO and each semantic feature. These capture the tendency of each participant to recall increasingly difficult words.We previously showed that, in healthy adults, these correlational indices are associated with neurocognitive mechanisms of semantic processing and control, but are statistically independent of processing speed and executive functioning (https://doi.org/10.3389/fnagi.2021.678588; https://doi.org/10.3389/fpsyg.2021.777838).This study tests whether these indices differ between normal adults and patients with mild cognitive impairment (MCI) at risk of progressing to AD.MethodCF performance from 60 MCI patients and 60 matched controls was scored following the above methodology. ANCOVAs were run to test the effect of diagnosis on z‐converted correlational indices, controlling for age, educational attainment, and number of CF entries at the basis of the correlations.ResultOf the nine indices, ‘SRO‐dominance’ was the only one differing between diagnoses. This correlation was ≈‐0.204 in controls and ≈‐0.362 in patients. Words 1‐8 were of similar dominance between groups. A difference was found instead for Words 9‐12.Conclusion‘Dominance’ is the ‘degree of control/power’ conveyed by a word. While the general tendency of CF performance is that of recalling words that are increasingly dominant, this trend is significantly more pronounced in MCI. This suggests a different use of semantic‐control resources between groups when the target category is explored in more depth. Although preliminary, these findings indicate that the SRO of CF words can help profile SM in patients with suspected AD. More work is needed, however, to study diagnostic statuses informed by biomarkers.
Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals
Authors: Xie Long , Wisse Laura EM , Das Sandhitsu R. , Lyu Xueying , de Flores Robin , Yushkevich Paul A. , Wolk David A. 
Published: June 2023

AbstractBackgroundNeurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD). However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.Methods420 CN (A‐/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1‐weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta‐amyloid status was determined with PET by standard cut‐offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Partial Pearson’s correlation, controlling for age, sex, and MRI‐PET date difference, was performed between MTL tau burden and structural atrophy measurements. Intracranial volume and MRI follow‐up time were additional covariates for cross‐sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A‐ subgroups.ResultsTau burden was significantly associated with cross‐sectional left BA35/36 thickness in the whole cohort and bilateral posterior hippocampus volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A‐ CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta‐amyloid PET SUVR.ConclusionsThe results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.