bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of AD‐brain tau aggregate internalisation by human astrocytes and the responses induced
Authors: Reid Matthew J , Perez‐Nievas Beatriz G. , Noble Wendy , Cao Pingting 
Published: December 2023

AbstractBackgroundHighly phosphorylated tau aggregates are deposited in tauopathy brain as disease progresses, driven by a prion‐like spread of tau seeds. Evidence suggests that astrocytes may influence tau spread. However, the efficiency of uptake of disease‐associated tau species is not well defined, nor are the effects of tau uptake on astrocyte reactivity and function. We investigate human astrocyte ability to internalise and clear tau aggregates derived from multiple Alzheimer’s disease (AD) cases, and their impact on astrocyte function and reactivity. We further explore alterations in endogenous tau expression, APP processing and cytoskeletal proteins following tau uptake.MethodControl human iPSC‐derived astrocytes were cultured for 70 days. Aggregated (sarkosyl‐insoluble) tau was isolated from postmortem AD brain. Post‐translational modifications (PTM) of isolated AD‐brain tau aggregates were analysed by mass spectrometry. Tau (0.1 ng/µL) and extracts from control human brain were spiked into astrocyte cultures. Internalisation of aggregated tau and the localised response of S100B and GFAP were quantified by ICC. Changes to tau, APP, functional and reactivity related genes were measured by qPCR and/or proteins by SDS‐PAGE.ResultAggregated tau from AD brain is readily internalised by human astrocytes, and sequesters GFAP and S100B. Differences in the rate of uptake, clearance and seeding of tau correlates with cytoskeletal protein accumulation and specific changes in astrocyte mRNA and protein levels. Work is in progress to relate these changes to characteristics of tau aggregates.ConclusionOur data shows that the capacity of AD brain aggregates to be internalised, cleared and induce seeding of endogenous tau varies by case. Investigations are underway to pinpoint the tau characteristics that underlie these differences. We also show that seeding ability is associated with changes in cytoskeletal elements and reactivity markers at mRNA and protein level. This work agrees with growing evidence that tau variability in AD is linked with specific cell type vulnerabilities that contribute to tau spread and disease progression.
Bilingualism in adult population without cognitive impairment: its relationship with aging in structural neuroimaging. A cross‐sectional study.
Authors: Estanga Ainara , Garcia‐Sebastian Maite , Altuna Miren , Ecay Mirian , Lopez Carolina , de Arriba Maria , Iriondo Ane , Tainta Mikel , Barandiaran Myriam , Marta Cañada , Clerigue Montserrat , Martinez‐Lage Pablo 
Published: December 2023

AbstractBackgroundAging is consistently associated with cortical gray matter (GM) reductions. Bilingualism has been described as a potential reserve contributor for successful brain aging and has been associated with a variety of structural changes in cortical morphology. In this study we aim to: 1) Explore differences between bilinguals and monolinguals on the whole brain cortical thickness, area and volume, 2) explore if correlations between age and cortical measures are different between bilinguals and monolinguals, and 3) to evaluate age‐bilingualism interaction effects on the cortical characteristics.MethodCross‐sectional study with healthy volunteers from the Gipuzkoa Alzheimer Project (GAP) cohort. Cognitively unimpaired (CDR Global Score = 0) with available 3T MRI were included and classified as bilinguals or monolinguals based on daily use of both Spanish and Basque languages or only Spanish. Subjects with diffuse white matter lesions (Fazekas scale = 3) were excluded. Cortical reconstruction was performed with Freesurfer package v5.1. as described in Montal et al., 2017. Analyses were conducted in the whole brain using linear modeling of the maps and Monte Carlo simulation corrected for multiple comparisons as implemented in FreeSurfer’s QDEC interface.ResultSample included 88 bilinguals and 83 monolinguals (see Table 1 for demographic and clinical characteristics). Whole brain cortical thickness, area or volume were not significantly different between groups. Age‐cortical thickness and volume correlation maps showed broader areas of negative associations in the monolingual than in the bilingual group, and inverse associations in the relationship with area characterized by negative correlations in monolinguals and positive and negative correlations in bilinguals (Figure 1). More specifically, significant age‐bilingualism interactions were found for thickness in the right superiorfrontal gyrus (p = 0.012), and for the surface area, in the inferiorparietal (p = 0.0001), supramarginal (p = 0.043) and lingual (p = 0.042) regions of the left hemisphere.ConclusionCortical thickness and area variations occurring in relation to aging in cognitively healthy individuals could be modulated by bilingualism.
Towards implementing physical activity guidelines into clinical practice in persons with mild cognitive impairment
Authors: Bruderer‐Hofstetter Marina , Tomovic Sara , Ejiwoudt Emiel , Deininger Roland , Muenzer Thomas 
Published: December 2023

AbstractThe positive effects of physical activity and exercise on general health, well‐being, and physical and cognitive functioning in persons with mild cognitive impairment (MCI) are well documented and resulted in respective guidelines [1, 2]. To support the implementation of these guidelines into clinical practice, we developed and evaluated a training manual for physiotherapists and allied health professionals and an accompanying handout for independent training for persons with MCI.The development process included a systematic literature search and patient and public involvement in design aspects. The training manual and handout were determined in four half‐day workshops with experienced physiotherapists. The goal was to describe specific exercises for every training dimension, i.e., endurance, strength, balance, and flexibility, including variations for progression and degression. For better comprehensibility, the handout was illustrated with pictures. Subsequently, both documents were evaluated in five geriatric clinics. The comprehensibility, acceptance, and usefulness of persons with MCI and physiotherapists’ perspectives were evaluated using structured questionnaires, including specific implementation outcomes.Overall, both, the physiotherapists and persons with MCI found the manual useful and acceptable. However, the responses on comprehensibility indicated a need for optimization. Accordingly, we revised the training manual and handout, e.g., by simplifying the language or reducing the descriptive text. The revised documents are now freely available to physiotherapists and patients.The training manual and accompanying handout may support the implementation of the physical activity recommendations into clinical practice and may be used in future research projects. In a subsequent project, we will implement the training manual and handout in a smartphone and tablet application to improve ease of customization and usability.[1] Chong TWH, Curran E, Ellis KA, et al. Physical activity for older Australians with mild cognitive impairment or subjective cognitive decline ‐ A narrative review to support guideline development. J Sci Med Sport. 2020;23(10):913‐920.[2] Izquierdo M, Merchant RA, Morley JE, et al. International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines. J Nutr Health Aging. 2021;25(7):824‐853.
Healthcare utilization prior to a diagnosis of young onset Alzheimer’s disease: A nationwide nested case‐control study
Authors: Damsgaard Line , Janbek Janet , Laursen Thomas Munk , Waldemar Gunhild , Jensen‐Dahm Christina 
Published: December 2023

AbstractBackgroundEarly symptoms of Alzheimer’s disease may be identified by altered healthcare utilization patterns in the years preceding the diagnosis. Timely diagnosis is especially important for patients with young onset Alzheimer’s Disease (YOAD), who are often in the prime of their career and whose families may be financially dependent on the patient. The aim of this study was to identify changes in healthcare utilization in the prodromal phase of YOAD, and to identify any specific types of healthcare contacts with a more pronounced association than others.MethodWe conducted a retrospective density‐matched nested case‐control study. Cases were identified using the nationwide Danish Quality Database for Dementia and included everyone diagnosed with YOAD in a Danish memory clinic during 2016‐2018. Due to the often long time‐lag between symptom onset and diagnosis, patients aged <70 years at diagnosis were included. Age‐ and sex‐matched controls were drawn from a nationwide cohort of all Danish citizens. Healthcare utilization during 10 years prior to the diagnosis was assessed in the nationwide healthcare registries. Contact rate ratios (CRR) were calculated using negative binomial regression analysis adjusted for highest attained educational level at age 40 and civil status.ResultThe study included 1082 YOAD patients and 3246 age‐ and sex‐matched controls. In the year preceding diagnosis, we found increased CRRs for all but one type of contacts (private practice medical specialists). CRRs for all types of contacts with a general practitioner were significantly increased also >1‐5 years and >5‐10 years prior to diagnosis. The highest CRR was for psychiatric emergency admissions (8.96, 95% CI 4.45‐18.05) ≤1 year prior to diagnosis. In a sensitivity analysis, we found that those with moderate/severe dementia at time of diagnosis generally had higher CRRs and showed vulnerability earlier than those with mild cognitive impairment/mild dementia at time of diagnosis.ConclusionOur results demonstrate that YOAD patients have an altered pattern of healthcare utilization from as much as 5‐10 years prior to the diagnosis. Awareness of the specific alterations in help seeking behavior may help healthcare professionals provide a timely diagnosis.
Receiving biomarker results is a Participant Right: why researchers should design studies with the option to learn
Authors: Walter Sarah , Taylor Angela , Tyrone Jamie , Wheaton Bonnie , Hummel Cynthia Huling , Pagan John‐Richard , Langer Sara , Gabler Sadie , Zallen Doris , Rosen Allyson C. 
Published: December 2023

AbstractBackgroundDespite dramatic advances in the specificity and sensitivity of biomarkers for Alzheimer’s disease and related dementias (ADRD), most studies do not offer participants the option to learn their individual results. Participants and support partners view disclosure of biomarker results as a right that should be offered as part of study participation. The preferences of the participant should guide how disclosure occurs, as well as in the post‐disclosure counseling and follow‐up. With the goal of stimulating change, the Advisory Group on Risk Education for Dementia (AGREEDementia) Stakeholder Committee developed a Study Participant Bill of Rights for Disclosure of Individual Research Results. The committee includes people with a diagnosis, study participants, care partners, representatives of dementia advocacy organizations, and other stakeholders in dementia research.MethodThree panelists will share lived experience with diagnosis, care, and research participation. Panelists will be identified by AGREEDementia and will broadly represent study participants: including individuals living with diagnosis, those at risk for dementia, care partners, and racial and ethnic groups under‐represented in research. Panelists will speak to the experience of learning their biomarker results, the personal value of those results, and share their recommendations for study design and conduct.ResultThis session will challenge ADRD researchers by offering the opportunity to understand lived experience of individuals that take part in research and their preferences in disclosure of biomarkers.ConclusionThis Bill of Rights demonstrates the value of designing studies that are centered on the preferences of participants, towards the ultimate aim of inclusive ADRD research.
Impact of learning amyloid PET results on test‐related distress and concern about dementia in a cognitively unimpaired observational cohort
Authors: Clark Lindsay R. , Chin Nathaniel A. , Erickson Claire M , Johnson Sterling C , Basche Kristin E , Rosario Hannah , Ketchum Fred B 
Published: December 2023

AbstractBackgroundAs biomarker testing becomes more widely available, people will have opportunities to learn Alzheimer’s disease (AD) biomarker results. We developed an AD biomarker disclosure protocol to return amyloid PET results to participants interested in learning this risk‐related information. Our current objective was to evaluate the impact of returning biomarker results on longitudinal psychosocial outcomes.Method97 cognitively unimpaired older adults (mean age = 71.9 ± 4.8; 66% women; 29% amyloid+) were recruited from an observational cohort study. Participants completed questionnaires assessing concern about dementia, future time perspective, and cognitive complaints at baseline (pre‐disclosure) and after learning amyloid PET result (1‐ and 6‐months post‐disclosure). Participants completed measures of results‐related distress (Impact of Events Scale [IES]; Impact of Neuroimaging in AD [INI‐AD]) 1‐3 days after disclosure and then again at 1‐, 3‐, and 6‐months post‐disclosure. Linear mixed‐effects regression models were used to test for main effects of amyloid PET result and time (visit number), and an interaction of amyloid result x time on self‐reported outcomes.ResultParticipants who learned amyloid PET results were elevated or non‐elevated had similar demographic characteristics (Table 1). A significant interaction between amyloid result x time was observed for concern about dementia (β = 0.30, p = .02), whereas future time perspective and cognitive complaints did not vary by result or time in study (main effect and interaction p’s > .12; Table 2). Results‐related distress measures showed different patterns: A measure of intrusive thoughts and avoidance was initially high in elevated participants but decreased over time (IES; result x time interaction β = ‐0.83, p < .001), while a measure of psychosocial reactions to learning results was consistently high in elevated participants (INI‐AD; main effect of amyloid result β = 12.08, p < .001) (Figure 1).ConclusionOlder cognitively healthy adults who learned elevated amyloid PET results reported increased concern about dementia and results‐related distress compared to those who learned non‐elevated results. Although intrusive thoughts/avoidance decreased over time in elevated participants, results‐related distress remained high. These indicate some increased psychosocial impacts, and possible need for post‐disclosures support, for those who learn elevated biomarker results.
Mastermind of the Alzheimer’s blood‐based biomarkers: development of cutoffs and a visualization tool for use in clinical practice
Authors: Verberk Inge M.W. , Kingma Maurice Y. , van Harten Argonde C. , den Braber Anouk , Vigneswaran Sinthujah , Gouda Mariam , van Engelen Marie‐Paule E. , Lemstra Afina W. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Schut Martijn C. , Wilson David , Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundPhosphorylated (P‐)tau, amyloid‐beta (Abeta)1‐42/1‐40, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are the current key Alzheimer’s disease (AD) blood‐based biomarkers. Interpreting results of the four biomarkers simultaneously in a clinical context is challenging. A decision algorithm could aid in the interpretation, tailored to clinically relevant questions: 1) identify positive amyloid status among preclinical and prodromal AD stages, 2) discriminate AD‐dementia from frontotemporal dementia (FTD), 3) discriminate AD‐dementia from dementia with Lewy bodies (DLB). We aimed to develop such an interpretation tool.MethodWe included 1199 participants from the Amsterdam Dementia Cohort (table 1) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD‐dementia, FTD (mixed pathologies) or DLB. Plasma P‐tau181, Abeta1‐42/1‐40, GFAP and NfL were measured with Simoa. NfL levels were adjusted for age (method: https://doi.org/10.1002/acn3.51676). We used LASSO regression with bootstrap (1000 iterations) to identify which plasma markers robustly contribute to the prediction of the outcomes of our clinically relevant questions. When a marker was selected in >95% of the iterations in at least one of the clinical scenarios, we qualified it as a contributing marker. Subsequently, we constructed UpSet plots applying Youden’s cutoffs as interpretation tool for the plasma results.ResultP‐tau181, GFAP and NfL were selected as contributing biomarkers. Abeta1‐42/1‐40 was not selected. The panel of P‐tau181, GFAP and NfL had an AUC = 83% (95%CI: 76‐90%) to identify amyloid positivity in SCD+MCI, AUC = 87% (95%CI: 79‐94%) to differentiate AD‐dementia from FTD, and AUC = 73% (95%CI: 62‐84%) to differentiate AD‐dementia from DLB. The UpSet plots show the simultaneous interpretation of P‐tau181, GFAP and NfL results for each clinically relevant question (figure 1): e.g., when all three biomarkers are abnormal in participants with SCD+MCI, there is 83% agreement with an abnormal PET or CSF amyloid status, and when all three plasma markers are normal, there is 88% agreement with a normal amyloid status.ConclusionThe combination of P‐tau181, GFAP and NfL in plasma could support decision making in different clinical contexts. UpSet plots enable easy interpretation of a combination of the markers, and could serve as a tool to support both detection and differential diagnosis of Alzheimer’s disease.
Soliciting Participant Program Guidance through the Development of An ADRC Participant Advisory Council
Authors: Nuttkinson Bonnie L. , SmithBA Tracy , Chin Erin , Lacey Erin , Blazel Hanna M. , Walaszek Art , Edwards Dorothy F. 
Published: December 2023

AbstractBackgroundStudies show that including participants and community members as partnering stakeholders in research contributes to identification of pertinent research questions that might elude investigators; help recruitment, retention, and research protocols; improves the efficacy of health promotion interventions and can enhance dissemination of study results. Participant advisory boards are particularly important for clinical trials and other longitudinal research programs that want to ensure effective enrollment and retention. Participant voices and perspectives are exceedingly useful for refining protocol design, consent form design, technology solutions, and communication materials. Despite these advantages, the majority of ADRCs rely on community advisory boards rather than participant advisory boards for stakeholder input. The Wisconsin Alzheimer’s Disease Research Center (WADRC) created a Participant Advisory Council (PAC) to solicit input on design of recruitment and retention programs, refine research questions and provide input on participant experiences. The outreach and recruitment cores selected two facilitators. PAC facilitators completed an intensive 10‐day training program focused on creating an inclusive environment, encouraging multiple perspectives and full participation from members.MethodWADRC staff identified 10 individuals enrolled in its Clinical Core to participant, eight of which volunteered. The PAC has 7 participants representing the MCI, control and IMPACT cohorts, and 1 study partner. The group is diverse with representation from 4 URG members, 1 veteran, 2 from rural communities; 7 have consented to be brain donors and 5 have completed lumbar punctures. PAC members receive a $50 honorarium each meeting and travel expenses for those living further away.ResultsThe inaugural meeting took place in April 2022 where members learned about the development of the PAC, organization and goals of the WADRC. The PAC meets bi‐monthly. Meetings are hybrid, with periodic in‐person meetings. Faculty and staff learn and benefit from the feedback provided by participants on a variety of topics. To date, the PAC has discussed education programing, how to communicate such programming, and ways to increase retention. The PAC will review and comment on WADRC and ORE Core specific aims in preparation for the upcoming grant renewal.ConclusionMeaningful engagement of participants is essential for long‐term retention and ongoing improvement of WADRC recruitment and retention.
CSF Proteomic Signatures are Associated With Cognitive Decline in the Alzheimer’s Disease Continuum
Authors: Vromen Ellen M. , van Harten Argonde C. , Berven Frode , Teunissen Charlotte E. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2023

AbstractBackgroundIndividuals with Alzheimer’s disease (AD) show variability in cognitive decline. Little is known about the underlying biological processes. Using an untargeted CSF proteomics approach, we explored the biological processes associated with cognitive decline throughout the AD continuum.MethodWe included 280 AD individuals from the Amsterdam Dementia Cohort (median age 66 (IQR:60‐70) years, 124 (44%) female, n = 34 preclinical AD, n = 77 MCI due to AD, n = 169 AD‐dementia, all abnormal CSF amyloid, Table 1). The CSF proteome was quantified at baseline using LC‐MS/MS in an untargeted manner based on TMT labelingWe included n = 2318 proteins measured in ≥50% individuals. We used the MMSE score as a proxy for global cognition, and created summary scores for cognitive domains (i.e., episodic memory, executive functioning, attention and language) using neuropsychological test scores. We applied linear mixed models to test the association between each protein and cognitive decline over time, with age, sex and education as covariates, a random intercept for patient ID, and a random slope for time; stratified for syndrome diagnosis. We performed pathway enrichment analysis on proteins associated with cognitive decline.ResultIndividuals with preclinical AD showed most decline on episodic memory compared to other domains. In preclinical AD, 150 proteins, enriched for cell death and cell adhesion, were associated with memory decline. Individuals with MCI showed most decline on episodic memory and executive functioning. Proteins associated with decline on memory (n = 188, Figure 1) and executive functioning (n = 213) were enriched for complement and coagulation cascade and innate immune processes. Proteins associated with memory decline were also enriched for synaptic plasticity. Individuals with AD‐dementia showed more decline on attention and language compared to other AD‐stages. In AD‐dementia, 69 proteins, enriched for innate immune processes, were associated with decline on the MMSE and 127 proteins, enriched for synaptic plasticity, were associated with decline on language.ConclusionProteins involved in innate immune processes, synaptic plasticity and cell death were associated with cognitive decline in AD, with different processes involved in different stages. These results provide insight into the pathophysiology of cognitive decline and hint towards potential therapeutic targets for prevention of cognitive decline in AD.