bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loneliness and daily subjective cognitive concerns among cognitively normal older adults and individuals with MCI
Authors: Harrington Karra D , Zhaoyang Ruixue , Mogle Jacqueline , Diaz Jose , Van Bogart Karina , Rabin Laura , Engeland Christopher G. , Graham‐Engeland Jennifer E , Sliwinski Martin J. 
Published: December 2023

AbstractBackgroundLoneliness is associated with increased dementia risk and is bidirectionally associated with cognitive decline across several years. Less is known about how loneliness and cognitive function are bidirectionally related on shorter timescales. This study examined daily associations between loneliness and self‐reported cognitive concerns in cognitively normal older adults and those with mild cognitive impairment (MCI).MethodCommunity‐dwelling older adults from the Einstein Aging Study (n = 311, age 70‐90 years, 65.9% female, 41.8% Black/African American, 12.5% Hispanic, 30.9% met Jak/Bondi criteria for MCI) completed a two week ecological momentary assessment (EMA) protocol via smartphone. Participants rated their current feelings of loneliness up to 5 times per day (4 via notifications, and 1 at end of day). These ratings were averaged to obtain a loneliness severity score for each day. Subjective cognitive concerns (prospective and retrospective memory lapses, attention/executive function difficulties) were assessed at the end of each day. Participants also reported how much each concern bothered them and/or disrupted their daily activities. Multilevel models were used to assess same‐day and next‐day associations between loneliness and each of the subjective cognitive concern outcomes bidirectionally.ResultsThere were bidirectional same‐day associations observed between loneliness severity and greater number and more bother of attention/executive concerns, as well as greater disruption of all cognitive concerns. When considering associations of present day loneliness with next day cognitive concerns, greater severity of loneliness predicted more bother of attention/executive concerns on the following day. Additionally, present day number of attention/executive concerns and disruption of all cognitive concerns predicted next day loneliness severity. All effects remained significant after adjusting for age, sex, years of education, and MCI status.ConclusionThese findings demonstrate that loneliness is dynamically associated with attention and executive function, but not memory lapses, on a day‐to‐day basis. Associations between loneliness and experience of bother and disruption due to cognitive concerns, suggest that loneliness may signal greater severity of, or less ability to cope with, cognitive difficulties.
Within‐Day Variability in Mobile Cognitive Assessments: Associations with Mild Cognitive Impairment and Sociodemographic Factors
Authors: Cerino Eric S. , Gamaldo Alyssa A. , Hyun Jinshil , Buxton Orfeu M. , Engeland Christopher G. , Katz Mindy J. , Wang Cuiling , Derby Carol A. , Lipton Richard B. , Sliwinski Martin J. 
Published: December 2023

AbstractBackgroundGreater within‐person variability in cognitive performance on mobile devices is emerging as a sensitive marker of mild cognitive impairment (MCI). It is unclear if sociodemographic differences are associated with this variability, and if so, whether these differences moderate associations between MCI status and within‐person variability. We use a digital health approach with ecological momentary assessments (EMA) to examine sociodemographic differences in within‐day variability among individuals with MCI and those who were cognitively unimpaired (CU).MethodA sample of 308 community‐dwelling older adults from the Einstein Aging Study (mean age = 77.49 years, SD = 4.86, range = 70‐90; 67% female; 45% non‐Hispanic White, 41% non‐Hispanic Black) completed neuropsychological testing and self‐reported questionnaires. Ninety‐eight individuals met Jak/Bondi criteria for MCI. All participants performed mobile tests of processing speed and memory binding on a smartphone up to six times daily over a two‐week period. We employed heterogeneous variance multilevel models to assess sociodemographic and MCI status associations with within‐day variability across assessments. We further tested whether differences in age, gender, race, and education moderated associations between MCI status and within‐day variability.ResultFor processing speed, greater variability was apparent in individuals with MCI, non‐Hispanic Black participants, and individuals with less education (ps<.001). A MCI status*gender interaction occurred; the association between MCI status and variability remained significant for both genders but was smaller among women (p<.01). For memory binding, greater variability was apparent in individuals with MCI, older participants, non‐Hispanic Black participants, and individuals with less education (ps<.001). Numerous interactions occurred; in separate analyses, associations between MCI status and variability remained significant, but were smaller among women, non‐Hispanic Black participants, and individuals with less education (ps<.05).ConclusionIndividuals with MCI exhibited greater within‐day variability in mobile cognitive performance than those who were CU, but the strength of these associations varied by sociodemographic factors. These indices of variability in everyday life may serve as sensitive markers of early cognitive impairment. Future research should examine daily mechanisms and environmental perturbations (e.g., stress, sleep, air pollution) that may explain why associations between MCI status and cognitive variability appeared smaller among women, non‐Hispanic Black participants, and individuals with less education.
Multi‐level Factor Analysis of Daily Data to Identify Subsyndromes of Behavioral and Psychological Symptoms
Authors: Pickering Carolyn E , Winstead Vicki , Yildiz Mustafa , Wang Danny , Yefimova Maria , Pickering Andrew 
Published: December 2023

AbstractBackgroundBehavioral and psychological symptoms in dementia (BPSD) are dynamic phenomena with a high amount of intraindividual variability. Many studies have used single‐level factor analysis approaches to identify subsyndromes of BPSD based upon meaningful groupings of co‐occurring symptoms yet, proposed subsyndromes have not been successfully replicated and lack stability over time. This may be due to measurement issues which do not account for dependencies in the data and create temporal misalignment. We applied an innovative multi‐level framework to overcome limitations of prior research to identify subsyndromes of BPSD.MethodsThis study used an intensive longitudinal design in which co‐residing family caregivers to persons living with dementia in the community were recruited to proxy‐report on their care recipient’s daily symptom experiences of 23 different BPSD for 8 consecutive days. A multi‐level exploratory/confirmatory factory analysis was utilized to account for nested data and separate within‐person variances from between‐level factor estimates.ResultsFamily caregivers (N = 70) were on average African American (54%) females (69%) most often caring for a parent with dementia (62%) average 74 years old requiring assistance with 4.5/7 activities of daily living. Data were provided on 79% of sampled days (n = 443 diaries). Exploratory factor analysis identified a 4‐between 3‐within factor structure based on fit statistics and clinical interpretability. The between‐level subsyndromes include wandering/aggression/care resistance (F1), affective/apathy/psychosis/vocalizations (F2), cognitive/ lability/ euphoria/ impulsivity/ compulsions (F3), and hallucinations/uncooperative (F4). Reliability estimates were high: 0.88 (F1), 0.91 (F2), 0.83 (F3), and 0.79 (F4).ConclusionThe between‐level factor structure identified through the multilevel factor analysis framework provide a more valid and reliable estimation of clinical subsyndromes within a population by separating out the variance due to within‐person daily fluctuations. At the between‐level, hallucinations was the only BPSD to cross‐load, which may indicate they are a byproduct of unmanaged depression in the affective/psychosis factor and their own unique subsyndrome. Support for the between‐level subsyndromes can be found in studies on shared neurobiological mechanisms of BPSD. The within‐level factors are similar to structures found in a recent systematic review. We argue these within‐level factors are more representative of symptom clusters, as they are driven by fluctuating contextual factors.
Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population
Authors: Seto Mabel , Hohman Timothy J. , Mormino Elizabeth C. , Papp Kathryn V. , Amariglio Rebecca E. , Rentz Dorene M. , Johnson Keith A. , Schultz Aaron P. , Sperling Reisa A. , Buckley Rachel F. , Yang Hyun‐Sik 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.MethodMeasures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐ε4 genotype, β‐amyloid (Aβ) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aβ was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aβ+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aβ levels and cognition covarying for the participant’s age, sex, and years of education where relevant.ResultAs previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aβ (p<0.001). The association between Aβ and history in both parents remained significant when covarying for APOE‐ε4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐ε4 and Aβ. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p<0.001) and in those with only maternal family history (n = 1776, p<0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: β = 0.03, p<0.001 in individuals with maternal history, β = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (βmaternal = 0.02, pmaternal = 0.01; βpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.ConclusionWe confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐ε4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aβ burden among asymptomatic older individuals.
Astrocyte reactivity potentiates longitudinal tau tangle accumulation in cognitively unimpaired individuals
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Rohden Francieli , Abbas Sarah , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Ikonomovic Milos D , Klunk William E , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundAβ accumulation precedes tau pathology in cognitively unimpaired (CU) individuals, which is an event closely related to the development of cognitive symptoms. However, Aβ leads to tau pathology in some individuals, but not in others, suggesting the presence of other processes triggering the deleterious effects of Aβ in the early Alzheimer’s disease (AD) stages. It was already demonstrated that glial fibrillary acidic protein (GFAP)‐positive astrocytes can internalize tau and might contribute to its propagation. Here we investigated whether astrocyte reactivity is a key element to determining the longitudinal accumulation and spreading of tau pathology in CU individuals.MethodWe assessed 147 CU individuals from the TRIAD cohort with available baseline Aβ‐ and Tau‐PET, plasma p‐tau181 and GFAP. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP levels of younger Aβ‐ individuals. Longitudinal analysis included 71 CU individuals with Tau‐PET (mean follow‐up:2.3 years).Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons. We measured the annual rate of progression in Tau uptake as the difference between follow‐up and baseline uptakes divided by the time between scans. To assess individuals’ percentage of abnormal regions, we used composite brain regions corresponding to Braak histopathological stages.ResultTau‐PET deposition occurred as a function of Aβ burden only in CU Ast+ and in regions expected to present the earliest tau deposition (Fig.1a). In the longitudinal analysis, we observed that the annual rate of tau‐PET accumulation was higher in the CU Ast+ group (Fig.2a) and predicted by baseline Aβ burden only in CU Ast+ (Fig.2b). Interestingly, while the baseline association was confined to the mesial temporal cortex, the longitudinal tau‐PET accumulation as a function of Aβ/Ast presented initial tau spread over the neocortex in Braak III‐IV regions (Fig.2c).ConclusionWe observed that Tau‐PET accumulation was highest in CU Ast+ individuals, with astrocyte reactivity being necessary for the spreading of tau over the neocortex. Our findings suggest that astrocyte reactivity is an important upstream event to unleash tau accumulation and spread in CU individuals, which might have implications for selecting individuals for early preventive clinical trials.
Feasibility and Efficacy of the LEAD Dementia Advance Care Planning Intervention
Authors: Iacob Eli , Dassel Kara B , Aruscavage Nancy R , Clayton Jordana L , Utz Rebecca , Supiano Katherine P 
Published: December 2023

AbstractBackgroundUsing our dementia‐focused advance care planning tool (ACP), known as the LEAD Guide (Life‐Planning in Early Alzheimer’s and Other Dementias),1‐3 we implemented a 9‐month NIH Stage‐14 behavioral intervention to promote ACP concordance in community‐based ADRD dyads. Dyads consisted of care recipients (persons concerned about dementia or those with a diagnosis of preclinical or early‐stage dementia) and their care partner. The goal of this study was to assess the feasibility and initial efficacy of the intervention.MethodFeasibility was assessed by examining the percent of enrollment of eligible participants, retention rate, and completion of data collection across study timepoints through the post intervention assessment. To explore the initial efficacy of the LEAD Intervention on study outcomes (ACP completion and dissemination, relationship quality, decision‐making self‐efficacy), we utilized longitudinal survey‐based measures to assess dyadic constructs that illustrate how the dyad functioned over time. Baseline to post changes were examined utilizing mixed effects models.ResultsWe screened 73 dyads, 58 dyads were eligible and 51 dyads participated in the study (see Figure 1 and Table 1). There were 34 dyads (67.7% retention) that completed baseline through the post‐intervention assessments. Table 2 shows results of changes in self‐report measures between baseline and post. Scores on the Decision‐Making Self‐Efficacy Scale5 revealed improved efficacy in both the care recipient and care partner at post intervention compared to baseline. Analysis showed no significant improvement in the positive domain of the Dyadic Relationship Scale6 in either care recipient or care partner, however, relationship strain domain significantly declined following the intervention in both the care recipient and care partner. Of the 51 starting dyads, 27 care recipients had already completed an advanced directive. By post, an addition 7 had completed an advanced directive, 9 were planning on completing, and 33 had shared ACP documents with others.ConclusionThe web‐based, self‐administered LEAD Intervention is a feasible and effective platform to promote ACP planning in community‐based ADRD dyads. Participation in ACP conversations and documentation can help reduce relationship strain and improve decision‐making self‐efficacy, thus promoting future care decisions that align with the care recipient’s values and preferences.
Association of reactive astrogliosis and microglial activation with tau pathology in Alzheimer’s disease
Authors: Ferrari‐Souza João Pedro , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Lussier Firoza Z , Leffa Douglas Teixeira , Therriault Joseph , Tissot Cécile , Benedet Andrea Lessa , Soares Carolina , Aguzzoli Cristiano Schaffer , Zalzale Hussein , Rohden Francieli , Wang Yi‐Ting , Chamoun Mira , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , Souza Diogo O. , Soucy Jean‐Paul , Gauthier Serge , Triana‐Baltzer Gallen , Saad Ziad S. , Kolb Hartmuth C. , Schilling Lucas Porcello , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Pascoal Tharick A. , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundGlial contributions to Alzheimer’s disease (AD) etiology and progression have been increasingly recognized. Experimental and clinical evidence suggests that both microglial activation and astrocyte reactivity have pivotal roles in the progression of tau pathology. However, it remains to be elucidated how microglia and astrocytes complement each other in AD pathogenesis. Here, we tested the associations between reactive astrogliosis and microglial activation with tau phosphorylation and aggregation in individuals across the aging and AD spectrum.MethodWe studied 95 participants (14 cognitively unimpaired [CU] young, 46 CU elderly, and 35 cognitively impaired [CI]) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aβ ([18F]AZD4694), tau tangles ([18F]MK6240), and microglial activation ([11C]PBR28). We further assessed reactive astrogliosis (plasma glial fibrillary acidic protein [GFAP]) and pathological tau phosphorylation (plasma phosphorylated tau [p‐tau] at threonine 231, 181, and 217).ResultDemographic characteristics of the study population are reported in Table 1. Regression analyses revealed that reactive astrogliosis and microglial activation were synergistically associated with higher plasma phosphorylated tau levels independently of Aβ pathology in CU but not CI individuals (Figure 1A). On the other hand, no interactive effects of reactive astrogliosis and microglial activation on tau‐PET burden were observed in either CU or CI individuals (Figure 1B). Similar findings were observed in sensitivity analyses excluding CU young participants.ConclusionOur results suggest that reactive astrocytes and activated microglia have Aβ‐independent synergistic effects on the early progression of AD pathophysiology by contributing to tau phosphorylation but not tau aggregation. These findings can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development novel therapeutic strategies for AD targeting the interplay between astrocyte and microglial reactivity.
Diagnostic reactive astrogliosis biomarkers in Alzheimer´s disease continuum
Authors: Nordberg Agneta K , Chiotis Konstantinos , Fontana Igor C. , Malarte Mona‐Lisa , Gillberg Per‐Göran , Bucci Marco , Bluma Marina , Kumar Amit 
Published: December 2023

AbstractBackgroundThe Alzheimer’s disease (AD) biomarker field is moving rapidly. Creating a platform where multi‐PET tracer approaches and various fluid biomarkers with discriminative power in the early pathological stages could provide deeper insight into the role of reactive astrogliosis in the AD continuum. Accumulating data indicates that reactive astrogliosis may play a critical role in the early stages and, perhaps, precedes other pathological hallmarks of AD. Different PET tracers for imaging reactive astrogliosis are now available along with plasma GFAP showing a direct correlation with increased brain amyloid‐PET. We also propose that alpha‐7‐nicotinic acetylcholine receptors (α7nAChRs) might be early modulators of reactive astrogliosis and Aβ‐pathology in AD. New α7nAChRs‐PET‐tracers might be promising future new biomarkers of reactive astrogliosis with potential early diagnostic properties.MethodTranslational molecular imaging studies including in vivo multimodal PET investigations ([11C]‐deprenyl, [11C]‐PIB, [18F]‐Flutemematol, [18F]‐FDG, [18F]‐RO‐948), MRI, plasma GFAP analyses in control, presymptomatic ADAD, MCI to AD dementia and in vitro PET tracer binding studies (deprenyl, SMBT‐1, and BU99008) in postmortem brains using small/large section‐autoradiography and tissue‐homogenates.ResultWe hypothesize from our in vivo PET/in vitro brain imaging translational/clinical studies a ‘first and second wave of reactive astrogliosis’ with distinct close‐loop relationships with other pathological biomarkers across AD continuum. Validation of newly developed PET‐tracers BU99008 and SMBT‐1 for mapping and visualizing reactive astrogliosis in the brain demonstrated multiple binding properties in AD brain and highlighted the crucial need of multi‐PET tracer approach for understanding the complexity of reactive astrogliosis in AD. We have observed a significant positive correlation between plasma GFAP levels and [18F]‐flutemetamol binding in patients undergoing memory assessment. In presymtomatic ADAD patients, high [11C] deprenyl binding is observed earlier in the disease evolution than increase in plasma GFAP levels following a divergent direction. This clearly suggests plasma GFAP as a later biomarker than [11C]‐deprenyl in AD trajectory, possibly reflecting different types of reactive astrocytes at different stages of AD.ConclusionIt’s an exciting time for the AD field with several new biomarkers/PET‐tracers for reactive astrogliosis, which will improve our understanding of underlying astrocytic complexity and add power to the existing diagnostic criteria in AD.