bluuebunny/crossref_metadata_2025_split huggingface dataset:
LEADing advance care conversations: concordance amongst ADRD dyads
Authors: Supiano Katherine P , Clayton Jordana L , Aruscavage Nancy R , Dassel Kara B , Utz Rebecca , Iacob Eli 
Published: December 2023

AbstractBackgroundThe LEAD Guide (Life‐Planning in Early Alzheimer’s and Other Dementias)1 is a validated paper‐based dementia‐focused advance care planning (ACP) guide that addresses changes in cognition and goals of care along the ADRD continuum, preparing surrogate decision‐makers for loss of the care recipient’s decisional abilities. Achieving agreement on decision elements of ACP in care partner (CP)/care recipient (CR) dyads may reduce ambiguity, increase CP confidence, and assure that preferences and values are honored. Using multiple approaches, we developed a working definition of ACP concordance amongst ADRD dyads.MethodUsing the LEAD Guide as the foundation we developed the pilot LEAD Intervention, a community‐based NIH Stage‐1 behavioral intervention.2 This 9‐month study guided CP/CR dyads through a dementia‐focused ACP process that integrates a digital version of the LEAD Guide with ACP educational modules delivered through a web‐based platform. Dyads had the option of recording their care conversation. To understand the process of achieving dyadic consensus in elements of ACP, we conducted a scoping review of the literature and a qualitative analysis of recorded interviews.ResultOf 61 eligible dyads, 41 completed the LEAD intervention; 7 in‐depth recordings were obtained. Our scoping review of 6,788 manuscripts identified no operational definitions of ACP concordance, 35 that revealed essential elements of successful discussion processes and only one that characterized essential qualities of CPs. Using descriptive analysis,3 seven themes illustrating agreement on ACP issues were discerned: Respect/Regard for each other; use of Clarifying Processes; Conveying Health Care Scenarios to justify wishes; Affirmation of Understanding; Recognizing Uncertainty; Humor and Expression of Positive Emotions; and Trust. Notably, all seven dyads voiced confidence that they “finished the discussion successfully,” meaning reaching a state of concordance.ConclusionOur synthesis of the research literature and our qualitative findings suggests that a working definition of ACP decision concordance is when the caregiver understands the patient’s values that inform the preferences and choices of the patient, understands those choices and preferences and the rationale for the choices and preferences, and expresses a willingness to accomplish the patient’s wishes to the best of their ability. This definition contributes to research clarity in ACP investigations.
Short sleep duration and hypertension: A double hit for the brain
Authors: Yiallourou Stephanie , Song Xuemei , Wiedner Crystal , Bernal Rebecca , Himali Dibya , Baril Andree‐Ann , Cavuoto Marina G. , Decarli Charles , Beiser Alexa S. , Seshadri Sudha , Himali Jayandra Jung , Pase Matthew P. 
Published: December 2023

AbstractBackgroundThe mechanisms linking short sleep duration to increased dementia risk remain unclear. Sleep duration has a powerful influence on blood pressure (BP), with short sleep durations increasing hypertension risk. Since high BP is a dementia risk factor, short sleep may increase risk of cognitive impairment via adverse effects on vascular health. We assessed whether the association of sleep duration with cognition and vascular brain injury was moderated by hypertensive status.Method684 dementia‐free participants (mean age 62±9 years; 53.1% female) from the community‐based Framingham Heart Study Offspring and Omni 1 cohort completed assessments of cognition, office BP, and self‐reported habitual sleep duration; 637 also completed brain MRI. Hypertensive status was defined as a combination of systolic BP ≥ 140mmHg and/or diastolic BP ≥90mmHg or use of anti‐hypertensive medication. Outcomes included the Trail Making Test B minus A, Visual Reproductions, Similarities, and white matter hyperintensity volume (WMHV) expressed as a percentage of intracranial volume. Linear regressions were performed between total sleep time and cognitive domains adjusted for demographic factors, APOE e4 positivity, use of sleeping pills, and BMI. An interaction term for hypertensive status was included in regression models.ResultShort sleep durations of ≤5 hours/night occurred in 13% of participants and 35% were hypertensive. There were no direct associations between sleep duration and any of the outcomes. However, there was a significant interaction between sleep duration and hypertensive status when predicting the outcomes of executive function/processing speed (Trail Making) and WMHV. When data were stratified by hypertensive status, shorter sleep duration was associated with poorer executive function/processing speed scores in the hypertensive group (β±SE = 0.04±0.02 per hour increase in sleep duration, p = 0.02), but not in the normotensive group (β±SE = ‐0.01±0.01, p = 0.22). Similarly, shorter sleep duration was associated with higher WMHV burden in the hypertensive group (β±SE = ‐0.13±0.06, per hour decrease in sleep duration, p = 0.03), but not in the normotensive group (β±SE = 0.01±0.04, p = 0.760).ConclusionThe combination of short sleep and hypertension is associated with worse cognitive performance and brain injury. Further work will examine this interaction more completely.
Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Leffa Douglas Teixeira , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Rohden Francieli , Abbas Sarah , Benedet Andrea Lessa , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Klunk William E , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick Ali 
Published: December 2023

AbstractBackgroundAstrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐β (Aβ) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aβ and tau differs in men and womenMethodWe assessed 1,016 CU individuals from three cohorts with available Aβ (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aβ‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aβ burden.An interaction between term between Aβ*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.ResultWe found that Aβ burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aβ with plasma p‐tau181 (β = 0.71,p<0.0001,Fig.1a) or p‐tau217 (β = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aβ and sex on plasma p‐tau181 (β = 0.47,p = 0.005,Fig1a) and p‐tau217 (β = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aβ and plasma p‐tau epitopes between men and women. In men but not women, Aβ‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.ConclusionA sex effect was observed in the association between Aβ burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aβ on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aβ therapies already showed different effects between men and women.
The Association of Blood‐based biomarkers and Cognitive Change as Measured by Ecologically Sensitive Digital Biomarkers
Authors: Lipton Richard B. , Garza Angel Garcia De La , Wang Cuiling , Derby Carol A. , Katz Mindy J. , Oravecz Zita , Hakun Jonathan G. , Sliwinski Martin J. , Ezzati Ali 
Published: December 2023

AbstractBackgroundThe Einstein Aging Study uses smartphones in an intensive burst design to digitally assess cognition up to 6 times daily for 2 weeks once a year. These burst assessments facilitate the estimation of novel cognitive markers including learning effects and asymptotic performance within bursts and over annual assessments. Here, we examine the influence of two blood‐based biomarkers, pTau‐181 and Neurofilament Light protein (NfL), on cognitive performance measured by digital cognitive markers at baseline and across 6 annual burst assessments.MethodParticipants were 293 older adults (Age = 77.4±4.9) free of dementia at baseline. Negative exponential models were used to examine two primary features of response time from the Symbol Search Test of processing speed: (1) learning rate across days within a burst and its change in rate of learning over annual follow‐up; and (2) asymptotic performance (i.e., fastest response time) at baseline and asymptotic change (the rate in which asymptotic performance changes across years). Asymptotic performance is thought to reflect best possible performance and to be relatively free of practice effects. The associations of pTau‐181 and NfL with these features at baseline and change over annual follow‐up were evaluated, adjusting for baseline age, sex, years of education and race/ethnicity.ResultPrimary model results are summarized in Table 1. The expected trajectory of symbol search response time across 16 study days within each of the six annual waves, for baseline levels of pTau‐181 and NfL is shown in Figures 1 and 2. Higher levels of both Tau‐181 and of NfL were associated with slower rates of learning in the baseline burst. Higher levels of these BBB at baseline were also associated with slower learning rates from burst to burst (over years) and with greater slowing in asymptotic performance over annual follow‐ups.ConclusionHigher levels of BBB of Tau and of neurodegeneration are associated with slower learning and with slower response times. These novel parameters derived from ambulatory cognitive testing show expected relationships with biomarkers supporting their validity. Future applications of ambulatory cognition could include the identification of subtle cognitive impairment and in measuring within person change in cognition in clinical trials or clinical practice.
Amyloid‐PET, tau‐PET, and their association in sporadic early‐onset Alzheimer’s Disease: Cross‐sectional and longitudinal data from the LEADS study
Authors: La Joie Renaud , Mundada Nidhi , Iaccarino Leonardo , soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Shankar Ranjani , Amuiri Alinda , Cho Hanna , Ackley Sarah F , Blazhenets Ganna , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D. 
Published: December 2023

AbstractBackgroundWe aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures.MethodsIn December 2022, we selected patients who fulfilled the following criteria: 1) clinical diagnosis of MCI or mild dementia, 2) available amyloid‐PET (18F‐florbetaben), tau‐PET (18F‐fortaucipir), and structural MRI, 3) positive amyloid‐PET based on a process including visual read and quantification. Image acquisition, quality control, and processing followed ADNI procedures. Florbetaben‐PET Centiloids and mean cortical Flortaucipir‐SUVR were extracted in native space using FreeSurfer. Cross‐sectional analyses were performed using general linear models; longitudinal analyses (up to 4 scans/patient) were performed using linear mixed effect models with random intercepts.ResultsOut of the 372 cognitively impaired patients included in LEADS, 280 (75.3%) were amyloid‐positive patients with sEOAD (Table 1 for demographics and clinical characteristics). Cross‐sectionally, Centiloids and cortical Flortaucipir‐SUVR were correlated (r = 0.29, p<.001; Fig 1a). Patient’s age was associated with cortical tau‐PET (older patients showing lower Flortaucipir‐SUVR, r = ‐0.47, p<0.001, Fig 1b) but not amyloid‐PET (r = ‐0.02, p = 0.68). Females showed greater amyloid (d = 0.43, p<0.001, Fig 1c) and tau‐PET burden (d = 0.35, p = 0.004), in the absence of sex differences in MMSE or CDR‐SB (d’s<0.16, p’s>0.37). Sex differences in tau‐PET remained significant (p = 0.04) when controlling for age and Centiloids. Both Centiloids and Flortaucipir‐SUVR increased longitudinally (p<0.001, Figure 3a‐b). The rate of Centiloid change was not modulated by age (time*age, p = 0.79) or sex (time*sex, p = 0.91). Changes in tau‐PET were independent of sex (time*sex, p = 0.15), but younger patients tended to show greater FTP‐SUVR progression (time*age, p = 0.07). In a subsample of 123 patients with at least 2 timepoints for both amyloid and tau‐PET (Fig 3c), rates of amyloid and tau changes were correlated (r = 0.22, p = 0.013).ConclusionIn patients with sEOAD, amyloid‐ and tau‐PET are modestly correlated at baseline and continue to increase together over time. In EOAD, younger age is associated with higher tau‐PET burden, independent of amyloid. Females show greater amyloid and tau burden than males despite similar clinical severity measures.
Exploring the Utility of Biofluid‐Based Biomarkers in Early‐Onset Alzheimer’s Disease
Authors: Dage Jeff L. 
Published: December 2023

AbstractBackgroundOne goal of the longitudinal early onset Alzheimer’s disease study (LEADS) is to define fluid biomarker characteristics of early‐onset Alzheimer’s disease (EOAD). In this mid‐study cross sectional analysis, participants have undergone clinical and cognitive assessments, magnetic resonance imaging (MRI), positron emission tomography (PET), lumbar puncture, and blood draws. There is limited data available concerning comprehensive analysis of fluid biomarkers in an EOAD population and this study represents first results from the mid‐study analysis of a large multi‐site cohort.MethodLEADS is an observational study with N = 371 subjects included in the mid‐study analysis (N = 165 with CSF and N = 324 with plasma biomarker data). CSF levels of Aβ1‐40, Aβ1‐42, tTau, pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay. Plasma levels of Aβ1‐40, Aβ1‐42, NfL, pTau231, and glial fibrillary acid protein (GFAP) were measured by immunoassay. Differences by diagnostic group and Spearman’s correlations with cognitive measures (MOCA, CDR‐SB, ADAS‐Cog) were evaluated for each fluid biomarker. Diagnostic accuracies were determined using area under the curve of receiver operating characteristics curve analysis which included APOE4 carrier status, age and sex in logistic regression models.ResultLevels of CSF Aβ42/40, pTau181, tTau, SNAP25, and Ng in the EOAD group were significantly different from both cognitively normal and early‐onset non‐AD dementia groups; CSF NfL, YKL‐40 and VILIP‐1 did not vary by diagnosis. The combination of APOE ε4 carrier status, age, sex and CSF Aβ42/40 and pTau181 (Figure 1A) or plasma Aβ42/40 and pTau231 (Figure 1B) separated the EOAD group from CN and EOnonAD with Area Under the ROC curves of 0.99 and 0.89 respectively. The diagnostic accuracies of plasma Aβ42/40 or pTau231 were 0.80 and 0.86 respectively. In the pooled analysis, all CSF biomarkers except SNAP25 were correlated with cognition (Figure 2A). Within the EOAD group only CSF Aβ42/40, NfL, Ng, and SNAP25 were correlated with at least one cognitive measure (Figure 2B).ConclusionThis study provides the first comprehensive analysis of fluid biomarkers in sporadic EOAD and will inform clinical trial designs that incorporate fluid biomarkers in patient selection, or as biomarker endpoints.
Cholinesterase inhibitors, cognitive decline, major cardiovascular events, and mortality in dementia with Lewy bodies
Authors: Xu Hong , Ferreira Daniel , Londos Elisabet , Eriksdotter Maria 
Published: December 2023

AbstractBackgroundCholinesterase inhibitors (ChEIs) are approved pharmacological treatment in Alzheimer’s dementia (AD) and dementia with Lewy bodies (DLB). Recent studies showed that ChEI‐use is associated with decreased risk of cardiovascular events and death in AD. This study explores the long‐term effects of ChEIs on cognition, the risk for hospitalization of major cardiovascular events and death in patients with DLB.MethodWe included DLB patients with mild‐moderate dementia(defined as Mini Mental State Examination(MMSE)≥10 points) from the Swedish Dementia Registry(SveDem). Patients starting on ChEI within 90 days of diagnosis were compared to patients with DLB not receiving ChEI. Major cardiovascular events(MACE) were defined as the composite of hospitalization of myocardial infarction or congestive heart failure or stroke. In an inverse probability of treatment weighting cohort, the association between ChEI‐use and cognitive trajectories were examined with mixed models and the risks of MACE or death with Cox models with balancing 45 confounders.Result893 ChEI‐use and 305 non‐users were included. The most frequently used ChEIs was rivastigmine(69%), followed by donepezil(21%) and galantamine(10%). There was no difference in MMSE scores between the two ChEI groups at baseline after weighting. During a median follow up time of 3.2 years (interquartile range1.7‐4.3), ChEI‐users showed slower cognitive decline (‐1.4 MMSE points/year, 95%confidence interval CI ‐1.8, ‐1.0) compared to non‐users (‐2.8 MMSE points/year, ‐3.9, ‐1.9). Of the ChEIs, galantamine was associated with the slowest cognitive decline (‐0.9 MMSE points/year, ‐1.8, ‐0.1). During follow up, 120(10%) events of MACE occurred, along with 666(56%) deaths. Compared to non‐users, ChEI‐use was not associated with risk for hospitalization for MACE (adjusted hazard ratio(aHR)0.89; 95% CI 0.43‐1.82) or risk of death (aHR 1.09; 0.87‐1.37).ConclusionIn patients with DLB, ChEI‐use was associated with slower cognitive decline over 3.2 years on average, where galantamine presented the strongest effect. This may be explained by its modulatory effect on nicotinic receptors as well as its inhibitory effect on acetylcholinesterase. Interestingly, in contrast to our previous findings in AD, ChEI‐treatment in DLB was not associated with reduced MACE or mortality risk, which might be related with the more prominent autonomic dysfunction in DLB than in AD.
Premenopausal bilateral oophorectomy (PBO) is associated with reduced late‐life white matter integrity on diffusion MRI
Authors: Mielke Michelle M. , Frank Ryan D. , Christenson Luke , Reid Robert I. , Fields Julie A. , Vemuri Prashanthi , Rocca Walter A. , Kantarci Kejal 
Published: December 2023

AbstractBackgroundSeveral studies suggest that premenopausal bilateral oophorectomy (PBO) is associated with an increased risk of cognitive impairment and dementia; however, the underlying brain changes are not well understood. Animal studies suggest that long‐term ovarian hormone deprivation in rats is associated with reduced white matter integrity, but few studies have been conducted among women. We assessed the impact of age at PBO before age 50 years on white matter integrity in a community‐based cohort of older women.MethodParticipants included 1,011 women enrolled in the Mayo Clinic Study on Aging (MCSA; 22 with PBO<40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years and 907 referent women). MCSA is a population‐based study of aging in Olmsted County, MN. PBO was abstracted from the medical records. Regional DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) were investigated using the Johns Hopkins University Atlas. Linear regression was used to examine the association between PBO age group and z‐scores of either FA or MD after adjusting for age at imaging and APOE.ResultThere were no differences in age at study visit (median = 72 years), education, APOE E4 frequency, or vascular comorbidities between the 3 groups of women with a history of PBO or referent women. Women with PBO<40 years, compared to referent women, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Women with PBO<40 years also had lower inferior frontal white matter FA and higher posterior thalamic radiation MD. Women who underwent PBO between 40‐44 years or 45‐49 generally did not have significant changes in white matter integrity compared to referent women.ConclusionWomen who underwent premenopausal bilateral oophorectomy prior to the age of 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for the education of women at a low risk for ovarian cancer who are considering PBO for benign conditions.