bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disseminating COVID‐19 and Alzheimer’s Disease Information to Underrepresented Communities Using Social Media
Authors: James Taryn T. , Levy George , Hills Ornella J , Ellis Tiffany , Benitiz Ashley , Lawrence Sacheen L. , Gleason Carey E. , Metoxen Melissa , Pinzon Maria C Mora 
Published: December 2023

AbstractBackgroundTo help address the impact of disinformation pertaining to the COVID‐19 pandemic on underrepresented groups (URG), members of the University of Wisconsin Alzheimer’s Disease (AD) Center formed a strategic team consisting of experts in communications, health research scientists, community advocates and community agencies to disseminate information to URG communities on social media platforms. Three Wisconsin communities were included: African American, American Indian (i.e. Oneida Nation) and Latinx communities. Our goals were 1) to share culturally tailored and medically accurate messages on the virus, vaccine, and related topics, 2) to quell disinformation, and 3) to offer information on pertinent health topics such as Alzheimer’s disease (AD) dementia that also disproportionately affect URG and for which COVID‐19 is now a risk factor.MethodOur experts convened weekly to discuss possible topics suggested by team scientists or community advocates based on feedback from their respective community. Our team scientist developed lay format materials which were further translated into culturally appropriate social media messages by community advocates. Advocates posted at least one social media message per week for a total of 804 posts across all three communities. Social media metrics (Reach, Engagement, Impressions) were collected at 10 months, 17 months, 24 months and 28 months after initial post, using Hootsuite, Sprout Social and Facebook Analytics. Posts focused on mental health (n = 38) and Alzheimer’s disease (n = 7) were tagged on the Facebook and Instagram pages targeting African Americans.ResultOverall from September 2020 – January 2023, the 804 mixed‐media informational posts on social media platforms, garnered 166,917 impressions and over 11,202 engagements (Table 1). Topics including mental health and AD were well received (Figure 1). Audiences resonated with personal posts surrounding health topics from the community advocates.ConclusionFacebook had higher engagement rates than Instagram, but AD posts had lower reach and engagement than those of mental health, suggesting that more efforts are necessary to increase awareness about AD. Using mixed‐media approaches, and utilizing community advocates to communicate health information to URG were impactful. These strategies could be extrapolated to other initiatives, including the recruitment of URG into dementia clinical trials which can aid in dismantling dementia related health disparities.
Exposure‐response modeling to describe the change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease
Authors: Willis Brian A. , Hussein Ziad , Hayato Seiichi , Takenaka Osamu , Penner Natasha , Yasuda Sanae , Reyderman Larisa 
Published: December 2023

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. Lecanemab has been tested as a disease‐modifying treatment for early Alzheimer’s disease in two clinical studies (NCT01767311 and CLARITY‐AD, NCT03887455). As part of these studies, amyloid PET scans were collected in a subset of patients, demonstrating that lecanemab leads to pronounced reduction in brain amyloid.MethodA model describing the relationship between serum lecanemab exposure and brain amyloid reduction from baseline was developed using data pooled from Phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population PK model and correlated with amyloid PET using an indirect response model, with a lecanemab‐dependent increase in the degradation rate of amyloid, introduced as linear function. The model was parametrized in terms of baseline amyloid load, elimination rate constant for amyloid removal (Kout) and exposure effect (DESLP). Inter‐subject variability was estimated for each of the model parameters. Covariates were included in the model using a forward‐inclusion (p<0.01) /backwards‐elimination (p<0.001) approach.ResultA total of 4129 observations from 1088 subjects were included in the dataset. The model estimate of Kout was 0.0496 yr−1 (95% confidence interval: 0.0206, 0.0827), suggesting a re‐accumulation half‐life of brain amyloid of ∼14 years. APOE4 carrier status (homozygous and heterozygous together) was a statistically significant predictor of baseline amyloid (APOE4 noncarriers: 65 CL; APOE4 carriers: 83 CL). Age was a significant covariate on DESLP, with older patients removing amyloid at a faster rate than younger patients. None of the other covariates explored, including presence of antidrug antibodies or baseline MMSE score, had a statistically significant effect on any model parameter.ConclusionAn exposure‐response model has been developed that describes the change in brain amyloid over time during treatment with lecanemab and after stopping lecanemab treatment. This model provides additional insights into factors that may drive differences in the rate of brain amyloid removal between patients.
In‐depth evaluation of protein domains improves classification of SORL1 variant pathogenicity in Alzheimer’s Disease patients
Authors: de Waal Matthijs W J , Hulsman Marc , van der Lee Sven J , Andersen Olav M. , Holstege Henne 
Published: December 2023

AbstractBackgroundRare pathogenic SORL1 gene variants have been identified as strong risk‐increasing factors in Alzheimer’s disease (AD). Recent analysis indicated that SORL1 loss‐of‐function (LoF) variants associated with a ∼40‐fold increased risk for early‐onset AD, while missense variants that were prioritized using in silico variant pathogenicity‐prediction algorithms associated only with a 2‐fold risk increase. However, current risk‐prediction strategies do not take SORL1‐specific features into account. We aimed to design a variant classification strategy that adds in‐depth knowledge of SORLA structural folding and function to the variant risk prediction.MethodWe identified coding SORL1 variants in a discovery/replication sample of whole exome sequencing data from the ADES/ADSP studies comprising 18,959 cases and 21,893 controls after quality control. We selected only the extremely rare variants (MAF<0.05%) and further divided these into LoF(n = 77) and missense variants(n = 539). With an in‐depth evaluation of protein functional domains (informed by pathogenic variants in homologous genes) combined with their predicted pathogenicity (REVEL algorithm) we prioritized missense variants into ‘high priority’, ‘moderate priority’ and ‘low priority’. We compared the age‐dependent penetrance of missense variants for each priority‐category and LoF variants, in context of APOE genotype.ResultCarriers of prioritized missense variants had a similar age‐dependent penetrance as LoF variants, with median age at AD‐onset of ∼65 years which is significantly lower compared to non‐carriers (∼72 years). In addition, carriers of prioritized SORL1 missense variants have an expedited age at onset by ∼7 years independent of their APOE genotype. If we look at a 80% penetrance level, SORL1 carriers with homozygous ε4 background had AD by age 61 (95%CI 60‐NA, n = 6) compared to age 73 (95%CI 72‐73, n = 1091) for SORL1 WT carriers. Carriers with a heterozygous background had AD by age 71 (95%CI 68‐76, n = 62) compared to 78 (95%CI 78‐78, n = 4816) for WT. For a non‐ε4 background the age at onset for carriers was 83 years (95%CI 78‐90, n = 54) compared to 85 years (95%CI 85‐85, n = 5773) for WT. The moderate and low priority group showed no significant difference compared to WT.ConclusionOur prioritization model can successfully identify likely pathogenic missense SORL1 variants, allowing for better identification of patients with possible SORL1‐associated‐AD.
Data‐driven comparison of neurodegeneration patterns between autosomal dominant and sporadic late‐onset Alzheimer’s disease
Authors: Aksman Leon M. , Guzman Samuel , Ringman John M 
Published: December 2023

AbstractBackgroundAutosomal dominant Alzheimer’s disease (ADAD) and sporadic late‐onset AD (LOAD) have similar biomarker profiles, supporting a shared pathophysiology. While both ADAD and LOAD are known to be heterogeneous, there are few studies that have compared the heterogeneity of neurodegeneration as indexed by volumetric MRI in LOAD to that of ADAD. Here we apply a data‐driven model of brain atrophy subtypes from LOAD to characterize atrophy within ADAD.MethodWe used cross‐sectional MRI from ADNI (LOAD) and the Estudio de la Enfermaded de Alzheimer en Jalisciences (EEAJ; ADAD). We used 13 cortical and subcortical Freesurfer‐based regions from 1,912 ADNI participants to train a Subtype and Stage Inference (SuStaIn) model of brain atrophy progression within LOAD. We built a three‐subtype model and applied it to subtype and stage 61 EEAJ participants: 47 carriers of the A431E mutation in PSEN1 and 14 carriers of the V717I mutation in APP. To harmonize the two datasets, we removed the effects of age, sex, education years, ICV and study (ADNI vs. EEAJ flag) from each regional volumetric biomarker prior to analysis. We retained 47 of the 61 EEAJ participants with an estimate SuStaIn stage greater than zero (in any subtype) for subsequent analyses.ResultThe progression patterns for each of the three data‐driven brain atrophy subtypes (typical, cortical, subcortical) are presented in Figures 1 A‐C. These are consistent with previous findings in LOAD. We found no difference in the percentage of participants in each subtype between LOAD, ADAD‐PSEN1 and ADAD‐APP groups (χ2 = 1.5, p = 0.84; Figure 1D). Within ADAD, those assigned the typical subtype had a slightly lower average stage of progression than those in the other two subtypes (t = ‐2.0, p = 0.049; Figure 2A). The triangle plot shows the probability of subtype membership is mostly clustered around the typical and cortical subtypes (Figure 2B), while the estimated stages increase dramatically after disease onset, as expected (Figure 2C).ConclusionWe found a comparable distribution of LOAD‐based atrophy subtypes within both the PSEN1 and APP carriers groups in ADAD, showing that heterogeneous neurodegeneration is another commonality between ADAD and LOAD.
Baseline Cognitive Performance Is a Determinant of Prospective Health Resource Utilization Among Adults with Chronic Stroke: A Secondary Analysis
Authors: Davis Jennifer C , Adjetey Cassandra , Eng Janice J , Falck Ryan S , Dao Elizabeth , Best John R. , Tai Daria , Bennett Kimberly J , McGuire Katherine , Hsiung Ging‐Yuek Robin , Middleton Laura E , Hall Peter A , Liu‐Ambrose Teresa 
Published: December 2023

AbstractBackgroundCognitive impairment is a costly public health problem globally. Among older adults with chronic stroke, the literature is devoid of prospective data that identify factors responsible for driving health care resource utilization. This study aimed to ascertain key determinants of health resource utilization (HRU) at 6 and 12 months among older adults with chronic stroke.MethodThis study was a secondary prospective analysis of an economic evaluation conducted alongside the Vitality study, a 6‐month randomized controlled trial with a 6‐month follow‐up which included 120 community‐dwelling adults with chronic stroke, aged 55 years and older. Participants were randomized into 1) exercise (EX) or 2) cognitive and social enrichment activities (ENRICH), or 3) stretching and toning program (BAT) (i.e., control group/ comparator). The primary outcome measure of the randomized controlled trial was the Alzheimer’s Disease Assessment Scale‐Cognitive‐Plus (ADAS‐Cog‐Plus), a global measure of cognitive performance using multidimensional item response theory. We constructed two linear regression models with HRU at 6 and 12 months as the dependent variables for each model, respectively. Predictors relating to mobility, quality of life, global cognition and executive functions were examined. Age, sex, comorbidities, and group allocation (i.e., EX, ENRICH or BAT) were included regardless of statistical significance. Costs were reported in 2022 Canadian Dollars.ResultThe ADAS‐Cog Plus was a significant determinant of total HRU at 6 months (intervention cessation; p = 0.001) and 12‐months (6‐month followup; p = 0.004).ConclusionThe ADAS‐Cog Plus, a measure of cognitive performance, was a significant determinant of HRU at 6 and 12 months among older adults with chronic stroke. This highlights the importance of interventions aimed at combating cognitive decline to minimize health care resource among individuals with chronic stroke.
Subtle cognitive difficulties increase risk of neurodegeneration, incident mild cognitive impairment, and dementia in older women.
Authors: Petkus Andrew J. , Wang Xinhui , Beavers Daniel P. , Espeland Mark A. , Resnick Susan M. , Salminen Lauren , Gatz Margaret , Rapp Stephen R. , Chen Jiu‐Chiuan 
Published: December 2023

AbstractBackgroundIdentifying individuals with preclinical Alzheimer’s disease and related disorders (ADRD) is important for prevention and eventual treatment. Here we aimed to integrate overall test performance with episodic memory process scores in a cohort of older women to identify those with subtle cognitive difficulties (SCD; e.g., individuals with the earliest declines in cognitive ability preceding a diagnosis of mild cognitive impairment (MCI) or dementia) and determine subsequent risk of MCI, dementia, and neuroimaging indices of neurodegeneration.MethodParticipants included 2,186 community‐dwelling older women without MCI or dementia (Mage = 73.4±3.8 years) who completed a comprehensive neuropsychological assessment as part of the Women’s Health Initiative Study of Cognitive Aging (WHISCA: 1999‐2000). Women were assessed annually for MCI and dementia until 2021, and 1,024 women underwent structural magnetic resonance imaging (sMRI) of the brain in 2005‐6. Women were classified as cognitively normal (CN), early SCD (e‐SCD; two episodic memory process scores 1 SD below normative means or one process score and one performance score 1 SD below normative means), or late SCD (l‐SCD; two overall performance scores 1 SD below normative means) at WHISCA baseline using validated criteria from the Alzheimer’s Disease Neuroimaging Cohort (Thomas et al., 2018 Journal of Alzheimer’s Disease). We used Cox proportional hazards to examine associations between SCD status and risk of developing MCI/dementia. Linear regressions were used to examine associations between SCD status and MRI indices of AD‐related neurodegeneration, global cerebrovascular damage, and brain volumes of structures that make up the medial temporal lobe. All associations were adjusted for sociodemographic, lifestyle, and clinical characteristics.ResultWomen with e‐SCD and l‐SCD were 1.58 (p<0.001) and 3.01 (p<0.001) times as likely to develop MCI/dementia compared to CN women, respectively (Figure 1). Women with l‐SCD (β = 0.20; p<0.001) had more AD‐related neurodegeneration compared to CN women (Table 1). Women with e‐SCD had marginally significantly greater AD‐related neurodegeneration (β = 0.14; p = 0.073) and had smaller volumes in the entorhinal cortex (β = ‐0.22; p = 0.009) compared to CN women.ConclusionOur study demonstrates the usefulness of the SCD criteria for the early identification of cognitively normal women who are at increased risk of MCI, dementia, and neurodegeneration.
CONCORDANCE BETWEEN VISUAL INTERPRETATION AND QUANTITATIVE ANALYSIS OF [18F]FLORTAUCIPIR PET IMAGES
Authors: Moscoso Alexis , Heeman Fiona , Raghavan Sheelakumari , Sparrman Kohl Johnson , Costoya‐Sánchez Alejandro , Camacho Valle , van Essen Martijn , Grothe Michel J. , Mainta Isminni , Ribaldi Federica , Devous Michael D , Pontecorvo Michael J. , Frisoni Giovanni B , Garibotto Valentina , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi , Schöll Michael 
Published: December 2023

AbstractBackgroundPositron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research.MethodWe included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA‐approved method. Visual reads were compared to an established approach for defining tau‐PET positivity based on SUVR values in a temporal meta‐ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined “lenient” (SUVR = 1.22) and “conservative” (SUVR = 1.30) cut‐points were explored. In addition, visual reads were compared to tau‐PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut‐points: SUVRMTL = 1.30, SUVRNEO = 1.37).ResultConcordance between visual and quantitative approaches was limited (Figure 1): the “lenient” and MTL‐NEO methods yielded high rates of quantitative‐positive, visual‐negative scans (73‐52% and 26‐18% for CU and CI, respectively), while the “conservative” cut‐point failed to detect 45% and 13% of the CU and CI visual‐positive scans, respectively. The prevalence of tau‐PET positivity in Aβ‐negative individuals was highest with the “lenient” cut‐point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual‐positive, quantitative‐negative individuals were more frequently Aβ‐positive than visual‐negative, quantitative‐positive individuals (“lenient”: 86% vs 50%, p<0.001; “conservative”: 87% vs 58%, p<0.001; MTL‐NEO: 85% vs 70%, p = 0.005). Among visually‐positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3).ConclusionVisual and quantitative methods for [18F]flortaucipir PET are non‐exchangeable. Tau‐PET positivity based on visual interpretation aligns better with Aβ‐pathology. A significant number of visually‐positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods.
Feasibility of implementing wearable technologies for in‐home assessment of behavioral and event‐related potential responses after sleep and wakefulness in Alzheimer disease
Authors: Hagan Brenna , DeCaro Renee , Dyer John , Schwartz Joel , Turk Katherine W , Murphy Brian , Waskow Emily , Lai Matteo , Mortera Andrea , Oglevee Catherine , Shinobu Leslie , Budson Andrew E 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is associated with impaired sleep that worsens over disease progression. To explore the circadian effects on memory consolidation and underlying neurophysiology in young versus old healthy volunteers versus patients with AD, we used two wearables in a repeated/longitudinal at‐home clinical paradigm that captured key behavioral and electrophysiologic responses after sleep and after daytime activity.MethodA participant home‐administered, behavioral, and event‐related potential (ERP) through electroencephalogram (EEG) platform (Cumulus Neuroscience) is administered over a two‐week period to healthy younger adults, healthy older adults, and older adult patients with AD. Participants engaged in behavioral (image recognition) testing coupled with EEG/ERP recordings twice daily ‐ once in the morning following approx. 12 hrs of sleep/rest and once after at end of day before retiring activity. Two‐minutes of resting state EEG/ERPs began each session, for twenty‐two total sessions. Reports of sleep, together with smart watch actigraphy (Empatica, Inc), are used to estimate the duration and intensity of the rest/sleep period versus daytime activity. This novel protocol explores whether each wearable generates data that is sufficiently reproducible and sensitive to track and interpret changes in episodic memory consistent with known changes expected based on age and AD status.ResultWe report on feasibility of implementation of the experimental paradigm and whether the sensors employed reliably yield interpretable data. We share data on recruitment rates and subject feedback regarding tolerability of Cumulus Headset and Empatica watch.ConclusionThe home‐based experimental paradigm is well‐tolerated with excellent adherence to the study design. Both sensors yielded experimental datasets of similar quality to those obtained in in‐house studies. Planned analyses focus on establishing whether this experimental paradigm yields data with sufficient sensitivity and reproducibility to confirm past observations regarding the effect of age and AD on memory consolidation.
The relationship between [18F]FDG‐PET signal and key‐players of brain glucose metabolism
Authors: Limberger Christian , Machado Luiza Santos , Ferrari‐Souza João Pedro , Povala Guilherme , Carello‐Collar Giovanna , Pascoal Tharick A. , Bouzier‐Sore Anne‐Karine , Pellerin Luc , de Souza Débora Guerini , Zimmer Eduardo R. 
Published: December 2023

AbstractBackgroundNeuronal activity is supported by activity‐dependent lactate production from astrocytes, as postulated by the astrocyte–neuron lactate shuttle (ANLS) hypothesis. Indeed, astrocytic glutamate uptake is a main trigger for brain glucose consumption. [18F]fluorodeoxyglucose (FDG)‐PET showing a hypometabolic signature has been used as an index of neurodegeneration in Alzheimer’s disease (AD). In the early stages of the disease, soluble amyloid‐beta (Aβ) has been associated with neuronal hyperactivity due to decreased astrocytic glutamate uptake. It is hypothesized that this phenomenon occurs especially in regions with high ongoing baseline activity. Over time, neurodegeneration and hypometabolism in such regions may contribute to the progress of the AD continuum. Thus, we investigated whether the [18F]FDG‐PET signal in typical hypometabolic regions in AD is associated with the expression of ANLS transporters and enzymes in the healthy brain.MethodGene expression of GLUT1, GLUT3, MCT1, MCT2, MCT4, LDHA, and LDHB (ANLS genes) from postmortem brain tissue of healthy individuals were obtained from the Allen Human Brain Atlas. [18F]FDG‐PET data from cognitively unimpaired individuals were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Pearson correlations were performed between the mean gene expression and the mean [18F]FDG‐PET SUVr across typically hypometabolic brain regions in AD (precuneus, angular and temporal gyri, and parietal and cingulate regions) and non‐vulnerable regions (uncorrected p‐value < 0.05).ResultsThe expression of ANLS genes had a stronger positive correlation with [18F]FDG‐PET SUVr across the AD hypometabolic regions than the non‐vulnerable regions (p < 0.05). Of note, the astrocytic glucose transporter GLUT1 presented a stronger correlation with [18F]FDG‐PET than the neuronal transporter GLUT3 in AD‐vulnerable regions. Figure 1 presents all correlations.ConclusionOur results show that the physiological expression of transporters and enzymes responsible for the brain glucose metabolism correlate more with the [18F]FDG‐PET signal in typical brain regions of the AD hypometabolic signature. This suggests these regions present a higher baseline activity and may be more susceptible to Aβ‐induced hyperactivation in early AD, which could lead to a bioenergetic collapse in later disease stages, as shown in the [18F]FDG‐PET of AD individuals.