bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the Role of Kidney Function and Comorbidities in Observed Racial/Ethnic Differences in Blood‐based Biomarkers of Neurodegeneration: Results from the Einstein Aging Study (EAS)
Authors: Garza Angel Garcia De La , Wang Cuiling , Derby Carol A. , Lipton Richard B. , Zetterberg Henrik , Engeland Christopher G. , Katz Mindy J. 
Published: January 2025

AbstractBackgroundRecent research reveals that Alzheimer’s Disease blood‐based biomarkers (BBB) are influenced by demographics as well as kidney function and comorbidities. Data on differences in BBBs by race and ethnicity are sparse. We examined whether racial/ethnic differences in BBBs persist after controlling for kidney function and comorbidities.MethodsAnalyses included data from 274 EAS participants (mean age 77.57, SD 5.01, 67.5% Female, 46.4% Non‐Hispanic‐White, 41.2% Non‐Hispanic Black, 12.4% Hispanic). BBBs included β‐amyloid (Aβ40, Aβ42), Aβ42:Aβ40 ratio, pTau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Estimated glomerular filtration rate (eGFR) was calculated using either age‐sex‐race‐adjusted (eGFR‐ASR) or age‐sex‐adjusted (eGFR‐AS) creatinine equations (Inker et al., 2021 NEJM). History of hypertension, diabetes, stroke, myocardial infarction, angina, and congestive heart failure were ascertained by self‐report. Linear regression was used to assesses race/ethnic differences in BBBs adjusted for age, sex, BMI, and MCI status. Further models adjusted for eGFR‐AS, eGFR‐ASR, and comorbidities. Non‐Hispanic Whites were treated as the reference group.ResultsInitial models indicated significantly lower Aβ40 in non‐Hispanic Black and Hispanic (global p = 0.014) individuals and lower Aβ42 in non‐Hispanic Black (global p = 0.005) individuals compared to non‐Hispanic Whites. Further adjustment for using eGFR‐ASR attenuated racial/ethnic differences for Aβ40 (p = 0.099) and Aβ42 (p = 0.038), while adjustment using eGFR‐AS did not. We observed lower levels of NfL in non‐Hispanic Blacks and Hispanics (p = 0.003) adjusting for age, sex, BMI, and eGFR‐AS but not when adjusting for eGFR‐ASR. Both eGFR‐ASR and eGFR‐AS were negatively significantly associated with all BBBs. None of the comorbidities were significantly associated with any of the BBBs, and adjusting for comorbidities did not impact the observed racial/ethnic differences.ConclusionRace/ethnic differences in Aβ40 and Aβ42 levels persisted after adjusting for eGFR‐AS and comorbidities. Race differences in BBBs were reduced in magnitude when adjusting for eGFR‐ASR, but not when adjusting for eGFR‐AS. Future research should pursue adjustment using the more accurate cystatin‐C eGFR equation to determine whether race differences persist. Understanding these biomarker level differences across various races/ethnicities is crucial for the future of personalized and effective diagnosis, progression monitoring, and treatment of Alzheimer's Disease.
Different functional structures of the brainstem according to dementia subtypes
Authors: Gi Kim Seul 
Published: January 2025

AbstractBackgroundThe extent of neurofibrillary changes, one of the pathological hallmarks of AD, correlates with the severity of AD in dementia. The brainstem is known to be the site of neurofibrillary changes in the early stages of Alzhimer’s disease. The neurotransmitter system in the brainstem processes information from subcortical and cortical circuits affect to various cognitive and behavioral responses in the cerebral cortex. This study aims to investigate we cluster the brainstem with respect to how they connect to the cortex and focus on the brainstem cluster of differences according to the subtypes of AD.MethodWe acquired the resting state fMRI data from 137 patients with several dementia types (96 females, mean age = 70.31 ± 7.13), which were collected from the BICWALZS (Biobank Innovation for chronic Cerebrovascular disease With ALZheimer's disease Study). They were divided into four dementia subtype groups: subjective cognitive decline(SCD) mild cognitive impairment(MCI)‐β‐amyloid negative(MCI‐), MCI‐β‐amyloid positive (MCI+), and AD (N=33). For physiological denoising in functional neuroimaging data of the brainstem, we used FSL's ICA‐AROMA, a data‐driven denoising approach. We extracted each regional‐mean time series using Schaefer 200 atlas and voxel‐wise time series of brainstem. A functional connectivity matrix is composed of the brainstem‐to‐cortex that regressed out dominant pattern, which is the weights of the connectivity across all 200 cortical regions that the brainstem had. Then we clustered the brainstem based on modularity according to the extent of connectivity similarity between the brainstem and cortex via connectivity matrix profiles. Finally, our study focused that comparison the pattern of clustering according to the subtypes of AD.ResultsWe found that each community in the brainstem is a group with a similar pattern of functional connectivity to the cortex. Different brainstem communities are observed in the distinct in accordance with the subtypes of AD, suggesting that in each disease group can characterize specific brainstem communities with functional connectivity to the cerebral cortex.ConclusionDifferent patterns of clusters in different subgroups of dementia may explain functional abnormalities in the brainstem as dementia progresses. The future study will characterize each connection between clusters of brainstem and cortical regions
Evaluation of a person‐centred care model for persons living with dementia in the hospital rehabilitation setting using the RE‐AIM framework
Authors: Burley Claire V , Williams Anna , Maiden Genevieve , Reyes Patricia , Cook Jacquelene , Brodaty Henry , Chenoweth Lynnette 
Published: January 2025

AbstractBackgroundOne in four persons living with dementia are admitted to hospital, presenting challenges to them, their carers and staff. Despite global evidence demonstrating the clinical and cost‐effectiveness of person‐centered care (PCC), it is not yet business as usual across healthcare settings. We used multi‐level stakeholder input to implement Kitwood’s PCC model into a sub‐acute setting.MethodsBetween June 2021 to June 2023, the PCC model was implemented and evaluated using the Consolidated Framework for Implementation Research (CFIR) and quantitative and qualitative methods to address the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE‐AIM) framework. Key stakeholders and a strong governance structure including persons living with dementia, family caregivers, clinicians, nurses, hospital leaders, community partners, government officials and policy makers, informed all aspects of implementation and evaluation. Co‐primary outcome measures were delirium and agitation. Data were collected pre‐, post‐ and 6‐months following PCC education.ResultsReach: Ninety nursing, medical and allied health staff (93% of hospital staff) completed online and/or in‐person PCC education; eight senior staff leaders completed in‐person PCC education and took on the role of ‘PCC Champion’ to support staff in implementing PCC. Effectiveness: Significant improvements (all p<.05) were observed in outcomes for persons living with dementia: delirium (phi = 0.73), incidents/injuries (phi = 0.99), psychotropic medication use (phi = 0.09), and readmissions (phi = 0.25). No change was observed for agitation. Adoption: Staff knowledge of and confidence in delivering PCC significantly improved (both p<.005). A significantly higher number of positive (person‐centered) interactions was observed following education (p = 0.000, phi = 0.60), though there was also a high number of neutral interactions. Implementation: PCC education delivery could and was efficiently adapted as required to unplanned crises (i.e. COVID‐19 pandemic). Maintenance: Six‐month follow‐up data showed staff maintained improved PCC knowledge and confidence (both p<.005). However, only three of the eight PCC Champions remained. Suggested modifications to aspects of the model include adopting reflective feedback processes with staff, PCC education for non‐clinical staff, reducing online content to fewer modules, and adapting the education to suit specific cultural groups.ConclusionsThe successful translation of a PCC education model into a sub‐acute rehabilitation setting during a global pandemic has implications for policy and practice.
Does the Current Evidence for Lecanemab Mechanism Support a Rationale for Continued Lecanemab Dosing?
Authors: Selkoe Dennis J. , Dhadda Shobha , Irizarry Michael C. , Kramer Lynn D 
Published: January 2025

AbstractAlzheimer’s disease pathophysiology is believed to involve various abnormalities, including those of amyloid beta (Ab) peptide and tau processing, inflammation, oxidative stress, and vascular risk factors. Aβ peptides exist in a dynamic continuum of conformational states from monomeric Aβ, to soluble progressively larger Aβ assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques). Various lines of evidence support the “amyloid hypothesis” that Aβ plays a central role in the pathogenesis of AD, and several immunotherapies have been developed to interact with this cascade in various different places which may reduce the number of soluble aggregates and insoluble Aβ fibrils deposited in the brain. Lecanemab is a novel humanized immunoglobulin G1 (IgG1) anti‐amyloid monoclonal antibody with highest affinity for Aβ protofibrils, a particularly toxic Aβ species. Lecanemab distinguishes itself from other anti‐amyloid antibodies in that it selectively targets large soluble protofibrils relative to monomers (greater than 1000‐fold over Aβ monomers), with preferential activity over insoluble fibrils (up to 10‐fold over fibrils). In the phase 3 Clarity AD study, lecanemab demonstrated a consistent slowing of decline over 18 months in clinical (global, cognitive, functional, and quality of life) outcomes which if used early in the clinical paradigm has shown to slow disease progression for up to 30 months, and reduction in brain amyloid in early Alzheimer’s disease. Herein, we will highlight the mechanism‐based rationale for continued lecanemab dosing, providing both the current supportive evidence and outstanding questions. Relevant Alzheimer’s disease background will be discussed, including the impact of the latest diagnostic criteria. We will share insights on Alzheimer’s disease pathophysiology, including how the ongoing/chronic nature of the disease requires continuous therapy. In addition, we will review the latest data on lecanemab mechanism and overview of the mechanistic rationale for development of lecanemab Aβ immunotherapy. The role of tau aggregates, a predictive biomarker for the emergence of neurodegeneration, will be explored. Additional insights on continued dosing based on current knowledge of lecanemab mechanism will be shared. An overview of the mechanistic differences and their implications among anti‐amyloid antibodies will be presented.
Generalizability of demographic and genetic variable interactions with amyloid driving tau burden in a heterogeneous group of cognitively normal older adults: A multi‐cohort study
Authors: Harrison Theresa M. , Ward Tyler J. , Chadwick Trevor , Taggett Jacinda , Baker Suzanne L. , Braskie Meredith N , Landau Susan M. , Jagust William J. ,   the U.S. POINTER Study Group, the Alzheimer's Disease Neuroimaging Initiative
Published: January 2025

AbstractBackgroundEfforts to increase heterogeneity in cohorts of cognitively normal older adults with Alzheimer’s disease (AD) neuroimaging biomarkers have resulted in large datasets with differing characteristics. It is unclear whether associations between AD biomarkers and key demographic and genetic factors are generalizable across heterogeneous cohorts.MethodPET and MR scans from cognitively normal older adults aged >55 in the Berkeley Aging Cohort Study (BACS), ADNI, the Health and Aging Brain Study‐Health Disparities (HABS‐HD) and POINTER Imaging were processed using harmonized pipelines. Global beta‐amyloid (Aβ) burden was quantified in centiloids (CL). Tau‐PET SUVRs in entorhinal cortex (ERC) and a temporal MetaROI were z‐scored using tracer‐specific reference cohorts of cognitively normal, Aβ‐ adults aged 60‐70yrs. Key demographic and genetic data (sex, race/ethnicity and APOE genotype) were obtained for each cohort and harmonized. Robust linear models predicting tau burden were used to test for interactions between these variables and continuous Aβ in a pooled sample and in cohort‐specific models. Cohort and age were covariates.ResultA total of 2,114 cognitively normal older adults were included across 4 cohorts which differed on many characteristics (Table 1). In pooled analyses, there was a sex by Aβ interaction on ERC (but not MetaROI) tau such that women had disproportionately more tau as Aβ increased (Table 2; Figure 1 shows raw data). In models focused on race/ethnicity, non‐Hispanic white individuals had more tau as Aβ increased compared to Black individuals. In models predicting ERC or MetaROI tau, e3/e4 or e4/e4 (versus e3/e3) individuals had higher tau as Aβ increased, respectively. Age and global Aβ were significant predictors in all models. In cohort‐specific analyses, findings were inconsistently replicated such that some results from the pooled sample were not observed in any individual cohort, and some cohort‐specific results were not observed in the pooled sample (Table 2).ConclusionIn a combined cohort analysis, sex, race/ethnicity and APOE interacted with Aβ on tau burden in unimpaired older adults. However, there was little between‐cohort consistency in associations between sex, race/ethnicity, APOE, and AD biomarkers, suggesting that cohort heterogeneity and statistical power have major influence on the observation of these effects.
Genetic predisposition to AD and inflammation determine vulnerable brain regions to air pollution
Authors: Vilor‐Tejedor Natalia , Genius Patricia , Rodríguez‐Fernández Blanca , Anastasi Federica , Cirach Marta , Nieuwenhuijsen Mark , Minguillón Carolina , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo 
Published: January 2025

AbstractBackgroundThe detrimental effects of air pollution on health are well‐documented, yet its impact on brain structure in the early asymptomatic stages of Alzheimer’s disease (AD) remains under‐explored. This study investigated the relationship between air pollution and brain imaging features, focusing on the moderating role of genetic factors associated with AD and inflammation.MethodsA total of 1,153 individuals from the ALFA cohort, many within the Alzheimer’s continuum, with available genotyping, air pollution estimation and magnetic resonance imaging were included (62.6% women, average age 55,6 years). Land use regression models were used to estimate individual levels of air pollution, including nitrogen oxide (NO2) and particulate matter (PM2.5, PM10), at the participants’ residential addresses. Functional genetic scores, including plasma pQTLs for inflammatory markers (PRS‐CCL2, PRS‐IL6, PRS‐CCL19), CSF pQTLs for AD pathology (PRS‐Aβ42, PRS‐ptau), genetic predisposition to clinical AD (PRS‐AD), and APOE‐ε4 carriership, were assessed. General linear models, corrected for age at MRI visit, sex and years of education, were computed to assess the main effects of air pollution on brain volumes. Modifiable genetic effects in gene‐environment interaction models were investigated.ResultsIndividuals at higher genetic predisposition to AD and APOE‐ε4 carriers exhibited increased vulnerability to air pollution, particularly in temporal and frontal regions [Figure 1A]. Individuals with high genetic predisposition for inflammatory markers showed distinct patterns of vulnerability, particularly affecting regions within the parietal and limbic lobes, with notable impact on hippocampal volumes and the subfields within the hippocampal formation [Figure 1B]. Finally, as pollution levels increased, reduction in transverse temporal volumes was observed in individuals at high risk of AD and altered CCL2 protein plasma levels [Figure 2]. Multiple comparison corrections were performed within brain lobes by regions.ConclusionsOur results suggested a differential impact of air pollution on brain structure, modulated by genetic predisposition to AD and inflammation. This underscores the importance of considering genetic information when assessing the neurological impact of environmental exposures. These findings pave the way for more personalized approaches in public health interventions, and highlight the need for targeted strategies to mitigate the impact of environmental factors on neurological health.
Achieving micron‐level precision MR‐Histology correlation for validating Alzheimer’s disease biomarkers in the human hippocampus
Authors: Wang Yixin , Ho William Hai Dang , Huszar Istvan N. , Taghavi Hossein Moein , Nirschl Jeffrey , Leventis Samantha , Schlömer Philip , Axer Markus , Shao Wei , Rusu Mirabela , DiGiacomo Phillip , Georgiadis Marios , Zeineh Michael 
Published: January 2025

AbstractBackgroundMRI offers potential noninvasive detection of Alzheimer's micropathology. The AD hippocampus exhibits microscopic pathological changes such as tau tangles, iron accumulation and late‐stage amyloid. Validating these changes from ultra‐high‐resolution ex‐vivo MRI through histology is challenging due to nonlinear 3D deformations between MRI and histological samples. We aim to address the challenge by a pipeline (Figure 1) for precise alignment of post‐mortem MRI data with histological images.MethodA human hippocampal specimen was dissected from a formalin‐fixed human brain and divided into hippocampal head and tail. We obtained high‐resolution multi‐echo gradient echo ex vivo MRI of each using a 7T Bruker scanner. The specimens were paraffin‐embedded and sectioned using a Leica Histocore Nanocut R microtome. An optical image of the tissue block's surface was captured before each section was cut (Blockface image) using a polarized filter at Brewster’s angle. The obtained 2D blockface images were aligned and filtered into 3D blockface volumes. These were registered with MRI using either Tensor Image Registration Library (TIRL) with Modality Independent Neighbourhood Descriptor, or ANTs SyN registration. Subsequently, the 2D MRI slices corresponding to the stained histology slides were identified in the 3D volume and underwent 2D deformable registration with TIRL or ANTs. To quantify the registration accuracy, we segmented hippocampal volumes into white matter, grey matter, and dentate gyrus for MRI, blockface, and histology data separately.ResultWhen comparing 3D MR and blockface 3D image segmentations (Figure 2, top), the average Dice similarity coefficient of hippocampal head and tail were 86.2% and 86.76% with TIRL, and 83.91% and 78.26% with ANTs SyN. Evaluating 2D MR registration to histological images, TIRL achieves the average Dice coefficient of 94.12% and 96.95%. ANTs performs marginally better across the whole tissue mask, but TIRL shows superior performance in the internal features (Table 1). High‐fidelity alignment shows very small features such as focal hypointensities (Figure 2, bottom, blue circles) and the dentate granule cell layer (orange arrows).ConclusionOur advanced correlative MRI‐histology pipeline achieves micron‐level precision coregistration methods at micron‐scale precision, propelling the development of MRI‐based AD biomarkers.
A lower plasma odd chain fatty acids composition accompanies a significant increase in the desaturase index in Alzheimer’s disease
Authors: Jose Joby , Fonteh Alfred N. 
Published: January 2025

AbstractBackgroundOdd‐chain fatty acids (OCFA) are gut microbiota‐derived metabolites that are important in energy generation, neuronal signaling, and memory. Since the composition of the gut microbiota affects cognitive function, we hypothesize that plasma saturated OCFA composition may be altered in AD compared to cognitively healthy older adults.MethodOlder adults (>65 years) were recruited, and demographic and neurological data obtained in an ongoing brain‐aging project. Participants were classified as cognitively healthy (CH) or clinically probable AD (AD) based on a comprehensive neuropsychological assessment. Overnight fasting plasma was collected, and unesterified fatty acids were extracted using acidified ethyl acetate. Plasma saturated OCFA (sOCFA: FA 5:0, FA 7:0, FA 9:0, FA 11:0, FA 13:0, FA 15:0, FA 17:0 & FA 19:0) and monounsaturated OCFA (mOCFA: FA 11:1, FA 13:1, FA 15:1, FA 17:1 & FA 19:1) compositions were measured using liquid chromatography tandem mass spectrometry after derivatization with dimethylaminophenacyl bromide (DmPABr). OCFA compositions were determined as a percentage (± SD, 95% CI) of 42 fatty acids detected in plasma, and the CH to AD differences were determined using Mann‐Whitney tests.ResultEight sOCFAs (FA 5:0‐FA 19:0) and five mOCFAs (FA 11:1‐FA 19:1) were detected and quantified in plasma. The findings indicated a general trend of decreased sOCFA in AD plasma as compared to CH plasma (Figure 1). The total sOCFA composition in CH (0.24 ± 0.18, 0.09–0.39, n = 8) was higher than in AD (0.1 ± 0.07, ‐0.09–0.25, n= 4, p= 0.0545). The desaturase index (ratio of mOCFA to sOCFA) for FA:11, FA:13, FA:17, and FA:19 was significantly higher in AD than in CH (Figure 2). The total CH (0.52 ± 0.14, 0.41‐0.64) desaturase index was significantly lower (p< 0.05) than in AD (0.86 ± 0.32, 0.34‐1.38).ConclusionThese data suggest that AD participants have a lower plasma sOCFA composition, which may be due to enhanced conversion of sOCFA to mOCFA, as evidenced by a higher desaturase index in AD compared to CH. Therefore, measurement of plasma sOCFA can be used to monitor AD‐associated lipid metabolism and pathways linked to microbiome status.
Comparison of local amyloid PET uptake patterns between black and white participants in the GAP Bio‐Hermes study
Authors: Wolz Robin , McGinnity Colm J , Joules Richard , Hughes Lynne , Mohs Richard , Dwyer John , Beauregard Douglas W. 
Published: January 2025

AbstractBackgroundAmyloid status is a core marker of Alzheimer’s disease and can be defined qualitatively through expert neuroradiologist visual read and quantitively through SUVR analysis. We investigate differences in amyloid status classification between racial groups.MethodWe analysed data from 944 participants enrolled in the Global Alzheimer’s Platform (GAP) Bio‐Hermes trial. After exclusion of technical failures (N=9), subgroups in the ‘Non‐Hispanic or Latino’ population were defined as follows: Group 1 ('Black or African American') and Group 2 (‘White’; see Table 1).ResultGCA SUVR was not statistically different between Groups 1/2 for pooled data. Figure 1a reveals that Aβ‐ participants in Group 1 had notably less occurrence of lower GCA SUVR values compared with Group 2, which resulted in a higher mean SUVR, driving the significant group difference observed between Aβ‐ participants (p<0.001).Aβ+ fraction based on visual read was 24% in Group 1 and 37% in Group 2; these fractions change to 38% and 41% respectively with a threshold of GCA SUVR > 1.1.Significant group differences were observed for Aβ‐ participants in the SUVRs for Grothe Stages 2, 3, and 4 (p <0.001, Figure 1b).In Aβ‐ subjects, statistically significantly higher SUVR was observed in ‘Black or African American’ participants (Group 1) compared to ‘White’ participants (Group 2) for the caudate, medial temporal, parietal and frontal lobes (p < 0.05 with Bonferroni correction).ConclusionOur findings suggest there may be differences in patterns of amyloid deposition between racial groups that may confound quantitative and visual classification of amyloid status. Further study is required to understand a potential impact on determining amyloid state for populations under‐represented in the definition of current criteria.