bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying patients with cognitive impairment in a large health system: an innovative initiative to facilitate detection in primary care
Authors: Gaster Barak , Suchsland Monica Zigman , Fitzpatrick Annette L. , Liao Joshua M. , Belza Basia , Hsu Amy P , McKiddy Sarah , Olivari Benjamin S. , Raetz Jaqueline G. 
Published: January 2025

AbstractThe prevalence of Alzheimer’s disease and related disorders (ADRD) is rising, and primary care providers (PCPs) will increasingly play a role in its detection. We developed an evidence‐based intervention to facilitate cognitive evaluation in primary care. We then implemented it as a set of web‐based trainings which were combined with specific tools embedded in the electronic health record (EHR) for PCPs to use in their practices. The model was adapted from the Gerontological Society of America’s KAER (Kickstart, Assess, Evaluate, Refer) Toolkit, and rolled out across 14 community‐based primary care clinics in a large health system. Outcome measures included: 1) the number of cognitive assessments entered into the EHR; 2) the number of patients diagnosed with mild cognitive impairment (MCI); and 3) change in PCP confidence and attitudes in identifying and managing dementia assessed by a validated survey tool, the General Practitioner’s Attitudes and Confidence Scale for Dementia (GPACS‐D). The number of cognitive assessments entered into the EHR in the six months before the intervention compared to the six months after increased from a mean of 5.2 to 21.2 per month (p<0.01); the number of patients newly diagnosed with MCI increased from a mean of 23.5 to 32.2 per month (p = 0.03); and fifty PCPs who completed the GPACS‐D survey reported significant improvement in confidence and attitudes (mean total attitude and confidence score increase from 3.33 to 4.09, p<0.01). This data suggests an initiative like this can improve cognitive evaluation and increase identification of MCI across a large primary care network. The initiative’s methods are designed to be easy to replicate, without requiring hiring new staff or building new services, making it highly scalable. The educational videos and EHR tools developed are available at no charge to anyone who wants to adapt this approach. Easy to deploy, with clear, reproducible outcomes, it has the potential to improve ADRD care. As new therapeutics for ADRD become available, initiatives such as this will increasingly be needed to improve referrals to specialists, foster an engaged primary care workforce for collaboration, and improve the lives of patients living with ADRD.
RWD insights into disease progression
Authors: Eriksdotter Maria 
Published: January 2025

AbstractBackgroundThe new anti‐Aβ antibody drugs aducanumab and lecanemab (approved in the US, not yet in Europe) must be followed up closely and regularly long‐term. Previous knowledge on progression of AD in routine clinical settings longterm is crucial when introducing new dementia medications. The Swedish national quality database on dementia/cognitive disorders, SveDem, where data on different dementia disorders at the time of the dementia diagnosis since 2007 and on mild cognitive impairment (MCI) since 2021 with annual follow‐ups of MMSE scores can provide this unique information.MethodsSveDem, www.svedem.se is to date the largest database in the world on different dementia disorders and from 2021 also on MCI. The registry includes individuals at the time of the MCI or dementia diagnosis with annual follow‐ups, at present with >122, 000 persons, who are followed through the chain of care. By linking SveDem to other registers, data on diagnostics including biomarkers, comorbidities, treatment, care, mortality and prognosis can be obtained.ResultsFrom SveDem have shown that mortality in dementia disorders over a 10‐year time period is decreasing, partly associated with changes in drug prescribing practices. Among the different dementia disorders, SveDem data show that AD has the best survival while the highest mortality is found in persons with DLB/PDD. Follow‐up data on use of the current dementia drugs choline esterase inhibitors (ChEIs) in an AD population of > 17 000 persons showed ChEIs to be associated with small but persistent cognitive benefits long term (5 years). Moreover, based on SveDemdata, ChEI treatment was found to be associated in an AD population with reduced risk for myocardial function, stroke, heart failure, kidney dysfunction and overall mortality. Additional data on disease progression will be presented.ConclusionClinical routine long‐term data on large populations of persons with AD (and other dementia disorders) treated with or without current dementia drugs, on prognosis, progression and mortality already exist to be used for long‐term comparisons with new approved AD medications. Moreover, the quality data base SveDem collects data regularly and will start gathering data on the new anti‐amyloid dementia drugs on effects/progression if approved in Europe.
Development of a serum miRNA panel for detection of Alzheimer's Disease
Authors: Zhang Xinyu , Su Chang , Cao Yuan , Yang Songtao , Qin Qi , Tang Yi 
Published: January 2025

AbstractBackgroundAn urgent need exists for minimally invasive testing for accurate detection of Alzheimer’s disease (AD). Circulating microRNAs (miRNAs) have been investigated as a promising candidate biomarker for AD diagnosis and prediction because of their involvement in multiple brain signaling pathways in both health and disease. This study developed and validated a serum miRNA panel in discriminating clinically diagnosed AD from age‐matched cognitively healthy controls.Method383 serum samples (194 AD, 189 cognitively healthy controls) were divided into three cohorts: discovery (n=59), training (n=126), and validation (n=198). In the discovery cohort, 49 miRNAs curated from literature databases were verified using individual serum sample via reserve transcriptase‐quantitative Polymerase chain amplification (RT‐qPCR). A logistic regression model was built with 11 differentially expressed miRNAs using the training cohort, and the final panel comprising 7 miRNAs with superior diagnostic performance was established. The diagnostic efficacy of the 7‐miRNA panel was further evaluated in the validation cohort by the receiver operating characteristic (ROC) analysis.ResultOf the initial 49 screened serum miRNAs, 11 differentially expressed miRNAs were selected for logistic regression model construction based on their potential for detecting AD patients (AUC ≥ 0.7). After model optimization and validation via RT‐qPCR, a 7‐miRNA panel (miR‐146a‐5p, let‐7i‐5p, miR‐21‐5p, miR‐29c‐3p, miR‐92a‐3p, let‐7f‐5p, and miR‐1285‐5p) was identified with area under the curve (AUC) of 0.970 and 0.932 in the training and validation cohorts, respectively. The sensitivity of 7‐miR test was 88%, and the specificity was 85% in the validation cohort.ConclusionThese findings suggest that the 7‐miRNA signature in serum serves as a novel noninvasive tool for the adjunctive diagnosis of AD. The panel shows promise for clinical application, setting the stage for future studies across diverse populations.
Plasma Proteomic Determinants of Small Vessel Disease of the Brain: the Multi‐Ethnic Study of Atherosclerosis
Authors: Kalani Rizwan , Fohner Alison E , Austin Thomas R. , Emrani Sheina , Jensen Paul N. , Frazier‐Wood Alexis , Bertoni Alain G. , Shah Sanjiv J. , Habes Mohamad , Rashid Tanweer , Charisis Sokratis , Walker Keenan A. , Longstreth William T , Tirschwell David L , Psaty Bruce M. , Floyd James , Tahir Usman A , Gerszten Robert Edgardo , Rotter Jerome I , Rich Stephen S , Heckbert Susan R. , Hughes Timothy M. 
Published: January 2025

AbstractBackgroundThe identification of novel blood‐based biomarkers of small vessel disease of the brain (SVD) may improve pathophysiologic understanding and inform the development of new therapeutic strategies for prevention. We evaluated plasma proteomic associations of white matter fractional anisotropy (WMFA), white matter hyperintensity (WMH) volume, enlarged perivascular space (ePVS) volume, and the presence of microbleeds (MB) on brain magnetic resonance imaging (MRI) in the population‐based Multi‐Ethnic Study of Atherosclerosis (MESA).MethodsEligible MESA participants had 2941 plasma proteins measured from stored blood samples (collected in 2016‐2018) using the antibody‐based Olink proteomics platform, and completed brain MRI scans in 2018‐2019. Participants with quality control exclusion of protein measurements, missing covariate data, and poor quality or missing MRI outcome variables were excluded. The cross‐sectional association between the abundance of each plasma protein (normalized protein expression – a relative protein quantification unit measured on a log2 scale) was modeled separately with WMFA, WMH volume, total ePVS volume, and the presence of MBs using multivariable linear or modified Poisson regression, adjusting for demographic variables, estimated glomerular filtration rate (eGFR), and SVD risk factors. The Benjamini‐Hochberg procedure was used to control the false discovery rate (FDR) <0.05 to account for multiple hypothesis testing. For proteins independently associated with the SVD markers on MRI, penalized regression with least absolute shrinkage and selection operator (LASSO) was used to create a parsimonious proteomic model.ResultsEligible participants (total N=709) had a mean age of 73 years, 53% were women, 25% were Black, 17% were Chinese, 19% were Hispanic or Latino, and 39% were White (Table 1). After adjustment for demographics, eGFR, and SVD risk factors, 769 plasma proteins were associated with WMFA (FDR <0.05) (Figure). LASSO regression identified a 37‐protein model predictive of WMFA (Table 2). We did not find plasma proteins to be independently associated with WMH volume, ePVS volume, or the presence of MBs.ConclusionMultiple circulating proteins – implicated in central nervous system myelination, lipid metabolism, angiogenesis, coagulation, cellular adhesion and migration, appetite regulation, energy homeostasis, systemic inflammation, and immune regulation – were independently associated with WMFA in a multi‐ethnic cohort of older adults.
Attention Network Dysfunctions in Lewy Body Dementia and Alzheimer’s Disease
Authors: Su Li 
Published: January 2025

AbstractBackgroundAttention deficits are notable in Lewy body dementia (LBD) and in Alzheimer’s disease (AD), however, its underlying neurobiology and neuropathology are unclear. Functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) provides information about attention deployment and regional neural oscillatory deficits in LBD and AD. In this study, we combined fMRI and EEG to detect neural correlates of attention dysfunctions in LBD and AD.MethodWe recruited 33 patients with LBD, 15 patients with AD and 19 elderly healthy controls. All participants underwent a 3T fMRI scanning and a subsequently EEG recording. During fMRI and EEG, participants performed the same modified Attention Network Task (ANT) to investigate the alert, orient, executive and conflict attention dysfunctions. Here, we have focused on the EEG part of the study while using the fMRI data to localise the EEG signal on the cortex.ResultBehaviourally, although both LBD and AD maintained a relative normal executive/conflict attention, we found that LBD had alert attention deficits and AD showed apparent orient attention dysfunctions. Based on source‐level EEG analyses, LBD had frontal‐central deficits for alert attention while AD showed inferior frontal and precentral impairments for orient attention. In addition, the insular and inferior frontal areas was hyper‐activated in LBD and AD for executive/conflict attention. Apart from these areas, LBD showed complementary temporal‐central‐occipital network for the modified ANT task. Furthermore, the oscillational sources for the ANT effects indicated that alpha and theta bands were partly impaired in dementia patients.ConclusionIn summary, using source localised EEG, we found that attention dysfunctions in LBD and AD have engaged different neural networks. This has important implications in understanding the symptomology in LBD such as recurrent visual hallucinations and cognitive fluctuation.
Discovery of Genes Underlying Cognitive Resilience in Individuals Predisposed to Alzheimer's Disease Risk
Authors: Tsai Wei , McNiff Caitlin E. , Reddy Joseph S. , Wang Xue , Quicksall Zachary , Nho Kwangsik , Dunn Amy R , Allen Mariet , Heckman Michael G. , Ren Yingxue , Zhao Na , Kantarci Kejal , Mielke Michelle M. , Petersen Ronald C. , Kaczorowski Catherine C. , Carrasquillo Minerva M. , Saykin Andrew J. , Ertekin‐Taner Nilüfer 
Published: January 2025

AbstractBackgroundTwo main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers.MethodWe applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts.ResultFour consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy.ConclusionOur results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.
Default mode network and posterior resting‐state electroencephalographic alpha rhythms in Alzheimer’s disease patients
Authors: Babiloni Claudio 
Published: January 2025

AbstractBackgroundAlzheimer’s disease dementia (ADD) is the most common neurodegenerative dementing disorder, explaining about 60‐70% of 50 million patients worldwide (www.who.int). Some previous studies in ADD patients showed significant neurodegenerative processes as revealed by reduced gray matter volume in the cerebral cortex, including the default mode network (DMN) cortical networks from structural magnetic resonance imaging (sMRI). Other studies in these patients reported a magnitude reduction in the resting‐state eyes‐closed electroencephalographic (rsEEG) alpha rhythms reflecting vigilance dysfunctions. Here, we tested the hypothesis of a significant relationship between these neurodegenerative and neurophysiological readouts, thus suggesting the sensitivity of rsEEG alpha rhythms to intrinsic AD processes.MethodsClinical, sMRI, rs functional MRI, and rsEEG rhythms in demographic‐ and age‐matched ADD (N = 45), subjective memory complaint (SMC, N = 160), and healthy cognitively unimpaired (Nold, N = 40) persons were available from an international archive (www.pdwaves.eu). Individual alpha frequency peak was used to determine the alpha frequency band on a personal basis. The eLORETA freeware estimated rsEEG sources. Freeware platforms served to analyze MRI data.ResultsThe core results showed (1) lower DMN volumes and posterior rsEEG alpha rhythms in the ADD than Nold participants and (2) a positive association of the functional connectivity of basal forebrain‐DMN and the posterior rsEEG alpha rhythms in the SMC participants negative but not positive to amyloid PET biomarkers (Figure 1).ConclusionsA prominent relationship was observed between DMN and the posterior rsEEG alpha rhythms across physiological and AD‐related aging, suggesting the enrichment of the A‐T‐N Framework with "Pathophysiology" (P) EEG biomarkers.
Differences between white matter hyperintensities lesion load across allostatic load risk in cognitive complaint subjects
Authors: Contreras Patricio Riquelme , Henriquez Fernando , Campo Cecilia Gonzalez , Buller‐Peralta Ingrid , Thumala Daniela , Lillo Patricia , Okuma Cecilia , Demanet Michele , Damm María Francisca , Godoy Claudio Román , Alvez Pamela Guevara , Wael El‐Deredy , Muniz‐Terrera Graciela , Chonchol Andrea Slachevsky 
Published: January 2025

AbstractBackgroundChronic exposure to stress, quantified by allostatic load (AL), has been postulated as a cause of structural brain changes in the context of dementia. White matter hyperintensities (WMH), detected in MRI FLAIR, are a common brain abnormality representing small vessel disease or degenerative changes in the brain. Here, we studied differences in tract‐specific WMH volume across three risk levels of AL in Chilean subjects with cognitive complaint, to explore links between chronic stress exposure and prodromal steps of dementia.MethodThe study included 135 subjects with cognitive complaint from a chilean cohort. Based in MoCA test, subjects were classified in mild cognitive impairment (MCI) (47) and subjective cognitive complaint (SCC) (88). To measure AL, we employed 15 metabolic, cardiovascular and immunity biomarkers, and the scores were classified in low, medium, and high risk levels of AL. WMH were calculated with Lesion Segmentation Toolbox, in SPM 12, and segmented according to John Hopkins University (JHU) and Human Connectome (HCP) atlases. To explore differences in tract‐specific WMH volume per risk level AL, we used a Kruskal Wallis test in each cognitive group (SCC and MCI). In significant tracts, a U Mann ‐ Whitney test was performed to establish the paired AL risk groups with significance.ResultIn the MCI group, we found a higher tract‐specific WMH load as a function of AL risk level in 10 tracts of the JHU atlas, and in 31 tracts of the HCP atlas. Differences were observed between low and medium‐risk of AL, with medium‐risk group showing a higher WMH load than low‐risk group.ConclusionWe observed significative differences in tract‐specific WMH lesion between low and medium risk of AL, only in MCI. It is according with literature that show the WMH burden could be associated with cognitive deficit, but not it’s risk. In this study, we further establish a link between chronic stress exposure and WM structural changes in early stages of neurocognitive disorders. We suggest that AL is a global measurement that could mediate the relation between vascular or neurodegenerative factors to WMH origin. Use of neurodegenerative and cardiovascular biomarkers can be useful to explore this mediation.
Choroid plexus volume as a novel candidate neuroimaging marker of the Alzheimer's continuum: a prospective cohort study
Authors: Jiang Jiwei , Li Wenyi , Jiang Shirui , Xu Jun 
Published: January 2025

AbstractBackgroundThe clinical role and potential mechanisms of the choroid plexus (ChP) in Alzheimer's disease (AD) remains unclear.MethodThis prospective cohort study enrolled 607 participants [110 healthy controls (HCs), 269 mild cognitive impairment (MCI), and 228 AD dementia] from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2021, and December 31, 2022. Relationship between ChP volume and the cerebrospinal fluid (CSF) pathological hallmarks (Aβ42, Aβ40, Aβ42/40, tTau, and pTau), neuropsychological tests [Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Activities of Daily Living (ADL) scores], and multimodal neuroimaging measures were analyzed using partial Spearman’s correlation. The mediating effects of ChP volume were examined on the relationship between CSF hallmarks and neuropsychological tests. The ChP volume performance to differentiate the presence/absence of cerebral Aβ42 deposition was determined using receiver operating characteristic analysis. Generalized linear mixed‐effects models discerned the association between baseline ChP volume and longitudinal changes in neuropsychological tests in patients on AD continuum.ResultThe participants' mean age was 65.99±8.79 years. Patients with AD dementia exhibited a larger baseline ChP volume than the other participants (P<0.001; Figure 1). ChP volume enlargement correlated with decreased Aβ42 and Aβ40 levels; lower MMSE and MoCA and higher NPI and ADL scores; lower volume, cortical thickness, and corrected cerebral blood flow in other cognition‐related regions (all P < 0.05). ChP volume alone mediated and ChP–hippocampal volume combined chain mediated the association of CSF Aβ42 and Aβ40 levels with the MMSE scores (16.91%, 37.15%, 14.25%, and 27.82%, respectively; Figure 2). ChP volume better identified the presence/absence of cerebral Aβ42 deposition than hippocampal volume (AUC: 0.762 vs. 0.724; Figure 3). Baseline ChP volume was associated with subsequent decline and faster worsening in the MMSE, MoCA, and ADL scores with 10.03±4.45 months' follow‐up (all P<0.001).ConclusionChP volume is a novel, candidate, non‐invasive neuroimaging marker associated with neurodegenerative changes in Alzheimer’s continuum. It can detect early cerebral Aβ42 deposition and predict prognosis in clinical practice.