bluuebunny/crossref_metadata_2025_split huggingface dataset:
AI‐derived endophenotypes are causally associated with Alzheimer's disease
Authors: Wen Junhao , Toga Arthur W. , Davatzikos Christos 
Published: January 2025

AbstractBackgroundBrain morphology changes due to both natural aging and various pathological conditions. We used magnetic resonance imaging (MRI) and artificial intelligence (AI) to derive three brain age gaps (Wen et al., 2023b) [gray matter (GM), white matter (WM), and functional connectivity (FC)‐BAG] for brain aging and 9 dimensional neuroimaging endophenotypes (Wen et al., 2023a) [DNE: Alzheimer's disease (AD)1‐2, autism spectrum disorder (ASD)1‐3, schizophrenia (SCZ)1‐2, and late‐life depression (LLD)1‐2) for disease heterogeneity (a.k.a., subtypes). We applied genome‐wide association study (GWAS) summary statistics of the 3 BAGs, 9 DNEs, and two AD case‐control studies (Lambert et al., 2013; Wightman et al., 2021) to decipher the potential causality between these AI‐derived endophenotypes and AD (Figure 1).MethodWe investigated whether the 3 BAGs and 9 DNEs (AD1‐2, ASD1‐3) were causally linked to AD using a bi‐directional two‐sample Mendelian randomization implemented in the TwoSampleMR R package (Hemani et al., 2018) with five different estimators. No individual data were used. The GWAS summary statistics of the 3 BAGs and 9 DNEs were performed using the UK Biobank data publicly available at https://labs.loni.usc.edu/medicine. The AD summary statistics are obtained at https://pgc.unc.edu/for‐researchers/download‐results/ for Wightman et al. and at https://gwas.mrcieu.ac.uk/ for Lambert et al., excluding the UK Biobank participants.ResultWe identified potential causal relationships from AD2, characterized by medial temporal lobe atrophy, to AD [P‐value=1.74x10‐4, OR (95% CI) = 1.25 (1.11, 1.40), number of SNPs=7], and AD to WM‐BAG [P‐value=7.18x10‐5, OR (95% CI) = 1.04 (1.02, 1.05), number of SNPs=13] (Figure 1). Regarding the latter, our sensitivity check indicated the absence of apparent outlier SNPs or horizontal pleiotropy (Verbanck et al., 2018) (Egger estimator intercept: ‐2.22x10‐3±3.87810‐3, P‐value=0.57). All five estimators demonstrated consistent causal effects. The funnel plot displayed no noticeable asymmetry. Most IVs exhibited positive effects on AD, with three showing a negative association. Additionally, leave‐one‐out analyses indicated that no single IV dominated this causal relationship (Figure 2).ConclusionThis investigation revealed a causal association between two AI‐derived endophenotypes and AD. These endophenotypes could be used to identify individuals at high risk of developing AD and select populations in future AD clinical trials.
Identification of high‐performance blood‐based biomarkers for early screening and staging of Alzheimer’s disease by large‐scale plasma proteomic profiling in mild cognitive impairments
Authors: JIANG Yuanbing , Uhm Hyebin , Ip Fanny C. F. , Lo Ronnie M.N. , Cao Xiaoyun , Tan Clara M.C. , Law Brian C.H. , Kwok Timothy CY , Mok Vincent Chung Tong , Zetterberg Henrik , Fu Amy K.Y. , Ip Nancy Y. 
Published: January 2025

AbstractBackgroundEarly detection of Alzheimer's disease (AD), particularly during the mild cognitive impairment (MCI) stage, is crucial for effective intervention and treatment. However, existing diagnostic methods, through cognitive assessments, brain imaging, or cerebrospinal fluid profiling, are subjective, expensive or invasive. We previously showed that the plasma proteome is altered in AD, suggesting the feasibility of utilizing blood biomarkers for AD detection. Therefore, to develop a blood test for early screening and staging of AD, it is important to identify blood biomarkers associated with MCI/early AD and the features of AD progression.MethodWe conducted a comprehensive profiling of the plasma proteome of MCI by measuring 1,160 proteins in a Hong Kong Chinese cohort, to identify novel blood biomarkers for MCI/early AD. We further developed a biomarker panel based on the identified MCI/AD‐associated blood biomarkers and validated its performance in an independent amyloid‐PET‐defined cohort.ResultWe identified 496 proteins that were dysregulated in MCI plasma, and these proteins, involved in different biological processes, exhibited distinct dysregulating patterns with disease progression. We further categorized these proteins into different groups based on their dysregulating patterns. By performing co‐expression network analysis, we identified an 18‐protein panel that captures the profile changes of plasma proteome in MCI and AD. This panel accurately classified MCI (AUC = 0.913‐0.925) and AD (AUC = 0.970‐0.993) in two independent cohorts. Moreover, this panel correlates with cognitive decline and the development of Aβ pathology in the brain, which outperforms some of the existing plasma ATN biomarkers.ConclusionThis study comprehensively profiled the MCI plasma proteome and demonstrates the feasibility of a blood‐based biomarker assay for early detection and staging of MCI and AD, potentially facilitating early screening, monitoring, and intervention in future clinical settings.
Development of a robust blood‐based multi‐pathway biomarker assay for early screening and classification of Alzheimer’s disease
Authors: Ouyang Li , JIANG Yuanbing , Uhm Hyebin , Ip Fanny C. F. , Lo Ronnie M.N. , Cheng Elaine Y.L. , Cao Xiaoyun , Tan Clara M.C. , Law Brian C.H. , Ortiz‐Romero Paula , Puig‐Pijoan Albert , Fernández‐Lebrero Aida , Contador José , Mok Kin Y , Hardy John A. , Kwok Timothy CY , Mok Vincent Chung Tong , Suárez‐Calvet Marc , Zetterberg Henrik , Fu Amy K.Y. , Ip Nancy Y. 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is a devastating neurodegenerative disease with delayed diagnosis until the manifestation of symptoms. Although the emergence of blood‐based biomarkers offers hope for easy detection of AD, existing AD‐associated blood biomarkers, known as the “blood ATN biomarkers”, mainly capture the pathological hallmarks of AD, overlooking other AD‐associated biological processes such as inflammation and vascular dysfunctions. Therefore, developing a blood‐based biomarker assay that captures dysregulation beyond the ATN biomarkers may help advance early detection and staging of AD, enabling a comprehensive examination of the disease statusMethodWe leveraged ultrasensitive proteomic technology to develop a blood‐based, multiplex biomarker assay for AD. This assay simultaneously measures the levels of 21 blood proteins associated with different biological pathways, including neurodegeneration, inflammation, innate immunity, vascular functions, and metabolic activities. Moreover, we developed an AD risk scoring system by integrating the level changes of these 21 proteins in a machine learning‐based model. The performance of this 21‐protein biomarker assay in AD classification and indication of AD‐related endophenotypes was evaluated in three independent cohortsResultWe showed that this 21‐protein biomarker assay accurately classifies AD (AUC = 0.9407–0.9867) and mild cognitive impairment (MCI) (AUC = 0.8434–0.8945). It also indicates amyloid pathology in Chinese and European populations. Moreover, this assay simultaneously evaluates changes in five biological processes, providing comprehensive assessment of disease status and revealing heterogeneity of AD among individuals. Notably, dysregulations of biological processes upon AD progression are different between Chinese and European populations, particularly in biological pathways related to inflammation and vascular functions.ConclusionOur findings demonstrate the utility of a blood‐based multi‐pathway biomarker assay for early screening and staging of AD in clinical settings and provide insights for patient stratification and the development of precision medicine.
Association of Neuroticism Personality According to the Degree of Social Contact with Incident Dementia
Authors: Liu Yufei , Tang Yi , Chang Jie 
Published: January 2025

AbstractBackgroundPersonality traits, especially neuroticism, can influence susceptibility to dementia. Although social contact can mitigate stress and risk of dementia, the extent to which social contact can mitigate excess risk associated with neuroticism remains unclear. The objective of study was to investigate changes in neuroticism‐associated excess risk of dementia arising from different levels of social contact.MethodThis prospective cohort study examined 393939 UK Biobank participants assessed from 2006‐2010 and followed up until December 2022. Participants without dementia at baseline or the first 2‐year follow‐up, and with complete neuroticism and social contact data were included. Neuroticism was measured using the Revised Eysenck Personality Questionnaire, categorized into low and high neuroticism. Low, intermediate, or high social contact levels were assessed based on household size, contact with family or friends, and group participation. Dementia incidence (all‐cause dementia, Alzheimer’s disease [AD], and vascular dementia [VaD]) were determined using linked electronic health records. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia risk, adjusted for multiple covariates.ResultAmong 393939 participants (mean [SD] age: 56.4 [8.1] years; 53.7% female), 6588 cases of all‐cause dementia were recorded over 13.7 years. High neuroticism was associated with increased all‐cause dementia risk (HR = 1.16, 95% CI = 1.10‐1.22) and cause‐specific dementia subtypes (AD: HR = 1.10, 95% CI = 1.02‐1.19; VaD: HR = 1.16, 95% CI = 1.05‐1.29). Among high neuroticism participants, excess risk of all‐cause dementia showed a stepwise decrease with increasing social contact (low contact: HR = 1.27, 95% CI = 1.15‐1.40; intermediate contact: HR = 1.20, 95% CI = 1.12‐1.28; high contact: HR = 1.07, 95% CI = 1.00‐1.15). High social contact similarly decreased excess risk of AD (HR = 1.06, 95% CI = 0.95‐1.17) and VaD (HR = 0.96, 95% CI = 0.82‐1.12), comparable to those with low neuroticism.ConclusionEnhanced social contact is associated with a stepwise reduction in dementia risk and may mitigate or potentially eliminate excess risk of dementia in individuals with high neuroticism, supporting social contact as a preventive strategy to reduce excess risks of dementia from neuroticism personality trait.
Characterization and Evaluation of Alpha‐Synuclein Aggregates: Unveiling Their Potential as a Biomarker for Parkinson's Disease (PD)
Authors: Debarnot Cecile , Challagundla Malleswari , Kleinert Christoph , Schulz Michael , Henn Claudia , Boehm Nils , Richter Mario 
Published: January 2025

AbstractBackgroundParkinson's disease (PD) is a debilitating condition that affects millions of people worldwide, yet there are currently no reliable biomarkers for its diagnosis. Alpha‐synuclein aggregation is a well‐known hallmark of PD pathology, but the behavior and kinetics of these aggregates are poorly understood. To address this gap in knowledge, this study utilized several approaches to evaluate the potential of alpha‐synuclein aggregates as potential biomarker for PD.MethodFirstly, the aggregation behavior of alpha‐synuclein (aSyn) oligomers and fibrils was evaluated using a Real‐time quaking induced conversion (RT‐QuIC) assay. This assay differentiated PD from healthy samples in human skin, brain homogenates, and cerebrospinal fluid (CSF) samples. Secondly, a symmetric ECL assay was used to quantify alpha‐synuclein oligomers and fibrils. Finally, direct stochastic optical reconstruction microscopy (dSTORM) was utilized to visualize the size and shape of recombinant alpha‐synuclein fibrils and RT‐QuIC end products (fibrils) at high resolution.ResultThe results demonstrated that fast‐aggregating samples had higher concentrations of aSyn oligomers in skin and other samples compared to slow‐aggregating samples. Interestingly, human skin as a biological matrix showed a better and significant differentiation of healthy and PD samples, compared to brain or CSF indicating skin as a promising specimen for detecting alpha‐synuclein aggregation. Preliminary analysis of the average length and width of alpha‐synuclein aggregates showed promise, and further experiments with a larger sample size are required to prove whether different species of alpha‐synuclein fibrils/oligomers exist in healthy and disease samples.ConclusionThese results provide a foundation for the continued investigation of alpha‐synuclein aggregation as a potential biomarker for PD.
Integrated Primary Care Model Reduces High‐Risk Medications for People Living with Dementia
Authors: Clevenger Carolyn K , Khakharia Anjali , Medders Laura J , Moore Miranda 
Published: January 2025

AbstractBackgroundHarmful care including the prescribing of high‐risk and potentially inappropriate medications for older people is widespread among older adults, including people living with dementia (PLWD). Integrated Memory Care (IMC) is a comprehensive dementia care model where patients and their family caregivers access dementia‐sensitive geriatric primary care.MethodsWe conducted a retrospective observational study of adult patients of IMC, Cognitive Neurology (CN), and Primary Care (PC) clinics aged 65 and older with a diagnosis of dementia in 2019‐2021. We matched patients by age, gender and race and measured the hospitalization, rate of deprescribing and inappropriate screening test referrals using logistic regressions controlling for clinic. Additionally, we conducted a regression adjusted for state of illness (proxied by activities of daily living (ADL)) for the IMC and CN clinics.ResultsOverall, 509 patients seen in IMC were matched with 490 CN patients and 509 PC patients. Most patients were female and white and aged 70‐85. IMC patients had higher overall ADL scores than CN indicating more functional dependence.IMC patients had higher odds of deprescribing high dose Antipsychotics (OR: 4.383, CI:1.405,13.677), benzodiazepines (OR: 3.338, CI: 1.541,7.231) and Opiates (OR: 1.004, CI: 0.415, 2.431) when compared to CN patients. After adjusting for ADL scores, the odds ratios were 4.952 (1.509,16.25), 3.434 (1.573, 7.494) and 0.991 (0.408, 2.404) respectively.IMC also had higher odds of deprescribing high dose Antipsychotics (OR 5.538 CI: 1.21,25.359), benzodiazepines (2.632, CI: 1.297, 5.341) and Opiates (1.424, CI: 0.571, 3.55) when compared to PC patients.ConclusionsPatients managed in a dementia‐sensitive primary care practice were deprescribed high‐risk medications after one‐year of management, reducing avoidable adverse events.
Community screening for dementia in Kenya: Lessons learnt from the DEM‐SKY program
Authors: Musyimi Christine W. , Ndetei David , Muyela Levi A. , Mutunga Elizabeth Kasimu , Masila Joe , Farina Nicolas 
Published: January 2025

AbstractBackgroundThe Integration and Evaluation of a Community‐Level Dementia Screening Programme in rural KenYa (DEM‐SKY) program, supported by the Davos Alzheimer’s Collaborative, leverages existing community resources to promote early detection of dementia among older adults and strengthen health system policy and practice in Kenya.MethodsThe DEM‐SKY program consisted of two key components: a training component and dementia screening component using then brief Community Screening Instrument for Dementia (brief‐CSID). The training component was divided into two stakeholder groups: Community Health Workers (CHWs) and hospital staff. Each group had different training needs to ensure the successful implementation of DEM‐SKY. Over a six‐month period, ten CHWs approached 3,546 older adults in Makueni County aged 60+ years to offer dementia screening. We adopted a process evaluation framework and used qualitative interviews to help identify factors that hampered or facilitated the successful adoption of dementia screening within the rural Kenyan context.ResultsOur findings revealed that 18% of older adults in rural Kenya have cognitive and functional impairment indicative of dementia, translating to over half a million older adults in Kenya. The DEM‐SKY program also illustrated the importance of collaborative partnerships with policy makers, health care providers and community members while encouraging a proactive approach in tackling challenges right from project conception. Through emerging themes and experiences, we also highlight opportunities that strengthened health care systems and promoted infrastructure readiness to address dementia care gaps during implementation of a novel dementia screening program in a low‐resource setting. These include use of existing community resources, community‐based participatory approaches and stigma‐reduction activities prior to program implementation.ConclusionThe implementation of the DEM‐SKY program has been a landmark in early detection of dementia in Kenya. It forms the first community‐based dementia detection program implemented in rural Kenya with limited specialists and inadequate infrastructure, hence providing timely initiation of care cascade for individuals with cognitive and functional impairment. This program could be used to inform governments to drive innovations that promote early detection and healthy ageing; and invest in future development and implementation of treatment and support systems for older adults with dementia in low‐resource settings.
Accommodating cognitive screening: An implementation study protocol for occupational therapists supporting clients with vision and/or hearing impairments
Authors: Dumassais Shirley , Wittich Walter 
Published: January 2025

AbstractBackgroundOccupational therapists (OTs) play a crucial role in rehabilitation, aiming to improve the lives of individuals with sensory impairment and an increased risk of cognitive decline. Despite being responsible for cognitive screenings on occasion, they have expressed limited confidence in performing these with their clients with visual and/or hearing impairments (VI/HI). To improve this situation, OTs should gain expertise in collaborative sensory rehabilitation. The primary aim of this multiphasic implementation study is to advance rehabilitation, particularly in occupational therapy, by enhancing the proficiency, knowledge, and skills of practicing clinicians when administering cognitive tests to individuals with sensory impairment(s).MethodsThis study employs a comprehensive five‐phase methodology, starting with (1) a scoping review to identify existing practices in the research context. Subsequently, (2) a clinical practice survey explores current approaches within the field of occupational therapy. (3) Interviews and focus groups with OTs provide further qualitative insights. Then, (4) educational training resources are developed, and (5) their efficacy is assessed in the final phase, ensuring their quality, application, and perpetuation.ResultsPresently, the first two phases of this project have been completed and the third phase is underway. In the scoping review, the identified common strategies s in the cognitive evaluation of older adults with dual sensory impairment (DSI) include expert team involvement, using visual‐free cognitive tests, modifying scoring procedures, and implementing communication and environmental strategies. In the survey, OTs indicated customizing accommodations for individuals with VI and/or HI. Strategies included encouraging the use of visual aids and adjusting lighting for VI, promoting hearing aids and controlling noise for HI, and employing diverse approaches for DSI, such as subjective screening and recommending assistive technology.ConclusionsBuilding on evidence‐based research as well as current practices, the collaboration between specialists and clinicians will bridge the knowledge‐to‐practice gap in rehabilitation through accessible education. Empowering OTs with such knowledge in their practice has the potential to improve the process of cognitive screenings as well as healthcare outcomes.
Effect of early Alzheimer's disease plasma markers on Aβ deposition: Evidence from SILCODE
Authors: Yu Xianfeng , Zhou Xia , Shi Rong , Jiang Jiehui , Han Ying 
Published: January 2025

AbstractBackgroundPrevious studies have found that AD‐related plasma markers are associated with Aβ deposition, but the specific effects remain unclear.MethodData were obtained from the Longitudinal Study of Cognitive Decline in China (SILCODE). Comprehensive neuropsychological assessments, MRI, plasma samples, and amyloid positron‐emission tomography (Aβ‐PET) data were collected. Through the SUVR value calculation and Aβ stage classification, as well as the correlation analysis between plasma biomarkers and voxel /ROI SUVR values and clinical scale information, respectively, mediation analysis was used to study the possible pathways.ResultThis study involved 148 participants from Xuanwu Hospital in Beijing, including 66 cognitively normal (CN), 59 subjective cognitive decline (SCD), 12 MCI and 11 AD patients in this dataset. The proportion of CN and SCD in stage A0‐1 was the highest, while A2‐4 MCI and AD increased. Analysis of variance showed that except Aβ42/Aβ40, the other three (p‐tau181, GFAP and NfL) plasma biomarkers had differences between groups, and GFAP showed significant differences in each stage. Plasma p‐tau181 was significantly lower in stage A0 and A1 than in stage A2 and A3. Plasma GFAP at stage A0 was significantly lower than that at stages A1, A2, and A3, and at stage 1, it was significantly lower than that at stages A2 and A3. Plasma GFAP at stage A3 was significantly higher than that at stage A4. There were two pathways that showed significant fully mediated effects: in the PET SUVR‐ plasma p‐tau181‐MMSE score pathway, all four meta‐ROI SUVR showed fully mediated effects, while in the PET SUVR‐ plasma GFAP‐MMSE score pathway, with only 2 meta‐ROI SUVR values, stage A2 and stage A4 showed mediation effects.ConclusionThe present study demonstrated the role of plasma in the early stage of AD, especially SCD, from the clinical diagnosis and Aβ stage dimensions. Studies have found that P‐tau181 has a good hint role throughout the course of AD, while GFAP may have a ceiling effect in the middle stage of AD and a significant hint role in the early and late stages of AD.