bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supervised clustering of MRI measures informed by incident cognitive impairment via aggregated survival model SHAP values
Authors: Petersen Kellen K. , Nallapu Bhargav Teja , Demirsoy Idris , Lipton Richard B. , Grober Ellen , Morris John C. , Hassenstab Jason J. , Gordon Brian A. , Ezzati Ali 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a complex heterogeneous neurodegenerative disease. Unsupervised clustering techniques have been used to identify disease subtypes, but such approaches are limited since subtypes may not directly be related to disease progression. Herein, we implement a novel supervised clustering approach that aims to identify MRI‐derived subtypes that are likely to experience incident cognitive impairment (ICI).MethodsWe used data from 822 cognitively normal individuals (68.4 ± 9.5 years old) with Clinical Dementia Rating® (CDR®) of 0 at baseline, from the Knight ADRC. We performed supervised clustering of eight volumetric MRI regional measures at baseline. MRI measures were adjusted for age, sex, and education. Mean aggregated time‐dependent Shapley Additive exPlanation (SHAP) values were derived from random survival forest models with an ICI outcome based on time‐to‐conversion from a CDR=0 to CDR>0 over 10 years of follow‐up. K‐means clustering was then applied to SHAP values. Analysis of Variance was used to assess cluster differences and linear regression was used to understand longitudinal trajectories of MRI volumetrics and CSF biomarkers.ResultsIn the entire sample, hippocampus, entorhinal, and amygdala SHAP values were determined to be the most important MRI measures in terms of estimated contribution to the model prediction with the hippocampus differentiating from other regional measure about 24 months from baseline (Figure 1). The optimal number of clusters was determined to be four. Cluster characteristics and significant differences among them are presented in Table 1 and Figure 1. Cluster 4 is characterized by the largest mean hippocampus SHAP value with approximately 89% of participants experiencing ICI. Figure 2 shows longitudinal linear trajectories for MRI and cerebrospinal measures. Cluster 1 was the healthiest across all longitudinal biomarkers. Whereas, Cluster 4 had the smallest hippocampal volume and abnormal CSF measures both at baseline and over time.ConclusionsWe implemented a novel application of SHAP values from survival models in a supervised clustering approach to identifying MRI‐subtypes with different probabilities of incident cognitive impairment. This approach could be used to elucidate the heterogeneity inherent in the relationships among AD biomarkers and longitudinal cognitive changes.
Data driven subtyping of individuals on the Alzheimer’s continuum using cortical microstructure from diffusion MRI
Authors: Javid Shayan , Zhu Alyssa H , Gari Iyad Ba , Jahanshad Neda , Nir Talia M 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD)‐related pathologic changes in the brain begin years before MRI‐detected atrophy and the onset of cognitive decline. Diffusion MRI (dMRI) can quantify microstructural alterations in brain tissue, and may be more sensitive to pathologic processes than standard MRI volumetric biomarkers. As AD is a heterogeneous disease, previous studies have used post‐mortem, structural MRI, and PET measures to subtype individuals by areas of the brain affected, identifying distinct patterns of degeneration and decline. Subtyping individuals using non‐invasive dMRI microstructural alterations, which likely occur before volumetric atrophy, may provide complementary assessments of possible trajectories of decline. We pool two datasets to subtype individuals using a data‐driven approach, and determine whether there are subtype differences in cognitive impairment, and more invasively derived metrics (PET and CSF derived assessments of beta‐amyloid (Aβ) plaques or tau tangles).MethodT1w and dMRI data were processed for 484 ADNI3 and 188 OASIS3 participants (Figure 1A). FreeSurfer was used to segment cortical lobes and subcortical structures; thickness or average MD was calculated in each. T1w and dMRI measures were harmonized across imaging protocols using ComBat. We used SuStaIn (Young 2018) to subtype individuals based on regional dMRI‐derived mean diffusivity (MD) and separately, based on cortical thickness and subcortical volume. We determined how derived subtypes relate to PET or CSF AB and tau levels, and cognitive scores using mixed effects regressions, covarying for age, sex, MRI scanning protocol, and diagnosis.ResultSuStaIn identified three subtypes for both T1w and MD data. When analyzing MD‐derived subtypes, significant pairwise differences between all subtypes were found for cognitive scores and tau PET. Progression and CSF tau was significant when comparing typical AD with the less altered MD subtypes. T1w‐derived subtypes differed significantly in cognitive scores but not tau measures. There were no significant associations with Aβ.ConclusionSuStaIn identified T1w and MD subtypes that reflect previously suggested subtypes, such as typical AD and minimal atrophy AD. Our findings comparing dMRI‐derived subtypes indicate that MD may be sensitive to tau aggregation. Future studies will evaluate staging, include a finer cortical parcellation, and data from additional studies to ensure generalizability of findings.
In Vivo Characterization of Neuroinflammation Using a Folate Receptor Targeted Nanoparticle Platform in a Mouse Model of SARS‐CoV‐2 Infection and Alzheimer’s Disease
Authors: Parekh Parag A , Badachhape Andrew A , Bonilla Lauren , Kneubehl Alexander R , Menon Renuka , Clinton Jennifer L , Bhandari Prajwal , Bhavane Rohan , Admane Prasad , Srivastava Mayank , Ronca Shannon E , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan 
Published: January 2025

AbstractBackgroundClinical studies in COVID‐19 patients have demonstrated evidence of neuroinflammation in patients infected with SARS‐CoV‐2. In this pre‐clinical work, we investigate neuroinflammation in vivo in a mouse model of Alzheimer’s disease (AD) that exhibits both amyloid and tau pathology, the 3xTg‐AD mice crossed with K18 hAce2 and infected with SARS‐CoV‐2 using a folate receptor‐targeted nanoprobe for molecular MRI (mMRI) followed by ex vivo histopathology.MethodIn vivo studies with SARS‐CoV‐2 were performed in an animal biosafety level 3 (ABSL3) facility. 3xTg transgenic mice, a model of amyloid and tau pathology, were bred with k18‐hACE2 transgenic mice to generate double transgenic k18‐hACE2/3xTg transgenic mice that express hACE2 receptors (critical for viral infection) and develop amyloid and tau pathology. 11–14‐month‐old transgenic k18‐hACE2/3xTg mice (n=6) were infected with 103 PFU of SARS‐CoV‐2 Delta variant and underwent mMRI studies 10 days post‐infection. Age‐matched non‐infected k18‐hACE2/3xTg mice (n=6) were used as controls. All mice underwent pre‐contrast and post‐contrast T1‐weighted MRI (T1w‐MRI). Post‐contrast T1w‐MRI was performed 4 days after systemic administration of a high T1 relaxivity folate targeted liposomal‐Gd contrast agent. Signal changes between pre‐contrast and post‐contrast MRI were determined in target regions of the brain. Animals were euthanized after final imaging session for microscopic analysis of the brain.ResultNon‐infected K18‐hACE2/3xTg mice showed relatively low brain signal enhancement in post‐contrast MRI (3.3 %) consistent with the absence of frank neuroinflammation. In contrast, K18‐hACE2/3xTg transgenic mice infected with SARS‐CoV‐2 demonstrated significantly higher brain signal enhancement (+10.9%) in post‐contrast T1w‐MRI compared to pre‐contrast MRI (Figure 1) suggesting infection‐induced neuroinflammation. Signal enhancement was seen in cortical and hippocampal regions of the brain. Microscopic analysis of mice brain sections depicting the hippocampus region show the folate nanoparticles in the vicinity of amyloid deposits. Quantitative analysis shows increasing amyloid deposition in infected mice. Activated microglia in infected mice staining is also observed at higher levels.ConclusionData suggests that the hybrid hACE2‐3xTg‐AD mice exhibit neuroinflammation and increased amyloid deposition following SARS‐CoV2 infection indicating acceleration of AD pathology in these mice.
Process and metrics surrounding disclosure of genetic and biomarker results in the Duke University/University of North Carolina Alzheimer’s Disease Research Center (Duke/UNC ADRC) cohort
Authors: Mayan Inbal , Whitson Heather , Roth Heidi L , Johnson Kim G 
Published: January 2025

AbstractBackgroundIncreasingly, research participants in Alzheimer’s studies are seeking disclosure of research results. However, there are no guidelines for result disclosure and specifically, few studies report on their biomarker disclosure procedure. The Duke/UNC ADRC seeks to disclose research results to participants in a standardized fashion with high participant satisfaction.MethodThe Duke/UNC ADRC cohort consists of participants aged 25‐80. Uniform Data Set (UDS) neuropsychological testing, MRI, APOE testing, CSF biomarkers including amyloid beta 42/40 (abeta 42/40), phospho tau (p‐tau) and total tau (t‐tau) are measured in the initial visits. A formal consensus panel confers a clinical and pathological diagnosis based on review of UDS and biomarker results. Participants receive their results during a telehealth appointment. With a standard slide presentation, the clinician educates participants about risk factors, biomarker significance and methods of clinical diagnosis. The clinician presents each participant’s unique results of APOE testing, CSF testing including amyloid and tau and consensus panel diagnosis. The conversation lasts about 25 minutes on average and participants are sent a survey through REDCap that consists of 5 questions. The post‐results survey, which takes 1‐2 minutes to complete, assesses anxiety levels, participant satisfaction and gives participants an option to seek more information.ResultResults were given to 50 participants. The post results survey completion rate was over 70% with 35 participants completing the survey. 94% (33/35) of participants were pleased with the decision to receive the results and reported the information helpful. Anxiety levels declined after receiving the results. While 46% (16/35) of participants reported medium/high level of anxiety before receiving results, only 17% (6/35) reported medium/high level of anxiety after receiving results.ConclusionWe show high participant satisfaction and low anxiety levels when receiving genetic and biomarker results. The process we developed shows promise to disclose biomarker information to participants in a standardized fashion, while providing education and sought after information about genetic and biomarker status.
Diffusion Basis Spectrum Imaging in Midlife Obesity: Associations with Abdominal Adipose Tissue
Authors: Dolatshahi Mahsa , Commean Paul K. , Rahmani Farzaneh , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , Mittendorfer Bettina , Sirlin Claude , Song Sheng‐Kwei , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A. 
Published: January 2025

AbstractBackgroundObesity and abdominal adiposity in midlife are shown to increase the risk of Alzheimer disease. However, it is not clear whether midlife adiposity is associated with increased neuroinflammation. We aimed to investigate the associations of obesity, BMI of 30 kg/m2 or higher, and abdominal visceral and subcutaneous adipose tissue (VAT and SAT) with brain histology, using diffusion basis spectrum imaging (DBSI) analysis;MethodIn total, 54 cognitively normal middle‐aged subjects (50.46±6.19 years, male: 21 (38.9%), obesity: 32 (59.3 %), BMI: 32.18±6.99 kg/m2) underwent brain and abdominal 3T MRI. Abdominal VAT and SAT were semi‐automatically segmented using VOXel Analysis Suite (Voxa). A DBSI scheme with a total of 98 diffusion samplings was acquired followed by movement and eddy current correction and brain tissue extraction in FSL. DBSI maps including fractional anisotropy (FA, overall integrity), axial diffusivity (AD, axonal injury), radial diffusivity (RD, myelin loss), restricted fraction (RF, inflammation cellularity), hindered fraction (HF, extracellular edema), and fiber fraction (FF, axonal density) were generated using in‐house software scripted in MATLAB. DBSI‐derived maps were processed using a tract‐based spatial statistics (TBSS) pipeline for whole‐brain white matter voxel‐wise analyses. Using the Randomize tool from FSL, the difference between obese vs. non‐obese, high‐VAT vs. low‐VAT, and high‐SAT vs. low‐SAT groups were investigated for each DBSI‐derived skeleton, with age and sex as covariates, and a threshold of 0.05 for false‐discovery rate. The sex differences were further investigated;ResultLower FF and AD and higher RF in widespread white matter areas were observed in the obese vs. non‐obese group, and in the high‐SAT vs. low‐SAT group. Lower AD and higher RF were observed for the high‐VAT vs. low‐VAT group. All of these differences were only significant in females, not males, but higher RF in obese vs. non‐obese was observed both in males and females;ConclusionOur data support lower axonal density and fiber integrity, as well as higher inflammation cellularity in cognitively normal, middle‐aged obese individuals, and those with high VAT and high SAT, especially in females. Overall, our data suggest the differential role of visceral and subcutaneous abdominal fat in promoting neuroinflammation and axonal damage.
The Environment Matters: Perspectives on Using the Physical Environment in a Skilled Nursing Facility for Clients with Dementia
Authors: DiGrado Jennie L 
Published: January 2025

AbstractOccupational therapists (OTs) are among the health care professionals who assist individuals with neurocognitive disorders (NCDs) to engage in self‐care and leisure activities in a skilled nursing facility (SNF) environment. OTs use various environmental modifications to help individuals with NCDs engage in various activities (Jensen & Padilla, 2017). Strong evidence has been found to support occupational therapy recommendations and interventions in adapting the physical environment to support person centered care (Gitlin et al., 2010; Jensen & Padilla, 2017; Zimmerman et al., 2013). This session aims to share findings from a qualitative case study regarding the perspective of OTs and how they use the built physical environment to help individuals with NCDs is a SNF engage in self‐care and leisure related activities. Recommendations from this study include nonpharmacological‐based intervention strategies that incorporate the use of the built environment in a SNF to improve the quality of life for clients with a NCD.
Tear proteomic signature associated with mild cognitive impairment and dementia: an exploratory analysis
Authors: Yuan Changzheng , Shen Jie , Huang Yuhui , Wu Minyu , Zheng Yan , Guo Tiannan , Xu Xin 
Published: January 2025

AbstractBackgroundTear samples were low‐invasive to access and may reflect changes in the brain. We performed an exploratory proteomic analysis using tear samples to identify proteomic signature and potential pathways that may be associated with mild cognitive impairment (MCI) and dementia.MethodWe performed a matched case‐control study using tear samples collected from community‐dwelling older adults, comprising 13 dementia, as well as 34 MCI and 34 age‐, sex‐, educational‐matched normal cognition (NC) controls (age: 73.3 ± 7.1 years; female: 68.4%). The disease staging has been distinguished by clinical dementia rating (CDR). PulseDIA‐based (gas phase fractionation‐assisted data‐independent acquisition mass spectrometry) proteomics analysis was performed. Logistic regression models were used to identify differential proteins when comparing dementia versus NC and conditional logistic regression models were used when comparing MCI versus NC. Identified differential proteins were used to perform enrichment analysis. Lasso regression models were utilized to select protein biomarkers for dementia prediction.ResultA total of 70 tear proteins were found to be significantly associated with dementia and demonstrated same directions in relation to MCI. In particular, 37 proteins were positively related to dementia, with OR ranging from 3.79 (KLHDC4) to 71.91 (GLO1); 33 proteins were inversely related to dementia, with OR ranging from 0.27 (ABCC2) to 0.03 (COPS7B). The 3 strongest pathways identified by the protein‐protein interaction enrichment analysis were central nervous system neuron development, Eukaryotic Translation Termination, and amide biosynthetic process. In addition, incorporating 13 protein biomarkers to the traditional risk factors‐based model significantly improved the predictive ability of dementia (AUC from 0.813 to 0.971, P = 0.032).ConclusionDifferential tear proteins between dementia and normal cognition were identified in this exploratory analysis, which may contribute to discovering novel and low‐invasive biomarkers of dementia.
Investigating the role of gut microbiome in alcohol consumption‐associated alterations to cognitive function and biomarkers of Alzheimer’s disease and related dementias
Authors: Peter Darby , Heston Margo B. , Jonaitis Erin M. , Chin Nathaniel A. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M. , Knight Rob , Kaddurah‐Daouk Rima , Blennow Kaj , Zetterberg Henrik , Rey Federico E. , Bendlin Barbara B. 
Published: January 2025

AbstractBackgroundHeavy alcohol consumption is associated with increased risk for Alzheimer’s disease and related dementias (ADRD), with mixed evidence suggesting a dose‐dependent nonlinear effect of alcohol on ADRD. Potential mechanisms by which alcohol may promote or attenuate brain pathology need further exploration. Although chronic alcohol consumption associates with gut microbiome alterations, it remains unclear whether microbial alterations mediate alcohol‐associated neurodegeneration and cognitive decline. Here we investigated whether the gut microbiome mediates alcohol consumption effects on cognitive function and biomarkers of neurodegeneration, glial activation, and AD.MethodCognitively unimpaired adults (n=178, Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center; Table 1) underwent neuropsychological evaluation, provided stool samples, and reported average daily alcohol consumption via questionnaire; a subset also underwent lumbar puncture (n=86). Fecal microbiome composition was characterized using 16S rRNA sequencing. A QIIME2/Phyloseq pipeline was used to complete denoising, feature classification, filtration of rare taxa and rarefaction to even sampling depth. Cerebrospinal fluid (CSF) biomarkers were quantified using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Multiple regression tested for associations between alcohol consumption and global cognitive function indicated by Preclinical Alzheimer’s Cognitive Composite (PACC3) scores (Donahue et al, 2014; Jonaitis et al, 2019), in addition to associations with CSF biomarkers. Non‐parametric methods tested associations between alcohol consumption and phylogenetic diversity as well as bacterial community structure.ResultA nonsignificant quadratic trend was observed between alcohol consumption and PACC3 scores (Figure 1). No significant associations were observed between alcohol and CSF biomarkers (Table 2). When testing associations between alcohol and gut microbiome independent from CSF and cognitive outcomes, no significant association was observed between alcohol consumption and phylogenetic diversity, nor was alcohol associated with significant alterations to bacterial community structure.ConclusionAssociations between alcohol consumption and cognition as well as CSF biomarkers were expected to be partially mediated by gut microbial alterations, but few relationships were observed, apart from a nonlinear trend between alcohol and PACC3. Of note, few individuals reported heavy alcohol use, which may have limited power to detect effects in this sample.
Investigating long‐term, progressive cerebral microvascular alterations in late‐onset Alzheimer's disease using APOE4 transgenic mice
Authors: Lee Jang‐Hoon 
Published: January 2025

AbstractBackgroundRecent studies show apolipoprotein E4 (APOE4), the strongest known genetic risk factor for late‐onset Alzheimer’s disease, is associated with vascular dysfunctions such as blood‐brain barrier breakdown, in both animal models and humans. However, there is a lack of understanding on how vascular alterations progress with age in APOE4.MethodHuman APOE4 (m/f, n=10 per group) and APOE3 targeted replacement mice (m, n=10) were used to investigate temporal dynamics of long‐term, progressive cerebral microvascular alterations in APOE4. we acquired a set of imaging data including optical coherence tomography (OCT) angiogram and doppler OCT to quantify relative changes in pial and penetrating vessels with age (starting at 13 weeks of age (WOA) and repeated every 4 weeks until 57 WOA). For assessing cognitive function, novel object location test (NOL) was used and performed every 4 weeks starting from 17 WOA.ResultWe compared the rate of change with age (RCA) values between the groups to find the effects of APOE4 and female. In pial vessel diameter, both APOE4‐m and APOE4‐f groups showed vessel diameter decreasing with age at a rate of 2.7 and 3.1% per month, respectively. In contrast, the control group (APOE3‐m) exhibited a slight increase in vessel diameter at a rate of 1.0% per month. When compared between groups based on RCA values, the age of significance (AOS) for the effect of APOE4 was 28 WOA. Adding the effect of female with APOE4, the result showed an earlier AOS of 26 WOA. In penetrating vessels (diameter/flow change in arterioles/venules), a similar trend was observed with both APOE4 groups exhibits more rapid decreasing RCAs and earlier AOS (27 WOA as earliest) than APOE3. More importantly, these AOS values were much faster than cognitive decline (51 WOA).ConclusionWe found vascular alterations in both pial and penetrating vessels occurred earlier than cognitive decline, being generally greater and earlier in female APOE4 than male APOE4 mice. This female effect in APOE4, although the underlying mechanisms behind such finding is beyond the scope of this study, could still provide valuable insights on understanding vascular dysfunction in sex‐dependent manner.