bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human postmortem studies as a driver of model development
Authors: Nguyen Aivi T. 
Published: December 2023

AbstractThe neuroimmune response in human aging and Alzheimer’s disease (AD) is complex and heterogeneous. Numerous genome wide associated studies have shown several AD genetic risk loci related to innate immunity and microglial function, of which APOE E4 and TREM2 R47H have been shown to influence microglial activation states. Microglial heterogeneity, characterized by morphology and function, has long been documented in human and murine literature. Using single‐nuclei RNA sequencing, one distinct reactive microglial subpopulation termed amyloid‐responsive microglia (ARM) was previously characterized in postmortem human AD brain tissue harboring various genetic risk variants, including APOE E4 and TREM2 R47H, and further validated in an expanded autopsy cohort using an immunohistochemical (IHC) marker for ARM. Herein described is an abbreviated study exploring the clinical utility of postmortem ARM IHC and its potential relationship to antemortem biomarkers, such as fluid and neuroimaging biomarkers, and cognition. Also discussed is the integration of digital pathology and artificial intelligence (AI)‐based algorithms to translate postmortem microglial findings into potential research application and model development.
Lessons from neuropathology to inform on fluid biomarkers of amyloid and tau
Authors: Mattsson‐Carlgren Niklas 
Published: December 2023

AbstractFluid biomarkers of amyloid and tau, including measures in both cerebrospinal fluid and plasma, have been used extensively in clinical and translational studies of Alzheimer’s disease and other neurodegenerative diseases. These biomarkers are now also increasingly used in clinical practice to inform on diagnosis and prognosis. Despite a successful development of new biomarkers with high diagnostic accuracy for Alzheimer’s disease, the exact relationship between fluid biomarkers and underlying pathological changes in the brain of patients with neurodegenerative diseases have long been unclear.Multimodal studies that integrate state‐of‐the‐art fluid biomarkers with neuropathological measurements are now beginning to inform on the exact relationship between alterations in soluble protein levels and underlying pathological changes. These findings have broad implications for the optimal use of fluid amyloid and tau biomarkers in clinical practice, research, and development of drugs targeting specific neuropathological mechanisms.This talk will highlight recent key findings in this field, discuss remaining challenges, and point out future directions for research.
Racial/Ethnic Disparities in the Alzheimer’s Disease Link with Cardiovascular Disease, based on Hawaii Medicare Population
Authors: Siriwardhana Chathura 
Published: December 2023

AbstractBackgroundThere is an expanding body of literature implicating heart disease and stroke as risk factors for Alzheimer’s disease (AD). Hawaii has the most diverse ethnic population in the US and there exist racial health disparities. E.g., Native‐Hawaiians/Pacific‐Islanders (NHPI) are well‐known as a high‐risk group for a variety of conditions. In this study, we explored the association of heart disease and stroke on AD development, focusing on racial disparities.MethodWe utilized nine years of Hawaii Medicare data to gather information on developing heart failure (HF), ischemic heart disease (IHD), atrial fibrillation (AF), acute myocardial infarction (AMI), stroke, and progression to AD, followed by multistate models. Propensity score‐matched control groups without heart disease or stroke were identified to compare the risk of AD after heart disease and stroke. Racial effects were tested on progression to AD, accounting for risk factorsResultWe found increased risk of developing AD for AF (Relative Risk [RR] = 1.09, p<0.001), HF (RR = 1.21, p<0.001), IHD (RR = 1.17, p<0.001), stroke (RR = 1.15, p<0.001) and a borderline significance for the AMI (RR = 1.09, p = 0.073), compared to whites. Socioeconomic status given by the Medicare/Medicaid dual eligibility status was found to be a critical factor in AD risk and regulating racial effects. Among the individuals with a poor socio‐economic background (dual eligible), increased AD risk found for NHPIs compared to whites, from HF (RR = 1.32, p = 0.046), IHD (RR = 1.37, p = 0.004), and stroke (RR = 1.41, p = 0.025), after adjustment for multiple covariates. NHPIs had consistently increased AD risks compared to Asians from all five states: AF (RR = 1.54, p = 0.004), AMI (RR = 1.72, p = 0.024), HF (RR = 2.23, p<0.001), IHD (RR = 2.39, p<0.001), and stroke (RR = 1.85, p<0.001). Interestingly, these relationships found to be different in the Medicare‐only group, in which reduced AD risks found in NHPIs compared to whites for many conditions, including AF (RR = 0.70, p = 0.037), HF (RR = 0.54, p = 0.006), and IHD (RR = 0.75, p = 0.034). NHPIs also had reduced risk compared to Asians from HF (RR = 0.73, p<0.001) and IHD (RR = 0.58, p<0.001) to AD transition.ConclusionThe risk of developing AD is high among heart disease and stroke patients, and it is varied among races.
Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)
Authors: Tazwar Mahir , Evia Arnold M , Ridwan Abdur Raquib , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundThe anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.MethodThis study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2).General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p<0.05.ResultLinear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p<0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p<0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p<0.05) (Fig.3B).ConclusionUsing graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.
MRI reveals cerebral iron, calcification and spinal cord atrophy in M83 mouse model of Parkinson’s disease
Authors: Tournant Agathe , Combes Benjamin F. , Law Man Hoi , Antunes Ines , Dias Santos , Noain Daniela , Klohs Jan , Baumann Christian R. , Razansky Daniel , Nitsch Roger M. , Ni Ruiqing 
Published: December 2023

AbstractBackgroundRodent models of Parkinson’s disease have been crucial tools for understanding the pathogenic mechanisms of alpha‐synuclein‐associated alterations. Here, we employed multiparametric high‐field magnetic resonance imaging (MRI) to examine the molecular alterations and neurodegeneration in the brain and spinal cord of transgenic M83 (A53T) murine model of Parkinson’s disease.MethodTen nontransgenic littermates and twelve M83 mice at 10‐11 months of age were assessed. Gradient echo MR for susceptibility‐weighted imaging (SWI) and T1 MR scans were acquired ex vivo at 9.4 T in the brain and spinal cord of mice. Histology and immunofluorescence staining for alpha‐synuclein inclusions (phospho‐S129), NeuN, GFAP and Iba‐1 for gliosis were used to investigate the nature of the imaging observations.ResultFrom T1 MR, a reduced area of white matter in the thoracic spinal cord (T1) and a reduced area of gray matter in the cervical (C6‐C8) and thoracic (T1) spinal cord were observed in the M83 mice compared to nontransgenic mice. In addition, lower left‐right length measurements in the cervical (C8) spinal cord were observed in M83 mice than in nontransgenic mice. SW images revealed regional hypointensities in the hippocampus, cortex, striatum, midbrain and thalamus of M83 mice, which in corresponding phase images indicated both diamagnetic (calcification) and paramagnetic (iron) lesions in the brains of M83 mice. Immunofluorescence staining demonstrated an increased Iba‐1 level in the brains of M83 mice, indicating microgliosis.ConclusionWe found cerebral iron, calcification, microgliosis and spinal cord atrophy in M83 mice.
DemenTitude® ‐ Applying the Concept of “LAN” with 16‐grid Dementia Care Model through the Voice of People with Dementia
Authors: Chui Kenny Chi Man 
Published: December 2023

AbstractUnderstanding the self‐perception of people with dementia and their interaction with the surrounding others is highly vital to exploring the unmet needs of people with dementia. In preserving the personhood through the person‐centred care approach, the synchronization with the experience of the person with dementia and listening to his/her voice of interpreting the surrounding things should be promoted. What is the meaning of the dialogues and the behavior of people with dementia? How can the “LAN” with 16‐grid dementia care model be applied to guide the care providers and the care partners in maintaining a good quality of care? In‐depth interviews and participatory observations were conducted during interviews in the community care and residential care homes of Hong Kong. Following the theoretical framework blending interpretivism and the sociocultural perspective on dementia, the finding was not only being used for getting more familiar with the experience of people with dementia but also designing the content of educational programme to the care providers and the care partners in Hong Kong.“LAN” model stands for “L‐listening to the experience and voice of people with dementia; A‐assess the condition of people with dementia through person‐centred care approach; N‐Needs of people with dementia to preserve personhood”. As the care providers and the care partners are trying to synchronize the experience of people with dementia, the subjective views and feeling of people with dementia formed by their interpretation will be the key to respond their unmet needs. A particular educational programme with 16‐grid of dementia care model was designed for the care providers and care partners. Focusing on the synchronization of the experience of people with dementia with LAN model, the participants got reflection and insights on this idea. In satisfying the needs of people with dementia, the participant should learn from the lens of people with dementia and VIPS approach. A proper caring attitude with this “LAN” model, called as DemenTitude®, was introduced. The evaluation of the educational training showed a significant improvement in the positive perception of dementia among the participants.
Thematic Analysis of How Scientists Are Perceived in Newspaper Articles About Contested Science and in the Associated Comments Sections
Authors: Donois Katrine Kergrohen 
Published: December 2023

AbstractBackgroundIn recent years, societal polarization over contested science has reached worrisome levels despite receiving much attention from researchers working in different fields spanning from neuroscience to journalism. In an attempt to understand the dynamics of polarization, much research focuses on media discourse. However, the newspapers’ comment sections (in which readers react) remain unexplored Thus, this study differs in that it argues that though the media may tell us what to think about, online commentators are telling us how to think about it.MethodReflexive thematic analysis was used to identify themes in 84 articles (all mentioning contested science of climate change, GMOs, or vaccines) and the associated comments sections (a total of 25.121 comments).ResultFour themes were identified, and they suggest that there are commonalities or patterns in the discourse surrounding contested science topics and in how scientists (or experts) are perceived across different fields. Understanding this pattern will help guide future communication strategies.ConclusionScientists are used by those for or against GMOs, vaccination, or climate change. For example, expert knowledge is drawn upon to strengthen, support, and serve as evidence for claims by journalists and commentators. However, people who distrust experts are not all advocates for misinformation or conspiracy theorists; some have (what they express as) legitimate grievances and worries. This study suggests ways for experts to improve science communication by taking the latter into account.
A comparison of word‐list and story recall tests for prediction of biomarker‐determined Alzheimer’s disease
Authors: Bruno Davide , Zinkunegi Ainara Jauregi , Kollmorgen Gwendlyn , Carboni Margherita , Wild Norbert , Carlsson Cynthia M. , Bendlin Barbara B , Okonkwo Ozioma , Chin Nathaniel A. , Hermann Bruce P , Asthana Sanjay , Zetterberg Henrik , Blennow Kaj , Langhough Rebecca E , Johnson Sterling C , Mueller Kimberly D 
Published: December 2023

AbstractBackgroundWord‐list and story recall tests are routinely employed in clinical practice for dementia screening. Previous research has shown that both types of tests are predictive of subsequent clinical diagnoses of dementia, including when examining process scores such as forgetting rate. In this study, our aim was to establish how well standard clinical metrics compared to process scores derived from word‐list and story recall tests in predicting biomarker‐determined Alzheimer’s disease (bdAD), as defined by CSF p‐tau/Abeta42 ratio.MethodData from 381 participants (mean age = 65, ± 9) were drawn from the University of Wisconsin – Madison Alzheimer’s Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer’s Prevention (WRAP). Rey’s Auditory Verbal Learning Test (AVLT; word‐list) and Logical Memory Test (LMT; story) data were available. The conventional clinical scores examined were: AVLT total recall, AVLT delayed recall, LMT immediate recall, and LMT delayed recall. The process scores examined were: AVLT recency ratio (i.e., recency forgetting), AVLT total forgetting, LMT recency ratio, LMT total forgetting, and LMT primacy ratio (i.e., primacy forgetting). Bayesian linear regression analyses were carried out with either the nearest or farthest CSF p‐tau/Abeta42 ratio as outcome; the standard and process baseline memory scores as predictors; and baseline age, time elapsed from baseline to lumbar puncture, APOE risk score, sex, and years of education as control variables. Sensitivity analyses were carried out with logistic regressions using a cut‐off of 0.038 CSF p‐tau/Abeta42 ratio as outcome, to assess diagnosticity. CSF biomarkers were measured using the NeuroToolKit (Roche Diagnostics International Ltd, Rotkreuz, Switzerland).ResultLMT recency ratio and LMT primacy ratio were the best performing predictors (BF10 > 1 billion) both when evaluating the nearest (Figure 1a) and the farthest (Figure 1b) outcomes. However, sensitivity analyses with a binary cut‐off favored the primacy ratio. Areas under the curve (AUCs) ranged from 0.86 to 0.87 (including covariates). Specificity was consistently high for primacy ratio with 94% probability of correctly identifying individuals without bdAD.ConclusionOur study shows that story recall tests may be better than word‐list tests for dementia screening, especially when employing process scores alongside conventional clinical scores.
Decline in proper name retrieval during story recall is associated with Alzheimer’s disease CSF biomarkers in cognitively unimpaired individuals
Authors: Mueller Kimberly D , Soldan Anja , Langhough Rebecca E , Basche Kristin E , Hale Madeline R , Sanson‐Miles Leah , Moghekar Abhay , Albert Marilyn S. , Pettigrew Corinne 
Published: December 2023

AbstractBackgroundRemembering names of people and places is a common problem in aging that is exacerbated in Alzheimer’s disease (AD). Because retrieval of proper names (PNs) has been associated with brain regions affected by AD (anterior and medial temporal lobe), PN retrieval may be an especially sensitive measure of early AD pathology. Extending results of a previous study from WRAP (Mueller et al., 2020), this study examined associations between cerebrospinal fluid (CSF) AD biomarkers and longitudinal delayed story recall PN retrieval.MethodParticipants were from the BIOCARD study, a cohort of late‐middle aged adults enriched for parental history of AD. Participants were cognitively unimpaired at baseline with longitudinal item‐level data from the Logical Memory (LM; WMS‐R) Story A recall (N = 218; M(SD) baseline age = 58(9); M(SD) follow‐up = 4.1(2.9) years). CSF amyloid beta (Ab42/40) and phosphorylated tau181 (p‐tau181) were measured using automated electrochemiluminescence assays; AD biomarker abnormality (+) was determined using the bottom quartile for Ab42/40 and the top quartile for p‐tau181. We calculated total Story A PNs (range 0‐4) and total score (0‐25). We performed longitudinal linear mixed effects (LME) models examining the interaction between time (LM age, centered) and last available Ab42/40 and/or p‐tau181 status as predictors of PNs and total recall (subject‐specific random intercepts).ResultOf the 218 participants included, forty‐nine (22.4%) were Ab42/40+, 60 (27.5%) were p‐tau181+, and the remainder were A‐/T‐ (Table 1). In LME models, CSF‐Ab42/40+*age was not a significant predictor of either outcome. The p‐tau181+*age interaction showed significantly greater annual decline in PNs in the p‐tau181+ group than the p‐tau181‐ group (interaction beta = ‐.01, p = .02; simple slope estimate p‐tau181‐ = .002, p‐tau181+ = ‐.01) (Table 2, Fig.1). Interaction patterns were weaker yet similar for total recall. In follow‐up analyses, 15 participants who converted to MCI or dementia were removed and results remained unchanged. In an exploratory model combining biomarker statuses, the Ab42/40+/p‐tau181+*age interaction was non‐significant.ConclusionAs in the WRAP study, these results from BIOCARD indicate that PN recall is more sensitive to preclinical change than the traditional story recall total score metric; results also indicate that decline is greatest in those with elevated CSF p‐tau. Future directions should include replication in other longitudinal cohorts.
A novel 3D imaging method to establish baseline amyloid‐beta plaque load and analyze compound efficacy in pre‐clinical Alzheimer’s disease animal models
Authors: Ferron Gianna , Linehan Stefan T , Ragan Tim , Elk Kevin J , Garceau Dylan , Sasner Michael 
Published: December 2023

AbstractBackgroundAmyloid‐beta (Aβ) plaque deposition in the brain represents a significant hallmark of Alzheimer’s Disease (AD). Standard laboratory approaches assessing Aβ lack the ability to pair high‐throughput whole‐organ imaging with region‐specific quantitation, and often require tissue homogenization. To analyze changes in Aβ spatiotemporally, we developed a novel Serial Two‐Photon Plus (STP2) pipeline to quantify plaque progression and depression as a function of brain region, resulting in indexed brain sections for secondary analysis using MALDI HiPLEX‐IHC with imaging mass spectrometry (IMS).MethodPlaques in the well characterized 5XFAD mouse model of AD were labeled with Methoxy‐X04, an Aβ plaque‐specific compound, prior to transcardial perfusion and whole‐brain excision. The STP2 platform uses a TissueCyte system to produce high‐resolution multi‐channel datasets, yielding 3D models of each brain. The Allen Mouse Brain Common Coordinate Framework (CCFv3) was registered to each brain, and our automated pipeline quantified plaque load and density per brain region. Select resulting sections were analyzed using AmberGen MALDI HiPLEX‐IHC and Bruker Daltonics IMS for Aβ42, pTau, GFAP, GLUT1, MBP, NeuN, NF‐L, PVALB, SNCA and SYN‐I.ResultQuantifying baseload plaque distribution in the 5XFAD model at 2, 3, 4, and 6‐months revealed significant changes in density of Aβ plaques both spatially and temporally. STP2 imaging, combined with CCFv3 mapping and secondary proteomic analysis allows for targeted evaluation of compound treatment on the Aβ plaques.ConclusionThe STP2 pipeline produces translational high‐throughput pre‐clinical AD data with enhanced sensitivity and precision, with resulting sections remaining in‐tact for further secondary analysis of spatial proteomics and pharmacodynamics in the brain.