bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation Between Atherosclerotic Carotid Plaque Composition and the Neuropathological Lesions of Alzheimer’s Disease: Partial Results
Authors: Barbosa Maria Eduarda , Leite Renata Elaine Paraizo , Grinberg Lea T. , Nitrini Ricardo , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Farias‐Itao Daniela Souza , Pontes Beatriz Carvalho , Braga Maria Eduarda , Justo Alberto Fernando Oliveira , Suemoto Claudia Kimie 
Published: January 2025

AbstractBackgroundPrevious studies suggest an association between Alzheimer’s disease and carotid artery atherosclerosis. However, the association between atherosclerotic carotid plaque composition and Alzheimer’s disease pathology (neuritic plaques and neurofibrillary tangles) has not been explored yet.MethodCarotid arteries were dissected and the segments with the largest obstruction in the carotid bifurcation, and the common and internal carotid arteries were obtained. Each segment was immersed in paraffin and stained using Hematoxylin‐Eosin (HE) and Masson’s Trichrome. Each histological slide was photographed using a stereomicroscope (SMZ 1000; Nikon). We analyzed artery obstruction, fibrous cap, the number of vasa vasorum, and plaque components, using the software Atherosclerotic Plaque Analyzer. We characterized the neuritic plaque deposition in the brain using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria and neurofibrillary tangle deposition using the Braak & Braak criteria. We performed ordinal logistic regression models adjusted for age, sex, education, hypertension, diabetes, dyslipidemia, smoking, excessive alcohol consumption, body mass index, and physical inactivity.ResultCross‐sectional data from 237 subjects from the Biobank for Aging Studies of the University of Sao Paulo Medical School were analyzed (mean age = 79.0±9.9 yo, 51.5% women, 59.9% white, 35.9% black and 3.8% Asian). As the percentage of smooth muscle cell area increased, neurofibrillary tangles deposition decreased (OR = 0.97, 95% CI = 0.94‐1.00, p = 0.03). Similarly, as the percentage of fibrous cap area increased, neurofibrillary tangles deposition increased (OR = 1.13, 95% CI = 1.00‐1.25, p = 0.04).ConclusionGiven that the fibrous cap is typically present in advanced atherosclerosis, and considering that smooth muscle cell area was solely assessed in the absence of well‐established atherosclerotic plaque, our examination of atherosclerotic plaque composition in carotid artery segments suggests a connection between atherosclerosis development and the accumulation of neurofibrillary tangles in the brain. We found an association with the fibrous cap proportion of the tunica intima area and an inverse association with the proportion of smooth muscle cells in the tunica intima area.
The role of heparan sulfate proteoglycans for tau pathology in vivo
Authors: Stopschinski Barbara E , Estill‐Terpack Sandi‐Jo , Batra Sushobhna , Pandey Shubhangi , III Jaime Vaquer‐Alicea , Diamond Marc I 
Published: January 2025

AbstractBackgroundThe prion model of tau propagation in Alzheimer’s Disease predicts that tau seeds are released from cells and taken up by neighboring cells, resulting in spreading of the disease. Our previous work revealed that tau aggregates bind to heparan sulfate proteoglycans (HSPGs) on the cell surface, followed by cellular uptake via macropinocytosis. HSPGs are glycoproteins, consisting of a protein core and decorated with linear glycosaminoglycan (GAG) chains called heparan sulfate (HS) with highly variable sulfation patterns. We have previously used a combination of biochemical, pharmacological and genetic tools to demonstrate that N‐sulfation (mediated by the N‐sulfotransferase NDST1) of the HS chain is critical for tau uptake in cell models. This project is a stepwise approach to validate HSPGs and specifically NDST1 as a therapeutic target to block tau spread in vivo.MethodWe induced NDST1 knockout using CRISPR/Cas9 followed by rescue experiments and tau uptake assays in HEK293T cells. Tau uptake assays with heparin were conducted in murine hippocampal neurons and astrocytes. We employed stereotactic adeno‐associated virus 8 (AAV8)‐mediated intracerebral delivery of small hairpin RNA (shRNA) to target NDST1 in PS19 mice, a tauopathy mouse model (collaboration with Merck).ResultOur data demonstrates that reduction of the N‐deacetylase activity with selected point mutations within NDST1 can decrease tau uptake substantially (Figure 1). Our experiments in primary murine neurons and astrocytes suggest that HSPGs are crucial for tau uptake in these cell types (Figure 2). NDST1 knockdown with shRNA in PS19 mice achieved >75% reduction of messenger RNA (mRNA) levels and was non‐toxic (Figure 3).ConclusionOur findings suggest that NDST1 is a potentially druggable target, and that the HSPG pathway plays a role for tau uptake in multiple cell types. We worked with GemPharmatech for the generation of a floxed NDST1 mouse line. We plan to breed the floxed NDST1 mice to PS19 mice and selected neuronal, astrocytic and microglial Cre driver lines. We anticipate that knockout of NDST1 in vivo will reduce tau spread in mouse brain. If successful, our study will inspire multiple lines of follow up work such as the design of enzymatic inhibitors and genetic silencing tools.
Elevated iron levels in the older adult brain are associated with higher R2 relaxation rate in gray matter and more white matter hyperintensities: An ex‐vivo MRI, pathology and mass spectrometry study
Authors: Yasar Md Tahmid , Bush Ashley I. , Ayton Scott , Agarwal Puja , Agrawal Sonal , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: January 2025

AbstractBackgroundElevated iron in brain is a source of free radicals that causes oxidative stress which has been linked to neuropathologies and cognitive impairment among older adults. The aim of this study was to investigate the association of iron levels with transverse relaxation rate, R2, and white matter hyperintensities (WMH), independent of the effects of other metals and age‐related neuropathologies.MethodCerebral hemispheres from 437 older adults participating in the Rush Memory and Aging Project study (Table 1) were imaged ex‐vivo using 3T MRI scanners. R2 maps were generated from multi‐echo spin‐echo data and then registered to an ex‐vivo brain template. WMH were segmented based on T2‐weighted images. WMH volume was normalized by the total hemisphere volume and then log‐transformed. Following ex‐vivo MRI, all hemispheres underwent neuropathologic assessment including Aβ plaques, neurofibrillary tangles, LATE‐NC, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy, gross infarcts, microscopic infarcts, atherosclerosis, and arteriolosclerosis (Table 1).Inductively coupled plasma mass spectrometry was used to measure brain trace metal levels. The assessed metals included iron, boron, titanium, manganese, copper, zinc, selenium, rubidium, molybdenum, and mercury (Table 1).Linear regression was used to test the association of R2 and WMH burden with iron levels. All models were controlled for all other metals and neuropathologies listed above, demographics (age at death, sex, years of education), the presence of the APOE‐ε4 allele, postmortem interval to fixation and to imaging, and scanner. Statistical analysis was performed using PALM, with tail‐accelerated 5,000 permutations. Statistical significance was set at p<0.05 after family wise error rate correction.ResultThe voxel‐wise analysis revealed a spatial pattern of higher R2 for higher iron levels, particularly in gray matter (Fig. 1). The pattern included basal ganglia structures such as the globus pallidus and putamen, and cortical regions including the precentral, postcentral and cuneus cortex (Fig. 1). Higher lobar and total WMH burden were also associated with higher iron levels (Fig. 2). No negative associations were observed.ConclusionThis investigation combined ex‐vivo MRI, neuropathology and mass spectrometry in a community‐based older adults and showed that higher iron levels were independently associated with higher R2 in gray matter and higher WMH burden.
Exploring Sex‐Specific Accelerated Hippocampal Atrophy Across AD Stages beyond APOE‐e4 Assessment in Genetic Risk Evaluation
Authors: Evans Tavia E , Vilor‐Tejedor Natalia , Rodrigo Albert , Genius Patricia , Rodríguez‐Fernández Blanca , Anastasi Federica , Navarro Arcadi , Adams Hieab H.H. , Gispert Juan Domingo ,   For the ADNI
Published: January 2025

AbstractBackgroundCurrent evidence suggests that hippocampal subfields have partially different genetic architecture and may improve the sensitivity of the detection of Alzheimer’s disease (AD). In this study, we investigated whether genetic predisposition to AD contributes to the accelerated rate of hippocampal volume atrophy across sex and AD stages and how this contribution is specifically driven by functional variants located in the APOE gene.MethodsThe study comprised 1,051 participants from ADNI cohort (75.2 yo; 42.3% women), with complete demographic, genetic, and magnetic resonance imaging scans at baseline and every 6 months for a total of 96 months (Controls (amyloid negative), CUN = 363; mild cognitive impairment, MCIN = 474, AD patients, ADN = 214). Hippocampal subfields were extracted using the longitudinal processing method within FreeSurfer (v6.0). Genetic predisposition to AD was assessed through polygenic scoring with and without considering the APOE región. Effects of polygenicity of plasma APOE, functional APOE brain eQTLs and CSF pQTL were also considered. Linear mixed‐effect models with random‐ time slope and intercept for individuals were used to investigate the association between genetic predisposition to AD and hippocampal subfields volumetric trajectories over time. Models were adjusted by age, sex, AD disease status, years of education and total hippocampal volume. Disease and sex status‐specific trajectories dependent on genetics predisposition were assessed by including an interaction term.ResultsSignificant hippocampal subfield volume reductions were observed, with more pronounced atrophy in MCI and AD participants [Figure 1A]. High genetic predisposition to AD was associated with accelerated atrophy in various subfields [Figure 1B]. MCI individuals with high genetic predisposition showed more severe atrophy in several subfields, with sex‐related differences observed, particularly in women [Figure 2]. Notably, these effects were non‐significant when excluding APOE variants. Further functional analyses pinpointed CSF pQTLS of the APOE gene and APOE‐e4 carriership status as primary drivers [Figure 3].ConclusionsOur findings underscore the significance of genetic predisposition, especially functional APOE variants, in understanding AD progression and sex‐specific trajectories. The results reveal varying atrophy patterns across disease stages, offering crucial insights for refining AD detection and tailoring interventions for more effective management.
Failure to replicate detection of grid‐cell like representations in human fMRI
Authors: Kransberg Jonas , Markus Sneve H , Falch Emilie Sogn , Bråthen Anne Cecilie Sjøli , Fjell Anders M , Walhovd Kristine B 
Published: January 2025

AbstractBackgroundGrid cells are spatially modulated cells in the entorhinal cortex (EC) that fire in a hexagonally patterned grid which tiles the environment. These cells are assumed important in human spatial navigation. The EC is vulnerable to neurodegenerative processes in both normal aging and Alzheimer’s disease and decline in grid cell function may be a key factor in understanding age‐related navigational decline.Recent work suggests that conjunctive grid and head direction cells can allow for the detection of grid‐like activity based on movement direction. If moving in alignment with a hexagonal grid, EC activation should be higher than movement not aligned with the grid. The present study attempts replicate findings from previous studies of grid‐like signals detected through fMRI.MethodsThe sample included 64 (40 female, 24 male) adults, ages ranging from 18 to 78 (M = 37.67). Participants were subject to a fMRI grid cell paradigm, tasked to passively navigate through a room and remember the location of objects. The movement directions in the virtual environment were used to find the mean grid orientation for each participant set through a general linear model with the sixfold pattern as a regressor, and this was used as a regressor in a second GLM to calculate the grid magnitude, a measure of the stability of the grid codes.ResultsA one‐sample t‐test showed no significant grid code magnitudes (M = 0.002, SD = 0.091) compared to zero for a sixfold symmetry t(63) = 0.19, p = .85. For age‐related analysis, the sample was divided into a younger and older sample through a median split using the median of 30.5 years. A Two Sample t‐test did not show any difference between the younger (M = 0.021, SD = 0.089) and older (M = ‐0.017, SD = 0.090) groups, t(61.99) = ‐1.68, p = .097. Figure 1 shows the mean grid code magnitudes for both age groups.ConclusionPreliminary results suggest no evidence for stable grid‐like representations in the present sample. The present study is reasonably powered relative to the previous study, and possible reasons and limitations hindering identification of grid‐like representations should be discussed and further researched.
The population of high CTLA‐4 expressing with CD56 positive T cell is diminished in Alzheimer’s disease patients
Authors: Chu Cheng‐I , Wu Ching‐Tse , Yu Wang Feng‐ , Yu Yang Hui‐ , Chang Chien‐Chung , Chang Chuang‐Rung 
Published: January 2025

AbstractBackgroundAbnormal brain inflammation is an important feature of Alzheimer’s disease (AD). Central nervous system (CNS) inflammation is highly related to immune cell activation. Homeostasis of immune cell activity regulation is crucial for CNS autoimmune response. Our previous study found that the expression of immune checkpoint PD‐L1/PD‐1 on T cells changed along with different stages of AD patients. We assayed the other immune checkpoint molecule, CTLA‐4, and its functional characteristics to characterize the changes of T cell populations of peripheral blood in AD patients.MethodAD patients (n = 14) and healthy elderly (n = 16) were enrolled. White blood cells collecting from blood were labelled with fluorescent antibodies and assayed by flow cytometry. To characterize changes in specific T‐cell populations and features, we used t‐distributed stochastic neighbor embedding (tSNE). The analysis results of all volunteers were pooled, aggregated, and integrated with different phenotypic and functional characteristics. Distribution patterns were delineated between AD and healthy elderly, differences were compared, and molecular features were identified for further subpopulation analysis.Result(A) In the phenotypic and functional characteristics feature distribution of T cells, the subpopulation distribution difference between AD and healthy elderly was related to the expression intensity of NCAM (Neural cell adhesion molecule, CD56). (B) Further distinguishing the T cell population with positive expression of CD56, three subpopulations were found, subpopulation A, B and C. Subpopulation A decreased in AD patients, subpopulation C increased in AD patients, and subpopulation B had no obvious difference. Prominent difference of these three subpopulations was the expression level of CTLA‐4. Subpopulation A was CTLA‐4HighCD56+ T cell subset; subpopulation B was CTLA‐4DimCD56+ T cell subset; subpopulation C was CTLA‐4MediumCD56+ T cell subset.ConclusionCD56 (NCAM) positive T cells with high expression of CTLA‐4 decreased in AD patients. CTLA‐4 played important role in T cell priming brake, and competed B7 ligand with CD28 to suppress T cell activation. Decrease of CTLA‐4 expression on CD56+ T cells indirectly promote the immune activation. Our research indicated immune imbalance in peripheral blood of AD patients. Changes of T cell subpopulations may be biomarkers of AD, and maintaining homeostasis of immunity may be potential treatment of AD in future.
APOE3 Christchurch influences amyloid induced tau seeding and spreading via effects on microglia
Authors: Chen Yun , Song Sihui , Parhizkar Samira , Lord Jennifer , Zhu Yiyang , Strickland Michael R , Wang Chanung , Park Jiyu , Tabor G. Travis , Jiang Hong , Li Kevin , Davis Albert A , Yuede Carla M , Colonna Marco , Ulrich Jason D , Holtzman David M. 
Published: January 2025

AbstractBackgroundA recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer’s Disease (AD) caused by a PSEN1‐E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear.MethodWe generated a humanized APOE3ch knock‐in mouse and crossed it to an amyloid‐β (Aβ) plaque‐depositing model. We injected AD‐tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Mouse samples were collected and used for multiple measurements including cholesterol test, WB, ELISA, IF, etc. We also designed and performed in vitro assays to evaluate the phagocytosis, degradation, competitive uptake, exocytosis, etc.ResultAPOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque‐associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans in vitro.ConclusionAPOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ‐induced tau seeding and spreading.
Alzheimer’s disease APOE neuropathology‐based score, amyloid, and ptau polygenic scores’ association with amyloid PET positivity
Authors: Hammad Yazan , Deming Yuetiva , Morse Jacob , Grover Ethan , Bendlin Barbara B. , Betthauser Tobey J. 
Published: January 2025

AbstractBackgroundAPOE is the greatest genetic risk factor for AD, however, other smaller genetic effects are often ignored. In this work, endophenotype‐informed polygenic scores (PGS) that exclude the APOE region were tested along with a separate, previously published, APOE neuropathology‐based score (APOEscore). The APOEscore serves as a more nuanced quantification of APOE genetic risk that considers the effects of the different haplotypes. PGS and APOEscore were compared to amyloid positivity, determined via PET imaging, which is used as a measure for AD risk and progression.MethodsAlzheimer’s Disease Neuroimaging Initiative (ADNI) participants with genetic data and Florbetapir (18F‐AV‐45) amyloid PET summary SUVR (whole cerebellum reference region) values were included in analyses. Amyloid positivity (A+) was defined as SUVR > 1.11. PGS were calculated using the weights from genome‐wide association studies (GWAS) of CSF Aβ42 (amyloid‐PGS) or ptau181 (ptau‐PGS), after excluding the APOE region (±500kb). APOE effects were accounted for using the APOEscore that was calculated following Deming et al (2023).Results1094 participants (618 A+) were included in the analyses (Table 1). The APOEscore was significantly associated with A+ after accounting for sex and age at scan (OR = 2.931, P = 6.38e‐45; Table 2). The amyloid‐PGS was also significantly associated with A+ (OR = 0.492, P = 0.026), whereas the ptau‐PGS did not quite reach significance (OR = 3.218, P = 0.054). After adding the APOEscore, the effect of amyloid‐PGS on A+ remained but did not quite reach significance (OR = 0.515, P = 0.072) and ptau‐PGS was not significant (OR = 1.845, P = 0.375).ConclusionThese results validate the utility of the APOEscore with PET amyloid as well as the potential value of including non‐APOE genes in quantifying the genetic risk for amyloid accumulation and AD. The significant association between amyloid‐PGS and A+, and near significance after adding the APOEscore, demonstrates the existence of additional genetic effects outside of APOE that have an impact on amyloid accumulation. While the ptau‐PGS did not reach significance, possibly due to sample size, the OR (3.218) was greater in magnitude than the amyloid‐PGS (1/OR = 2.033). Future work will explore these relationships in other cohorts and with other PET AD biomarkers.
SCARF2 in the CSF of Asymptomatic subjects With a Parental History of AD and in the Cortex of Autopsy‐Confirmed Alzheimer’s Disease Cases
Authors: Aumont‐Rodrigue Gabriel , Picard Cynthia , Labonté Anne , Poirier Judes ,   PREVENT‐AD research Group
Published: January 2025

AbstractBackgroundScavenger receptors (SR) are a group of receptors involved in the endocytosis of various ligands, such as modified LDL and soluble β‐amyloid, which connects them to Alzheimer’s disease (AD). SCARF2 (SREC‐II) is part of the SR family, but unlike other scavenger receptors, internalizes a low amount of modified LDL. Its main function revolves around the binding of Aβ (Vo et al. 2023). Other studies found SCARF2 to be a SCARF1 inhibitor (Ishii et al. 2002). This study compares gene expression and protein levels of SCARF2 in post‐mortem brain tissue of AD and control subjects, as well as in the CSF of participants with a family history of AD. The goal is to track the progression of AD using the expression pattern of SCARF2.MethodSCARF2 CSF protein levels were assessed in the PREVENT‐AD (PRe‐symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease) cohort which is composed of asymptomatic subjects with parental history of AD. SCARF2 has been measured with a primer extension assay using Olink technology. ELISA immunoassay has been used to quantify SCARF2 protein levels in frontal cortex homogenates of 86 brains from the Douglas Bell Canada Brain Bank (DBCBB). mRNA prevalence was measured using Gene Chip Clariom D human microarray. All statistical analyses were performed using JMP pro 17 software.ResultSCARF2 Protein levels, but not mRNA, are significantly lower in brains with AD (p<0.001). SCARF2 protein display a strong negative association with plaques bound Aβ, despite being a well‐established Aβ receptor (R2 = 0.277, p<0.0001). Interestingly, CSF protein levels correlate positively with AD biomarkers such as total and phosphorylated(181) tau (R2 = 0.235, p<0.0001; R2 = 0.288, p<0.0001) and Aβ to a lesser extent (R2 = 0.045, p = 0.0318).ConclusionOur study unveils a distinctive role for SCARF2 in AD pathogenesis. Despite being a known Aβ receptor, SCARF2 exhibits lower cortical protein levels in AD brains, inversely linked to plaques bound Aβ. In contrast, elevated CSF SCARF2 protein levels correlate positively with CSF AD biomarkers in the presymptomatic phase of the disease; suggesting differential response to amyloid and tau deposition. These findings shed light on the intricate interplay of SCARF2 in AD pathophysiology, offering potential avenues for further research.