bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrospinal fluid apoe glycosylation associates with biomarkers of Alzheimer’s Disease pathology
Authors: Nedelkov Dobrin , Tsokolas Zoe , Sible Isabel , Mack Wendy J , Han S Duke , Rodman John CS , Yassine Hussein N 
Published: January 2025

AbstractBackgroundThe apolipoprotein E (ApoE) Ɛ4 allele is associated with a significant risk for both late‐onset Alzheimer’s Disease (AD) development and cerebral amyloidosis, but the degree to which cerebrospinal fluid (CSF) apoE glycosylation affects disease progression is unclear. The objective of this study was to examine the relationship of CSF apoE glycosylation with t‐tau, p‐tau181, and Aβ1‐42 CSF levels, and to delineate the effect of the APOE4+ genotype (vs E4‐) on glycosylation.MethodTotal glycosylation and apoE isoform‐specific glycosylation were analyzed in baseline plasma and CSF samples from a longitudinal cohort of older individuals (n=188, ages 55 ‐ 89) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). ApoE glycosylation was assayed using Mass Spectrometric Immunoassay (MSIA) that simultaneously detects the apoE isoforms and their glycosylation percentage. We performed pairwise comparisons between each apoE isoform and utilized linear mixed‐effects modeling to analyze longitudinal associations of apoE glycosylation with AD biomarkers, adjusting for age, sex, race, education, and clinical status.ResultWe examined glycosylation as a function of individual apoE isoforms and found that both total and secondary CSF glycosylation had the same trend: the E4 isoform had an overall lower % glycosylation compared to E2 and E3 isoforms (p<0.0001). Similarly, the E3 isoform had lower total and secondary CSF % glycosylation compared to the E2 isoform (p<0.0001). We further assessed whether the % apoE glycosylation in the baseline samples were associated with CSF t‐tau, p‐tau181, and Aβ1‐42 CSF levels in the longitudinal samples. Total CSF and secondary CSF glycosylation demonstrated highly significant associations with decreased levels of t‐tau (p < 0.002; p < 0.02 respectively) and p‐Tau181 (p< 0.006; p<0.02 respectively) over a 10‐year period. Secondary CSF glycosylation was significantly positively correlated with increased CSF Aβ1‐42 levels over a 10‐year period (p < 0.04).ConclusionThe degree of CSF ApoE glycosylation is strongly associated with concentrations of CSF t‐tau, p‐Tau181, and Aβ1‐42, and is predictive of biomarker changes over time. These novel discoveries underscore the importance of understanding the mechanisms involved in apoE glycosylation in the brain, which can lead to new targets and therapies for AD.
An X chromosome‐wide DNA methylation study of Alzheimer’s disease
Authors: Wang Lily , Zhang Wei , Gomez Lissette , Kunkle Brian W. , Lukacsovich David , Schmidt Michael A. , Varma Achintya , Griswold Anthony J. , Bush William S. , Martin Eden R. 
Published: January 2025

AbstractBackgroundSex is an important factor that contributes to both clinical and biological heterogeneity in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex differences in AD are still not well understood. DNA methylation (DNAm) is an epigenetic modification that regulates gene transcription and is known to be involved in AD. However, due to analytical and biological complexity, few previous DNAm studies analyzed the X chromosome, where many genes influencing cognitive abilities and immune functions are located.MethodWe performed a sex‐specific X chromosome‐wide analysis of the DNAm data generated by the longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. We used mixed effects logistic regression models with AD status as the outcome, adjusted for age, sex, batch, and immune cell‐type proportions, random subject effects, and corrected for inflation.ResultOur analysis included 632 female DNAm samples (188 cases, 444 controls) and 652 male DNAm samples (239 cases, 413 controls), measured on blood samples of 179 and 219 independent subjects with ages older than 65 years. Given our modest sample size, we considered CpGs with suggestive significance at the prespecified significance threshold of P < 1×10‐5. In females, we identified 2 significant CpGs (cg04150893 and cg16580361), mapped to the intergenic region and gene body of the HMGN5 gene. No significant CpGs were identified in male samples. Interestingly, blood DNAm at cg16580361 is significantly associated with DNAm in the prefrontal cortex (Blood Brain DNA methylation Comparison Tool: r = 0.599, P = 1.74×10‐8). Consistent with our observed hypermethylation at cg16580361 in ADNI data (OR = 1.11, P = 6.14×10‐6), the HMGN5 gene is also significantly upregulated in the frontal cortex of female AD subjects (Agora database https://agora.adknowledgeportal.org: OR = 20.227 = 1.17, adjusted P = 5.7×10‐6). The HMGN5 gene is involved in the metabolism of the brain antioxidant glutathione. Decreased levels of glutathione have been implicated in both AD onset and progression.ConclusionOur analysis of the X chromosome in the ADNI study dataset nominated cg16580361 located on the HMGN5 as a plausible biomarker for AD. Future studies that validate our findings in larger and more diverse community‐based cohorts are needed.
A Brief Digital Neuropsychological Protocol – I: Using Artificial Intelligence Assisted Technology to Assess Process and Errors
Authors: Libon David J. , Swenson Rodney , Tobyne Sean , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro 
Published: January 2025

AbstractBackgroundThere is an urgent need for neuropsychological screening tests that are easily deployed and reliable. We have developed a digital neuropsychological screening protocol that is administered on a tablet, automatically scored using artificial intelligence, and requires approximately 10 minutes to administer. This tablet‐administered protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illnessMethodThe digital protocol was administered to 77 ambulatory care/ memory clinic patients (Table 1). The protocol is comprised of a 6‐word version of the Philadelphia (repeatable) Verbal Learning Test [P(r)VLT], three trials of 5 digits backward (BDST), and the ‘animal’ fluency test. The protocol provides a panel of six traditional measures as would be obtained using paper/ pencil tests and manual scoring of (P[r]VLT free recall/ recognition hits, backward digit span, ‘animal’ fluency output); a variety of outcome measures quantifying errors and the process used to bring tests to fruition; and two separate, norm‐referenced summary scores measuring executive control and memory.ResultCluster analysis using the panel of 6 traditional measures classified participants into normal (nl= 23), amnestic MCI (aMCI= 17), dysexecutive MCI (dMCI= 23), and dementia (dementia= 23) groups. Subsequent analyses of error and process variables operationally defined key features associated with amnesia including rapid forgetting such as (P[r]VLT immediate free recall trial 2 vs. delay free recall (aMCI & dementia < dMCI & nl; p< 0.001), the production of extra‐list intrusion errors (dementia > nl; p< 0.002); profligate responding to recognition foils (aMCI & dementia > dMCI & nl; p< 0.001); key features underlying reduced executive measures (i.e., BDST perseveration/ related errors (dMCI & dementia > aMCI & nl, < 0.050); and the strength of semantic association from successive ‘animal’ fluency responses (nl & dMCI > dementia; p< 0.028). The novel executive and memory index scores dissociated all four groups from each other (p< 0.014).ConclusionThis digitally administered and scored protocol yields patterns of impaired performance similar to paper/ pencil tests. The availability of both traditional and error/ process measures suggests that subtle, nuanced indications of early emergent illness may be identified in a fast, efficient, yet comprehensive way.
The ABCA1 agonist CS6253 shows favorable safety and pharmacokinetics in IND‐enabling toxicology and Phase 1 human studies aimed at the indication of Alzheimer’s disease
Authors: Johansson Jan O. , Winblad Bengt , Michaelson Daniel M , Zetterberg Henrik , Cummings Jeffrey L. , Yassine Hussein N 
Published: January 2025

AbstractBackgroundABCA1‐mediated cholesterol transport is a central feature in many lipid‐ dependent diseases including APOE4‐associated Alzheimer’s disease and atherosclerosis‐CVD. ABCA1 upregulation of RNA transcription by nuclear factors (LXR, RXR) have been associated with liver side‐effects because of the common promotor element for ABCA1 and Fatty Acid Synthase. The ABCA1 agonist CS6253, derived from the C‐terminal of apoE was designed to stabilize and enhance ABCA1 function, thereby providing a safe alternative to transcriptional upregulation. CS6253 has in various mice models shown favorable neuroprotective and vascular‐metabolic effects suggesting potential for APOE4 MCI/AD and mixed MCI/AD.IND enabling studies in Wistar rats and Cynomolgus monkeys(cynos) were performed, and a Phase 1 SAD‐MAD study initiated, to explore the safety, PK and biomarker effects of CS6253.MethodConventional IND enabling toxicology studies, including 30‐day GLP studies in male and female rats and cynos were performed, in which CS6253 was injected as IV bolus injection every other day. Following clearing the IND a Phase 1 SAD‐MAD double‐blind, placebo‐controlled study was initiated, including elderly with and without APOE4 genotype, the SAD part ending in March 2024.ResultToxicology studies showed that cynos was the more sensitive species with the No Observable Adverse Effect Level (NOAEL) being 75 mg/kg. In plasma exposure/AUC in cynos was linear up to 25 mg/kg and showed already from 10 mg/kg transient increases in preb1‐HDL, small HDL and triglycerides which was associated with a significant increase in amyloidb42/40‐ratio.ConclusionEnhancing ABCA1 functions by CS6253 to form small HDL appears to be a promising approach with neuroprotective properties as indicated by pharmacology, IND‐enabling toxicology, and Phase 1 studies. The development of a safe and efficient ABCA1 agonist addresses several indications with unmet medical, notably for Alzheimer’s and brain vascular diseases.
ABCA7 high‐risk genotype predicts working memory decline among older cognitively healthy African Americans
Authors: Sheikh Mustafa , Piaszczynska Wiktoria , Arnasalam Alyssa , Oyono Arcande , Perez José Mojica , Budak Miray , Fausto Bernadette A. , Gluck Mark A. 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline1. APOE‐ε4 has been identified as the most prevalent genetic risk factor for the early onset of AD, while ABCA7‐80 (rs115550680) has been shown to have a stronger effect size than the APOE‐ε4 allele and is associated with the development of late‐onset of AD among African Americans2,3. Although the efficiency of executive functions declines with age, some basic attentional functions and preserved knowledge may help mitigate the effects of aging on working memory4. Nevertheless, the impact of APOE ε4 and ABCA7‐80 genotypes on attention and executive function in preclinical AD remains unclear5. This study investigated the influence of APOE ε4 and ABCA7‐80 genotypes on working memory among cognitively unimpaired older African Americans.MethodParticipants were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. 838 participants (ages ≥ 60) completed saliva collection for genotyping and neuropsychological battery for cognitive assessment with a fraction repeating each assessment multiple times as part of returning visits. Simple linear mixed models were applied for longitudinal statistical analysis.ResultABCA7‐80 high‐risk genotype was found to be a risk factor for decreased cognitive performance, as assessed by Trail Making Test Part A (ß = 5.819, p = 0.030) and Part B (ß = 39.964, p < 0.001), Digit Span Total (ß = ‐2.092, p= 0.045), Controlled Oral Word Association (ß = ‐4.708, p = 0.019), as well as a significant association with increased depression.ConclusionThe ABCA7‐80 high‐risk genotype may indicate early working memory declines in preclinical AD and may serve as a predictive biomarker among cognitively impaired older African Americans.
Comparing the diagnostic performance of plasma pTau181 and pTau217 for the identification of Alzheimer’s disease co‐pathology in Lewy Body Disease
Authors: Smith Alena , Plastini Melani J. , Ashton Nicholas J. , Montoliu‐Gaya Laia , Wilson Edward N. , Arslan Burak , Young Christina B. , Winer Joseph R. , Shahid Marian , Vossler Hillary , Kerchner Geoffrey A. , Cholerton Brenna , Andreasson Katrin I. , Yutsis Maya , Henderson Victor W. , Montine Thomas J. , Tian Lu , Mormino Elizabeth , Zetterberg Henrik , Poston Kathleen L. , Abdelnour Carla 
Published: January 2025

AbstractBackgroundLewy body disease (LBD) often co‐occurs with Alzheimer’s disease neuropathological change (ADNC), which can be detected using plasma pTau181 and pTau217. Few studies have investigated these biomarkers in LBD, nor have studies investigated plasma pTau217 in Parkinson’s disease (PD) cognitively normal patients (LBD‐CN), or in alpha‐synuclein positive (asyn‐positive) participants. Furthermore, uncertainties remain regarding LBD‐specific cut‐points for these biomarkers.We aimed to determine whether there is a difference in the diagnostic performance of plasma pTau181 and pTau217 for detecting ADNC and amyloidosis in LBD. We also determine whether cut‐points for these biomarkers in LBD differ from those for AD. Finally, we conducted a sensitivity analysis in asyn‐positive participants.MethodWe included 230 Stanford research participants: 110 cognitively normal (CN), 43 LBD‐CN, 41 LBD with cognitive impairment (LBD‐CI), and 36 AD. Plasma pTau181 was measured with the Lumipulse G platform, and pTau217 with the ALZpath pTau217 assay. A‐syn positivity was assessed in CSF with SYNTap®. Diagnostic accuracy of pTau181 and pTau271 in distinguishing ADNC (determined by CSF pTau181/Aβ42) and amyloidosis (determined by CSF Aβ42/Aβ40 or amyloid‐β PET) were evaluated with receiver‐operating characteristic (ROC) analyses. The Youden index was used to determine optimal cut‐points in distinguishing ADNC and amyloidosis, and the DeLong test to compare model performance.ResultIn the LBD‐CI group, plasma pTau181 and pTau217 had similar diagnostic performance in distinguishing ADNC+ from ADNC‐ (Figure 1A). Similarly, in the LBD‐CN and LBD‐CI groups, both biomarkers had similar diagnostic performance in distinguishing Aβ+ from Aβ‐ participants (Figure 1B). However, in the sensitivity analysis, pTau217 outperformed pTau181 for detecting Aβ+ in asyn‐positive participants (AUC: 0.88, 95%‐CI: 0.77‐1 vs 0.77, 95%‐CI: 0.64‐0.90, p=0.045) (Figure 2B). Finally, plasma pTau181 and pTau217 cut‐points for detecting ADNC and amyloidosis in LBD differed from those for AD (Figures 1‐3).ConclusionWe present, for the first time, the diagnostic accuracy of plasma pTau217 in LBD‐CN and asyn‐positive participants. Our results indicate that plasma pTau181 and pTau217 reliably detect concomitant ADNC and amyloidosis in LBD. Particularly, plasma pTau217 appears more sensitive for detecting amyloidosis in asyn‐positive participants. Additionally, our findings underscore the importance of establishing LBD‐specific cut‐points for AD biomarkers.
Measuring the Potential Risk of Re‐identification of Imaging Research Participants from Open‐Source Automated Face Recognition Software
Authors: Prakaashana Carl M. , Savvides Marios , Gunter Jeffrey L. , Senjem Matthew L. , Vemuri Prashanthi , Kantarci Kejal , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Schwarz Christopher G. 
Published: January 2025

AbstractBackgroundResearch subjects can potentially be re‐identified from de‐identified MRI, CT, and PET brain scans with up to 98% accuracy using Microsoft Azure’s cloud‐based commercial facial recognition software. This showed the need to “de‐face” publicly shared research brain scans. Subsequently, Microsoft has begun restricting its face recognition services, intending to prevent misuse. This study tests a variety of popular open‐source computer vision and facial recognition software packages to measure the re‐identification risk with only unrestricted free software.MethodThis study used brain MRI from Siemens 3T scanners and face photographs from 182 participants (ages 30‐90+) in the Mayo Clinic Study of Aging. Each participant had photos taken with an iPad, which were cropped loosely around the head and converted to black and white. A total of 81 renders (2D reconstruction images; Figure 1) were made from each 3D T2‐FLAIR MRI, simulating various camera and lighting positions. These face renders approximate black and white photos, allowing use with software packages developed for matching faces/features between photographs.Open‐source Python packages (OpenCV, DeepFace, face_recognition, scikit‐learn) and their included pre‐trained models (designed for photographs) were used to match participant photographs to the labelled library of MRI‐based face renders. A correct match was recorded when the top‐scoring render or set of renders automatically chosen by the algorithm was from the MRI of the correct participant.ResultFeature matching with ORB and SWIFT (both from OpenCV) produced no correct matches, despite a prior publication reporting moderate success. The best match rates (Figure 2) were 58‐59% accuracy using face_recognition or DeepFace packages with support vector machines (SVMs). Without SVMs, these packages performed modestly worse (51%‐55%).ConclusionWhile the highest match rates obtained by widely available open‐source packages (roughly 60%) are much lower than those of a limited‐access commercial product (Microsoft Azure, with 98%), they show that actors with only access to no‐cost readily available software could still re‐identify a research subject from a brain scan most of the time. This further highlights the need for image refacing software, such as mri_reface, to protect the privacy and identifies of research volunteers.
NODDI measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer’s disease pathology and cognitive outcomes
Authors: Parker Dana M , Adams Jenna N. , Kim Soyun , McMillan Liv , Yassa Michael A. 
Published: January 2025

AbstractBackgroundDiffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting‐edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD‐related changes in medial temporal lobe (MTL) WM than traditional tensor metrics.Method199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75; 60% female; cognitively unimpaired, n=121; cognitively impaired MCI/dementia, n=78) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate; Figure 1). A subset of participants received 18F‐florbetapir or 18F‐florbetaben to measure Aβ (n = 146; converted to Centiloids), 18F‐flortaucipir to measure tau (n=135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR‐SB) and memory composite score (ADNI‐MEM).ResultNODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures (Figure 2). For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus (r=‐0.375; p<0.001) and the uncinate (r=‐0.373; p<0.001), and with ODI in the fornix ST (r =‐0.288; p=0.004). Both ODI and NDI across the majority of tracts were associated with CDR‐SB and ADNI‐MEM (see Figure 2). In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid‐beta, while MD in MTL tracts showed limited correlations with pathology or cognition.ConclusionNODDI metrics offer additional insights about MTL WM integrity in AD that were previously missed due to the limitations of DTI analyses. These results highlight the sensitivity of NODDI applied to multishell diffusion MRI acquisitions to further investigate how WM degeneration contributes to cognitive decline.
Assessment of the potential neuroprotective effect of PhKv toxin, isolated from Phoneutria nigriventer venom, in vesicular acetylcholine transporter‐deficient mice
Authors: Nogueira‐Souza Ana Caroline , Fonseca Cristina Guatimosim , Tenza‐Ferrer Hèlia , Borges Marcia Helena , de Marco Luiz Armando Cunha , Romano‐Silva Marco Aurélio , Gomez Marcus Vinícius 
Published: January 2025

AbstractBackgroundAcetylcholine, a neurotransmitter critical for cognitive functions, including attention, memory, and sociability, is essential for maintaining synaptic integrity. Deficits in acetylcholine levels are linked to cognitive impairments. Heterozygous VAChT KD (VAChT KDHET) mice, characterized by reduced vesicular acetylcholine transporter protein production, exhibit cognitive impairments due to diminished acetylcholine release. This study explores the therapeutic potential of PhKv toxin, derived from the Brazilian wandering spider Phoneutria nigriventer, as an acetylcholinesterase inhibitor, aiming to prolong acetylcholine presence in the synaptic cleft of murine subjects.MethodsCognitive deficits in VAChT KDHET mice (n = 8) were assessed using the novel object recognition task. Thirty‐six VAChT KDHET mice were divided into three groups: PhKv (n = 12), galantamine (n = 12), and control/sham (n = 12). The PhKv group received subcutaneous vehicle (0.9% saline) and intracerebroventricular PhKv toxin (100 pmol/site). The galantamine group received subcutaneous galantamine (1 mg/kg) and intracerebroventricular vehicle (1x PBS). Controls received both vehicles. Preceding treatments, mice underwent habituation (HAB) and familiarization (FAM) in the novel object recognition test. Post‐FAM, mice received subcutaneous galantamine or vehicle, followed by intracerebroventricular PhKv or vehicle to minimize FAM‐related injection effects. After 24 hours, long‐term memory (LTM) was assessed.ResultsVAChT KDHET mice displayed impaired object recognition memory, with sex‐related short‐term memory differences. PhKv‐treated mice exhibited memory improvements comparable to galantamine‐ or vehicle‐treated mice, indicating potential memory enhancement. Further analysis revealed memory improvement in both vehicle‐treated and naive mutant mice.ConclusionPhKv shows promise in memory improvement, warranting in‐depth investigations into its mechanisms. Ongoing research explores the molecular aspects of PhKv’s action on acetylcholinesterase. Our study suggests PhKv’s therapeutic relevance in addressing cognitive deficits associated with acetylcholine dysregulation.