bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex‐Specific Effects of APOE Genotype on Contextual Fear Discrimination
Authors: Mohammed Hassan E , Coniglio Jackie , Luna Victor M. 
Published: January 2025

AbstractBackgroundThe Apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic late‐onset Alzheimer’s disease (AD). Moreover, the link between APOE4 and AD is more pronounced in women than in men. In this study, we investigate how APOE genotype and sex impact emotional pattern separation. This is a cognitive faculty that enables discrimination between highly similar emotional and non‐emotional experiences, deficits of which are key neuropsychiatric symptoms of AD progression.MethodTo determine the role of APOE alleles in emotional pattern separation, 6‐month‐old male (n = 14) and female mice (n = 15) expressing humanized APOE2, 3 or 4 alleles (CureAlz) were tested on a contextual fear discrimination (CFD) task that is dependent on the dentate gyrus and on adult hippocampal neurogenesis. Mice were evaluated on their ability to distinguish between an aversive Context A (with foot shock) and a similar yet non‐aversive Context B (no foot shock) for 5 days. For each Context, visual and olfactory stimuli in the chamber were altered while the tactile features of the floor were kept the same. As part of CFD protocol, mice also underwent standard contextual fear conditioning (CFC) testing.ResultWe found no significant effect of sex or APOE allele on CFC learning. However, in the CFD task, we found that female E2 mice performed significantly better than female E3 and E4 animals. E3 females appeared to discriminate between aversive and non‐aversive contexts better than E4. In contrast, we found that APOE allele did not impact CFD in males. Finally, we found that E2 females significantly outperformed E2 males in the CFD task. E3 and E4 females performed similar to their male counterparts.ConclusionOur results suggest that early in adulthood, the APOE2 allele greatly impacts emotional pattern separation in a sex‐dependent manner. To determine the underlying synaptic mechanisms for our CFD findings, we have been investigating how APOE alleles impact the expression of all glutamate receptor subunits in the dentate gyrus as well as neurogenesis levels. Most importantly, we have been aging our mouse colonies to determine how age, APOE allele, sex, and glutamate receptor composition together dictate emotional pattern separation related to AD.
Proteomic prediction of myelin water fraction using the SomaScan 7k platform
Authors: Joynes Cassandra M , Resnick Susan M. , Bouhrara Mustapha , Walker Keenan A. 
Published: January 2025

AbstractBackgroundMyelin loss occurs as part of neurodegenerative and neuroinflammatory conditions. Myelin water fraction (MWF), a surrogate of myelin content, can be estimated using multicomponent relaxometry MRI. In this study we investigate the relationship between 7289 plasma proteins and MWF to derive a protein‐based indicator of myelin content.MethodIn the Baltimore Longitudinal Study of Aging (BLSA) plasma proteins were measured using the SomaScan proteomic platform; BMC‐mcDESPOT was used to measure MWF. Univariate analyses adjusted for age, sex, eGFR, and age2 examined the association of protein levels with MWF. Public datasets were used for determination of the cell (HPA)‐ and tissue (GTex)‐specificity used for candidate protein annotation. Multivariate analyses used stepwise linear regression, following the selection process described in Figure 1, to generate a protein‐based estimate of MWF (eMWF).Result64 cognitively normal participants from the BLSA (mean age at MWF visit 55.32 years [range 22.4 to 94.4], 48% males) were included in the discovery analysis. Adjusted univariate analyses found 231 proteins associated with MWF at an uncorrected p<0.05. However, none survived FDR correction. Plasma proteins CUTC (β = 0.02, p = 0.0003), COL20A1 (β = 0.04, p = 0.001), and PRSS27 (β = ‐0.03, p = 0.001) showed the strongest association with MWF (Figure 2A). Proteins positively associated with MWF were enriched for vasoconstriction, MAPK integrin signaling, amyloid‐beta binding, and complement and coagulation cascades. Proteins inversely associated with MWF were also enriched for complement and coagulation, as well as TRAIL signaling, and TP53 transcriptional regulation (Figure 2B). In a multivariable analysis of MWF, stepwise linear regression selected the proteins PRSS27, ZC4H2, IFNL3, RNF146, RFESD, PROK1, and DCAF11, as well as age and age2, for model inclusion (protein function annotated in Figure 3D). R2 of the model when fit on the full dataset was 0.86 (fivefold cross validation R2 = 0.51, Figure 3A). Observed and estimated MWF both show similar nonlinear trajectories with age (Figure 3B‐C).ConclusionWe developed a protein‐based proxy for total myelin content and validated the predictive ability of this measure. Future studies will test eMWF in neurodegenerative and demyelinating conditions.
First‐of‐its‐kind identification of two novel tau mutations associated with cognitive resilience to Alzheimer’s disease neuropathology
Authors: Jamison Danielle , Taglialatela Giulio 
Published: January 2025

AbstractBackgroundTo date, mutations in the MAPT (i.e., tau) gene within Alzheimer’s disease (AD) patients are either benign or have an unclear effect on pathogenicity. Significant prior literature and evidence from other tauopathies support the hypothesis that mutations can alter tau’s structure and function. Approximately one‐third of neuropathological autopsies identify individuals with comparable AD neuropathology (i.e., extracellular amyloid‐beta (Aβ) plaques and intracellular tau‐containing neurofibrillary tangles (NFTs)) without similar clinical manifestations or cognitive deficits (herein referred to as non‐demented with Alzheimer’s neuropathology or NDAN). The comparable neuropathological burden with divergent clinical manifestations between AD patients and NDAN individuals led us to hypothesize that a mutation in the NDAN MAPT gene could explain, at least in part, this dichotomous presentation.MethodRNA was isolated from the frontal cortices of seven NDAN individuals (4M, 3F) using a commercial RNA kit. Primers to amplify the tau coding sequence were found in the literature and confirmed to amplify the tau coding sequence. With assistance from UTMB’s Next Generation Sequencing core, the RNA quality was first assessed, and subsequently, library generation and sequencing were performed.ResultTwo novel somatic mutations were identified in all seven individuals with frequencies consistent with mosaic mutant frequencies. The first, an aspartic acid to alanine mutation, occurred at a position where no prior mutations have been documented. The second occurs at the serine immediately preceding tau’s amyloid motif, VQIVYK; in this mutation, the phosphoresidue is replaced by a charged and bulky arginine. Analysis using the Ensembl Variant Effect Predictor (VEP) predicted both mutations to be, at a minimum, moderately damaging to tau’s function, which is logical considering the amino acid substitutions occurring. The severity of each mutation’s effect on the tau structure and function was isoform specific.ConclusionWe identified, to the best of our knowledge, two completely novel tau mutations uniquely associated with individuals that remain cognitively intact despite abundant AD neuropathology. These mutations may help contextualize the unique phenotype observed in NDAN individuals, such as cognitive resilience and spreading with minimal toxicity.Funding Support: R01422460 and R0142690 to GT. Attendance at this conference was supported by an AAIC 2024 Conference Fellowship.
The Global Neurodegeneration Proteomics Consortium ‐ Biomarker and Drug Target Discovery Across >40,000 Biosamples for AD, PD, ALS, FTD, and Aging
Authors: Bringmann Martin , Imam Farhad , Krish Varsha 
Published: January 2025

AbstractBackgroundLimited understanding of biological mechanisms behind the onset and progression of Neurodegenerative Disorders has been a burden for the discovery of novel biomarkers and treatments. Large, harmonized, patient‐derived datasets will be key in unraveling the complex biology leading to neurodegeneration. The Global Neurodegeneration Proteomics Consortium (GNPC) is a major biomarker discovery effort to unite and expand the available proteomic data for thousands of patient samples from leading dementia cohorts from around the world and comprises, to our knowledge, the largest discovery proteomics dataset to date.MethodThe GNPC has brought together over 40,000 samples from over 20 different international cohorts to create and collaborate on a fully anonymized Harmonized Dataset (HDS). The HDS spans multiple neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Secure access to GNPC data is facilitated through the Alzheimer’s Disease Data Initiative ‘s online platform, the AD Workbench. De‐identified datasets submitted by each participating cohort were harmonized and further anonymized by professional data vendors. After one year of intra‐consortium analysis, the HDS will be accessible by the broader research community as a shared, global resource.ResultThe first version of the Harmonized Dataset (HDS) includes over 40,000 unique samples on the SomaScan 5k and/or 7k proteomics array platform. All samples are accompanied by >40 phenotypic indicators including demographic, cognitive data, clinical scores, and disease‐specific genotype. Central hosting of de‐identified and harmonized data within the secure cloud environment provides the necessary data security, access to scalable compute resources, and facilitated collaboration between participants in diverse geographies and regulatory environments.ConclusionWith over 300,000,000 unique protein measures, the GNPC represents the largest protein biomarker discovery effort for neurodegenerative diseases to date. Initial research underway is organized via several core workstreams, including cross‐sectional and longitudinal profiling, proteogenomic mapping, multivariate prediction, and combinatorial analysis across a single disease area.
Validation of Large Language Models to Identify Dementia Cases in Electronic Health Records
Authors: Yang Richard , Wang Liqin 
Published: January 2025

AbstractBackgroundDementia diagnosis presents global healthcare challenges due to its elusive nature and inconsistent documentation in Electronic Health Records (EHRs). Approaches relying on diagnostic codes and rules may overlook undiagnosed cases or mistakenly identify others, as these codes are frequently used for purposes beyond disease diagnosis. This highlights the need for more sophisticated diagnostic tools. The advent of artificial intelligence (AI) and large language models (LLMs), with their advanced natural language understanding, promises more accurate detection. This study evaluates LLMs’ performance in identifying dementia cases using aggregated EHR data.MethodThe study utilized the EHR from Mass General Brigham (MGB) to identify potential dementia patients through keywords and codes indicating cognitive decline. From this pool, 200 patients underwent independent chart reviews by two experts, with discrepancies resolved by a third. We employed two LLMs, GPT‐3.5 and GPT‐4, and two data preparation approaches for dementia detection: daily medical record aggregation and patient record aggregation. The first approach concatenated daily records related to cognitive decline and analyzed the data chronologically with zero‐shot prompting using both LLMs. Conversely, the second approach concatenated entire patient medical records related to cognitive decline and applied GPT‐4 with few‐shot prompting. For comparison, we included a baseline that requires two separate dementia ICD diagnoses in different years, at least 30 days apart. We assessed each approach using accuracy, positive predictive value (PPV), sensitivity, specificity, and F1 score.ResultThe patient record aggregation plus few‐shot prompting strategy with GPT‐4 had the best performance, achieving an accuracy of 0.86 and an F1 score of 0.80. In the daily medical record aggregation approach, GPT‐4’s zero‐shot prompting outperformed GPT‐3.5, with F1 scores of 0.78 and 0.57, respectively. The baseline rule‐based approach scored a good F1 of 0.74 but showed lower sensitivity, suggesting underdiagnosis with traditional methods.ConclusionThis study demonstrates that LLMs can significantly enhance dementia diagnosis using EHRs. Our findings reveal that the aggregated patient record and few‐shot prompting strategy with GPT‐4 outperforms traditional methods, offering a more comprehensive and accurate evaluation of dementia.
Lower resting‐state phasic LC activity is associated with cortical tau deposition and Aβ‐related cognitive decline in preclinical Alzheimer’s Disease
Authors: Prokopiou Prokopis C. , Schultz Aaron P , Rentz Dorene M , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L. 
Published: January 2025

AbstractBackgroundThe locus coeruleus (LC) is one of the earliest regions accumulating tau pathology in Alzheimer’s Disease (AD). As the disease progresses, tau in the LC has been linked to increasing cortical tau and amyloid‐beta (Aβ) pathologies and cognitive decline. Previous animal research suggested that novelty‐like phasic LC activity protects against AD‐related cognitive decline. In this work, we investigate whether in‐vivo resting‐state phasic LC activity is associated with AD pathology and cognitive decline in preclinical AD.MethodNinety‐two participants (56 Female, mean age at baseline = 74.99±9.0 years) from the Harvard Aging Brain Study underwent longitudinal cognitive testing (mean follow‐up = 5.37±1.88 years), PiB(Aβ)‐PET, FTP(tau)‐PET, and 3T resting‐state BOLD‐fMRI scans (TR/TE = 800/37 ms, voxel = 2 mm3) performed within 1.5 years of each other (mean time difference = 0.96±0.0 years; Table 1). Spontaneous phasic LC activity events were extracted directly from the LC BOLD‐fMRI time‐series using deconvolution and positively‐constrained LASSO regression. The proportion of LC activity explained by the detected events was quantified using the R‐squared coefficient of determination. Vertex‐wise linear regression analyses adjusted for age, sex, and multiple comparisons (pcl<0.05) were used to detect significant associations between LC phasic activity and cortical tau. Longitudinal linear mixed‐model analyses adjusted for age, sex, and years of education were used to evaluate the relationship between LC phasic activity and cognitive decline (composite, see Fig. 2 caption) at different levels of cortical Aβ.ResultRepresentative spontaneous LC phasic events and their associated BOLD‐fMRI signal fluctuations are illustrated in Fig. 1A‐B, respectively. Lower resting‐state phasic LC activity was associated with greater bilateral inferior‐temporal tau deposition (Fig. 1C), also confirmed by a region of interest analysis (Fig. 1D; p = 0.03). No relationship between phasic LC activity and Aβ was observed. Furthermore, lower LC phasic activity was associated with steeper cognitive (Fig. 2; p = 0.02) decline, particularly at elevated Aβ levels.ConclusionThis preliminary work demonstrates that lower levels of spontaneous phasic LC activity are related to elevated cortical tau pathology and steeper downstream AD‐related cognitive decline. These results could inform the design of targeted interventions to support optimal LC phasic activity, promoting resilience. Further research is needed to elucidate these relationships further by utilizing longitudinal data on AD pathology and cognitive function across different subdomains.
Survey on knowledge of Uruguayan neurologist about the FINGER intervention
Authors: Contreras Valeria , Charamelo Ana , Dansilio Sergio 
Published: January 2025

AbstractBackgroundThe Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm‐FINGERS) is based on the study FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) in which participate 12 Latin American countries. Is the first non‐pharmacological multicenter randomized clinical trial to prevent cognitive impairment in Latin America (LA), and investigates the feasibility of a multi‐domain lifestyle intervention and the efficacy of the intervention in LA.We were interested in knowing what information Uruguayan neurologists have on the subject. In Uruguay, according to official information, in 2021 there were 139 registered neurologists. No surveys have been carried out on the subject in Uruguay.Objectives: To know what information the Uruguayan neurologists have about the results of the FINGER intervention and the frequency of indication of primary prevention measures to people at risk of cognitive impairment.MethodsThis is a cross sectional, observational and descriptive trial. A survey was designed in the SurveyMonkey application with 13 questions and it was sent to neurologists through social networks. Informed consent was requested.ResultsThe survey was answered by 41 neurologists. 38.5% of responders were aware of the results of the FINGER intervention in Finland and 36% have made prevention recommendations taking them into consideration.40 participants responded regarding primary prevention measures. Of these, 90% stated that they made recommendations to people at risk of cognitive impairment. 30% reported making nutritional suggestions frequently, 95% suggested cognitive stimulation exercises and 92.5% suggested participating in regulated physical activity programs.47.5% knew about the LatAm FINGERS initiative and 42.5% knew that Uruguay was participating in it. All respondents expressed interest in knowing the results of the LatAm FINGERS initiative when it has concluded.ConclusionsMost Uruguayan neurologists make recommendations on primary prevention measures for cognitive impairment. There was moderate knowledge about the results of the FINGERS study, but there is a marked interest in learning more about the topic.It is planned to extend the survey to other medical specialists involved in the care of people at risk of cognitive impairment.
Rapid discovery and optimization of novel brain shuttles and shuttle‐enabled anti‐amyloid therapeutics using multiplexed in vivo biologics design
Authors: Lofgren Shane 
Published: January 2025

AbstractBackgroundDrug delivery to the central nervous system has long been hindered by the restrictive properties of the blood‐brain barrier (BBB). Recent advances have highlighted the ability of certain antibody “shuttles'' to traverse the BBB and enhance the delivery of diverse therapeutic payloads. However the true potential of this approach remains underexplored and is limited by traditional in vitro screening platforms that fail to capture the complexities of in vivo biology. Novel technologies that facilitate the development of brain shuttles and shuttle‐enabled neuromedicines could improve the uptake, efficacy, safety, and dosing of broad classes of therapeutics, and transform the treatment of vast numbers of patients with neurological disease.MethodHere, we introduce a high‐throughput in vivo screening methodology based on Manifold’s mCodeTM technology to evaluate BBB penetration and uptake of over 1000 brain shuttling antibody candidates targeting 10+ different receptors (Figure).ResultOur approach reveals antibody shuttles with diverse molecular properties and distinct pharmacokinetic profiles in brain, blood, and other peripheral tissues. We leverage this large in vivo dataset using machine learning to further engineer these antibodies for enhanced brain uptake and residence time. Engineering of brain shuttles with anti‐amyloid antibodies against BACE1 and amyloid beta significantly improved the uptake and efficacy of these fusions versus unshuttled controls and comparator shuttled molecules.ConclusionCollectively, our work (1) expands the pool of known targets and molecules capable of shuttling therapeutic payloads across the BBB, (2) validates the utility of these molecules toward the design of novel neuromedicines for Alzheimer’s disease, and (3) signifies a paradigm shift in utilizing thoughtfully‐designed, high‐throughput in vivo screening in early stages of drug discovery.
Unmet ADL/IADL Needs among Veterans with Dementia: An Analysis of the HERO CARE Multi‐site Survey
Authors: Desir Marianne E , Munoz Richard A , Hansen Jared , Tang Fei , Dang Stuti 
Published: January 2025

AbstractBackgroundReceiving sufficient assistance with ADLs/IADLs can support dementia patients’ physical and psychosocial health, as well as aging in place. The Department of Veterans Affairs has prioritized supporting Veterans in aging at place a home when this is their preference. We aimed in the current study to analyze if there are demographic characteristics and/or comorbidities of Veterans with dementia that are predictive of having unmet ADL/IADL needs.MethodIn 2021‐2022 the caregivers of 741 Veterans with dementia completed round one of the HERO CARE survey, a prospective longitudinal panel design survey administered to caregivers and VHA‐enrolled Veterans across five VHA sites, with oversampling of Veterans with higher predicted risk of long‐term institutionalization. 314 of these surveys had sufficient response data for inclusion in the current analysis. Multiple linear regression was used to regress the outcome of combined total score of unmet ADL/IADL needs (minimum = 0, maximum = 15, mean = 4.86, SD = 4.92) on specific demographic characteristics and comorbidities (using Hierarchical Condition Categories) across five models. The model of best fit was identified by AIC.ResultNon‐white/non‐Hispanic race‐ethnicity (β = 3.14, se = 0.64) and having Parkinson’s or Huntington’s diseases (β = 2.718, se = 0.870) were associated with having more unmet ADL/IADL needs at the 5% significance level. Having major depressive, bipolar, and/or paranoid disorders (β = ‐ 1.395, se = 0.656) was associated with having less unmet ADL/IADL needs at the 5% significance level. When controlling for the other predictors, having non‐white/non‐Hispanic race‐ethnicity was associated with an average increase of 3.25 unmet ADLs/IADLs, having Parkinson’s or Huntington’s Disease was associated with an average increase of 2.72 unmet ADLs/IADLs and having major depressive, bipolar, and/or paranoid disorders was associated with a 1.40 decrease in unmet ADLs/IADLs.ConclusionThe Veterans Affairs Healthcare System (VAHS) may have characteristics that support the provision of ADL/IADL assistance for patients who have dementia in conjunction with major depressive, bipolar and/or paranoid disorders. Increased attention to ADL/IADL supports among VAHS patients who have dementia and non‐white/non‐Hispanic race/ethnicity and/or Parkinson’s or Huntington’s diseases may support Veteran health, wellbeing, and aging in place.