bluuebunny/crossref_metadata_2025_split huggingface dataset:
Portable, Low‐field MRI for Alzheimer’s Disease
Authors: Kimberly W. Taylor 
Published: January 2025

AbstractBackgroundLow‐field magnetic resonance imaging (LF‐MRI) may facilitate point‐of‐care assessment of patients with Alzheimer’s Disease (AD) that can increase accessibility. However, image quality may be limited by lower signal‐to‐noise ratio (SNR). We developed a machine learning pipeline to quantify brain morphometry and white matter hyperintensities (WMH) using LF‐MRI, validated the volumes against conventional high‐field (HF) counterparts, and compared the volumes with aged controls.MethodsPatients with a diagnosis of mild cognitive impairment (MCI) or dementia due to AD (n = 45, age 73±8 years) were prospectively enrolled in the MGH Memory Division outpatient clinic. A separate cohort of controls (n = 23, age 64±8 years) were enrolled from the Yale Emergency Department and used for comparison. All patients underwent LF‐MRI acquisition on a 0.064T MRI which included T2 FLAIR and T1w sequences. We processed images through FreeSurfer‐based pipelines using LF SynthSR and SynthSeg for quantification of brain volumes and WMH‐SynthSeg to measure WMH burden. HF‐MRI (1.5‐3T) scans obtained within 8±12 months of LF‐MRI acquisition were used for comparison. Whole brain, hippocampal, and lateral ventricle volumes and WMH were quantified from HF and LF scans in patients and controls, normalized to intracranial volume (mean±SD).ResultsBrain volumes quantified on LF‐ and HF‐MRI were correlated, including hippocampal (r = 0.82, 95% CI 0.72‐0.93), whole brain (r = 0.97, 95% CI 0.96‐1.0) and lateral ventricle (r = 0.98, 95% CI 0.96‐1.0) volumes (all p<0.0001). WMH burden was also correlated (r = 0.80, 95% CI 0.66‐0.91) between LF‐ and HF‐MRI scans. Compared to controls, hippocampal volumes were smaller among those with MCI or AD (2.3±0.2−3 versus 2.6±0.3−3, p = 0.0001). A similar reduction in whole brain volume was observed in MCI/AD patients (591.2±19.8−3 versus 621.3±20.5−3, p = 0.0001), which was accompanied by ventricular enlargement (18.6±7.4−3
cf. 13.1 ±7.3−3, p = 0.0007).ConclusionPoint‐of‐care LF‐MRI of patients with MCI or dementia due to AD is feasible and generates accurate brain volumes and WMH burden when combined with machine learning algorithms. Collectively, our findings demonstrate LF‐MRI’s potential in cost‐effective image evaluation for cognitive impairment that may reduce disparities in access. Our findings also highlight the future potential for routine longitudinal assessment, disease staging, and monitoring during anti‐amyloid treatment.
Oral Microbial Dysbiosis Associated with Alzheimer’s Dementia in Puerto Ricans: A Preliminary Report
Authors: Morales Hiram , Herrero‐Rivera Carlos Alberto , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Olivieri‐Henry Gerianne , Godoy‐Vitorino Filipa , Sepulveda Vanessa 
Published: January 2025

AbstractBackgroundNew studies have linked epidemiological and pathophysiological relationships between oral microbiota and Alzheimer’s disease (AD), a neurodegenerative disease more prevalent in the Puerto Rican population. Dysbiosis of the oral microbiome induces periodontal disease, which increases systemic chronic inflammation, an important component in the multifactorial pathogenesis of AD. This project aims to characterize the oral microbiota’s composition and diversity in AD patients compared to healthy controls, and explore the potential role of oral dysbiosis in dementia.MethodA total of 52 participants were recruited (28 with Alzheimer’s Disease and 24 healthy controls), IRB #2290033626. Evaluations included a complete medical history and physical exam, and psychologic assessments with the Montreal Cognitive Assessment (MOCA) and Clinical Dementia Rating (CDR). Blood samples were collected for genotyping of the APOE gene. Oral samples were collected for genomic DNA extractions and microbiome characterization using 16S rRNA genes (V4 region) via Illumina MiSeq.ResultA statistically significant difference in bacterial composition was found in beta‐diversity between AD group and Controls (p‐value = 0.027). Among cognitive stages by CDR (p‐value = 0.04), a significant difference in beta‐diversity is also seen between participants with “no dementia”, “mild dementia”, and severe dementia”, which also correlates with distinctive richness at the genus‐level. LEFSe and Correlation analysis showed an increased abundance of oral genus Haemophilus in controls as compared to AD, and in increase in Corynebacterium in AD patients. Additionally, there is an increase in the proinflammatory bacteria Prevotella and a decrease in anti‐inflammatory bacteria Proteobateria also occurs in AD participants with abundance correlating with grades of cognitive impairment.ConclusionThis research underscores the intricate interplay between oral microbiota dysbiosis, periodontal disease, chronic inflammation, and Alzheimer’s Disease (AD). Our preliminary findings suggest a potential association between alterations in oral microbiota composition and the presence and severity of AD. Further investigation, including periodontal assessments and analysis of chronic inflammatory markers, is warranted to elucidate the mechanistic links and potential therapeutic avenues in managing AD within the Puerto Rican population.
Fibrinogen as a Key Binding Partner in Human Plasma for Lecanemab Biosimilar IgG
Authors: Bellier Jean‐Pierre , Viera Andrea M. Román , Christiano Caitlyn , Anzai Juliana A. U. , Moreno Stephanie , Campbell Emily C. , Godwin Lucas , Li Amy , Chen Alan Y. , Alam Sarah , Saba Adrianna , Yoo Han bin , Yang Hyun‐Sik , Chhatwal Jasmeer P. , Selkoe Dennis J. , Liu Lei 
Published: January 2025

AbstractBackgroundTherapeutic monoclonal antibodies targeting amyloid beta‐protein (Ab), such as lecanemab, represent a promising approach for disease‐modification in Alzheimer’s disease (AD). Due to its relatively short half‐life, lecanemab is given as a bi‐monthly infusion (typically 10mg/kg). Binding to high abundance plasma proteins (PPB) can influence the pharmacokinetics of drugs in the blood, including their half‐life.MethodIn this study, we investigated the potential of PPB for lecanemab using a biosimilar synthetized from publicly available lecanemab sequence (Lec‐bs). Lec‐bs biosimilar immunoreactivity was assessed in human plasma fractions obtained by size exclusion chromatography using both ELISA and Western blotting. The binding of lec‐bs to candidate PPB was validated through Western blotting, ELISA, and surface plasmon resonance analysis.ResultUsing a combination of equilibrium dialysis, ELISA, and Western blotting of human plasma, we first describe the presence of likely PPB for Lec‐bs, and then identify fibrinogen as a probable major plasma protein binding partner for Lec‐bs. Utilizing surface plasmon resonance, we confirmed that Lec‐bs binds to fibrinogen, albeit with lower affinity (318 µM) than to monomeric Ab (324 nM).ConclusionIn the context of lecanemab therapy, these results suggest that fibrinogen levels may influence free antibody levels in blood and that fibrinogen may act as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration for the clinical use of therapeutic antibodies in neurodegenerative disease.
Unraveling the complexities of educational and socioeconomic factors in cognitive decline with an AI model
Authors: Puentes Paola Ruiz , González Nestor , Crovo Daniel , Grimaldi Beatriz , Mukunda Ram 
Published: January 2025

AbstractBackgroundHigh formal education level is widely recognized as a protective factor against cognitive decline, influenced by the reserve hypothesis. However, in multiple studies educational experience is confounded with cultural and socioeconomic factors, leading to contradictory findings. Factors such as an individual’s living environment, including socioeconomic conditions, rather than individual variables such as education, are hypothesized to be factors influencing cognitive decline. This study leverages data from the Mexican Health and Aging Study (MHAS) and the Mexican Cognitive Aging Ancillary Study (Mex‐Cog), which provide information on the living conditions of older adults and their cognitive status. Through artificial intelligence models, this research aims to provide a nuanced understanding of cognitive decline risk factors as it relates to educational and socioeconomic factors.MethodsThe Mexican Health and Aging Study (MHAS) provides national‐level data on individuals aged 50 and over across six waves from 2001 to 2021, including detailed cognitive assessments (Mex‐Cog) in 2016 and 2021. We trained a traditional machine learning and a deep learning algorithm, specifically a random forest and a transformer‐based model, to predict participants' Mini‐Mental State Examination (MMSE) scores. For this task we used a comprehensive dataset that includes historical and current data on demographics, health, health care utilization and insurance, cognition, financial and housing wealth, income, pension, family structure, employment, assistance and caregiving, stress and psychosocial scores, and end of life planning. We employed Shapley‐based analyses to identify the most influential factors and their interactions in the MMSE score predictions. We present our initial findings on factors influencing cognitive decline.ResultsCertain algorithms, especially random forests are superior to other algorithms that we tried to use. Our approach, while limited to the Mexican data, shows, for example, education plus income as a superior indicator of risk for cognitive decline than education alone.ConclusionOur model, with further analysis, has far‐reaching public policy implications. We continue to expand the algorithm to include multiple factors beyond education to assess risk of cognitive decline.
Free water and white matter hyperintensities volumes among diverse individuals aged 54 to 103
Authors: Posis Alexander Ivan B. , Maillard Pauline , George Kristen M. , Gilsanz Paola , DeCarli Charles S. , Corrada María M. , Whitmer Rachel A. 
Published: January 2025

AbstractBackgroundFree water (FW) and white matter hyperintensities (WMH) are key biomarkers of white matter integrity yet are understudied in racially/ethnically diverse populations and those over age 80. We describe FW and WMH across age, sex, and education in a diverse cohort.MethodData were harmonized from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE; mean age = 78±6 years) Study, Study of Healthy Aging in African Americans (STAR; mean age = 69±9 years), and LifeAfter90 (LA90; mean age = 93±2 years) Study, which are ongoing cohorts of racially/ethnically diverse participants who are long‐term members of Kaiser Permanente Northern California. Participants received neuroimaging via 3T MRI, with harmonized protocols, to measure FW and WMH. WMH was log‐transformed and we calculated residual values accounting for total cranial volume. FW and WMH were described by decade of age at scan, gender, race/ethnicity, and education using mean, standard deviation, and range. Differences in FW and WMH by participant characteristics were tested using analysis of variance tests. We tested the interaction of race/ethnicity with each characteristic in relation to FW or WMH using separate linear regression models.ResultIn 840 participants, median age at imaging was 78 years (range = 54‐103). Fifty‐nine percent were women, 42.3% African American/Black, 18.1% Asian, 16.2% Hispanic/Latino, 21.4% White, and 2% Other. As age increased, FW and WMH increased (p<0.01; Table 1; Figure 1). Participants with ≤High School/GED education had greater FW and WMH. Asian participants had the highest overall mean WMH, followed by White and Hispanic/Latino (p<0.01). However, African American/Black participants generally had greater mean WMH when examined across decade of age at scan (Figure 2). The interaction of gender and race/ethnicity was significant such that African American/Black and Asian women generally had slightly lower mean FW compared to men (p = 0.04). There were no significant interactions between decade of age at scan or education with race/ethnicity.ConclusionIn this diverse cohort, FW and WMH were associated with increased age, and WMH differed by race/ethnicity and gender. Our findings suggest the utility of FA and WMH among diverse individuals, across a large age range, which is critical for advancing neuroimaging biomarker research.
Pathways underlying selective vulnerability to Alzheimer’s disease in aminergic brainstem nuclei
Authors: Ehrenberg Alexander J. , Petersen Cathrine , Pereira Felipe Luiz , Buxton Jessica J. , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Ferretti‐Rebustini Renata Eloah de Lucena , Ferrioli Eduardo , Nitrini Ricardo , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Seeley William , Spina Salvatore , Kaufer Daniela , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundThe Neuromodulatory Subcortical System (NSS) consists of nuclei exhibiting early vulnerability to tauopathies, including Alzheimer’s Disease (AD). Within the NSS, there is a spectrum of vulnerability that becomes apparent in the earliest stages of AD, offering a chance to probe factors underlying vulnerability to AD.MethodIn this study, we applied bulk RNA sequencing in well‐characterized postmortem human tissue from n = 22 cases at early (Braak 0‐III) AD‐tau stages to understand why this susceptibility gradient exists by examining two nuclei with very similar neurons but differing in their vulnerability to AD the locus coeruleus (LC) and substantia nigra (SN).ResultWe identified 3421 differentially expressed genes between the LC and SN among Braak 0 cases. Gene set enrichment analysis directed attention towards cholesterol homeostasis, neuroinflammation, and oxidative stress as factors potentially underlying the differential vulnerability of the LC and SN to AD.ConclusionWeighing the limitations of bulk RNA sequencing against the expression patterns of the constituitive genes within each gene set, we conclude that cholesterol homeostasis likely explains the differential vulnerability of the LC and SN to AD (Figure 1).
Association between in vivo structural integrity of the posterior hypothalamus, cognition and Alzheimer’s disease pathophysiology
Authors: Baillet Marion , Betthauser Tobey J. , Salmon Eric , Jacobs Heidi I.L. 
Published: January 2025

AbstractBackgroundAbnormal tau accumulation is first observed in several neuromodulatory subcortical nuclei before its emergence in the allocortex, and long before the first deposits of amyloid‐beta (Aβ) plaques. Crucially, the posterior hypothalamus has been put forward as a critical site for Alzheimer’s disease (AD) pathogenesis but its role in AD‐related processes remains poorly investigated in humans. Here, we aimed to investigate whether the structural integrity of the posterior hypothalamus, as assessed in vivo, is associated with PET‐measured AD pathology and cognitive performance in cognitively unimpaired (CU) and impaired older individuals.Methods151 CU individuals, 75 mild cognitive impairment (MCI) and 35 AD patients (mean ± SD age = 76.6 ± 6.7y., 137 women; Table 1) from the ADNI3 dataset were included. The volume of the posterior hypothalamus (corrected for intracranial volume) was derived from structural T1‐weighted images using a deep convolutional network algorithm (Figure 1a). [18F]Flortaucipir‐PET was used to measure tau burden in the entorhinal cortex (standardized uptake volume ratio [SUVR], partial volume corrected values). Amyloid‐β (Aβ) positivity was determined with [18F]Florbetaben‐ or [18F]Florbetapir‐PET in a cortical summary region (SUVR values). Cognition was evaluated with the Preclinical Alzheimer’s Cognitive Composite (PACC). Analyses were adjusted for age, sex, and education.ResultsAD patients exhibited lower posterior hypothalamic volume compared to CU Aβ‐ (p = 0.003) and CU Aβ+ participants (p = 0.01) but no significant difference was observed between CU and MCI patients nor between MCI and AD patients (Figure 1b). Linear regression models revealed that lower posterior hypothalamic volume was associated with higher entorhinal tau‐PET values (p = 0.02, Figure 2a). In addition, CU Aβ+ with higher posterior hypothalamic volume exhibited higher entorhinal tau‐PET values compared to a negative slope in CU Aβ‐ participants (p = 0.05, Figure 2b). Finally, lower posterior hypothalamic volume was related to lower PACC scores (p<0.001, Figure 2c), which was mainly driven by AD patients (p<0.05 for comparisons with CU and MCI, Figure 2d).ConclusionsOur findings indicate that the posterior hypothalamus is linked to disease‐related pathophysiological and cognitive changes. Future analyses will explore whether posterior hypothalamic volume is associated with inflammatory markers and changes in tau accumulation and cognitive performance over time.
SHIP1 phosphatase as a Late‐Onset Alzheimer’s Disease therapeutic target
Authors: Singhal Kratika , Hamdani Adam K , Jesudason Cynthia D , Beck Daniel E , Clayton Brent , Richardson Timothy I. , Mesecar Andrew D. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a highly complex neurological disorder, with Late‐Onset AD (LOAD) being its most common form. INPP5D has been identified as a risk gene for AD and is involved in the TREM2 signaling pathway, which is crucial for microglial activity. INPP5D encodes SHIP1, a protein phosphatase that disrupts TREM2 signaling by converting PIP3 into PIP2, thereby inhibiting the PI3K‐mediated activation of Akt‐dependent signaling, which is essential for the clearance of amyloid oligomers, fibrils, and plaques. SHIP1 is a large, multidomain protein, and many aspects of its structure and function are poorly understood.MethodWe have expressed, purified, and characterized the kinetic and biophysical properties of various domain constructs of SHIP1 to better understand the roles of individual domains. Ongoing work involves screening of inhibitors using a range of biochemical and biophysical assays with different constructs of SHIP1.ResultThe response of different SHIP1 domain constructs with different substrates surprisingly revealed no significant differences in kinetic parameters between different domain constructs with the same substrate suggesting that the various domains surrounding the catalytic domain do not influence catalysis in solution. However, use of a designed chemical probe with a covalent warhead that targets SHIP1 allosterically between the catalytic and C2 domains shows significant inhibition of SHIP1 (in the absence of its SH2 domain) identifying a potential druggable site. X‐ray crystallography was used to confirm the binding pose within this site. Binding affinity with additional compounds has been determined for different domain constructs using enzyme kinetics and biophysical methods including Microscale Thermophoresis (MST) and Differential Scanning Fluorescence (DSF).ConclusionSHIP1 is highly active in vitro (solution) without much regulation of its catalytic activity by surrounding domains. A potential druggable site has been identified between the SHIP1 catalytic and C2 domains that can be targeted allosterically by small molecule compounds. These discoveries will aid in identifying new molecules that can inhibit SHIP1 as a potential therapeutic target for AD.This research was supported by grant 1U54 AG065181 (IUSM‐Purdue TREAT‐AD Center) from the National Institute of Aging, National Institutes of Health.
APOE‐ε4 interacts with the BTBD7 testis‐eQTL to reduce longevity in males
Authors: Park Junyoung , Guen Yann Le , Greicius Michael D 
Published: January 2025

AbstractBackgroundThe ε4 allele of the APOE gene (APOE‐ε4) and male sex are well‐established risk factors for reduced longevity. While many genetic studies of longevity have modeled sex and APOE, independently, few have considered the interaction of these two risk factors. Here, we model the interaction between APOE‐ε4 and sex in a genome‐wide association study (GWAS) of longevity.MethodThis study included a total of 408,780 participants with 36,981 age‐at‐death (male = 21,912, female = 15,069) and 371,799 last‐known‐age (male = 165,849, female = 205,950) from European ancestry participants in UK Biobank (Table 1). We performed a GWAS stratified by sex to find significant variant APOE‐ε4 genotype interactions associated with longevity using imputed genotype data for common variants (allele frequency>1%). Additionally, we conducted colocalization analyses with expression quantitative loci (eQTL) in GTEx v8 to identify potentially causal genes.ResultIn males (p = 4.1×10−8), but not in females (p = 0.33), we found a significant interaction between APOE‐ε4 and rs11626499 near BTBD7, which was associated with decreased longevity (Figure 1). The survival analysis revealed that in the male APOE‐ε4 carrier group, the individuals with the rs11626499_G had a higher risk of mortality (p = 2.8×10−7, HR = 1.12), but this risk was not observed in the male APOE‐ε4 non‐carrier group (p = 0.06) or in the female APOE‐ε4 carrier group (p = 0.14). Furthermore, the GWAS signal colocalizes with associations of BTBD7 and UNC79 expression in testis (Figure 2).ConclusionWe identified an interaction between APOE‐ε4 and rs11626499 that increases mortality risk only in males. Additionally, rs11626499_G is associated with decreased BTBD7 and increased UNC79 expression in testis but not in female‐specific tissues. These findings demonstrate the importance of modeling the interaction between APOE and sex in studies of longevity.
Pharmacokinetic Effects of THC and Melatonin Co‐administration in Elderly Population
Authors: Naranjo María Paula , Camargo Fabio , Rao Jagadeesh S , Delgado‐Murillo Laura , Venegas Margarita , Tangarife Maria Alejandra , Arbelaez María Juanita , Gutiérrez Evelyn , Sánchez Laura Tatiana , Shahnawaz Saadia , Ghazaryan Varduhi , De Jesus William Julio , Grimaldi Claudia , Hong Elliot , Mukunda Ram 
Published: January 2025

AbstractBackgroundCannabis‐based therapies have gained interest in treating different ailments in the elderly population, including severe or chronic pain, sleep disturbances, and more recently Alzheimer’s Disease. This raises the importance of understanding the influence of age on the pharmacokinetics (“PK”) of delta‐9 tetrahydrocannabinol (“THC”).IGC‐AD1 comprises THC at a low concentration and melatonin. The PK of THC/Melatonin co‐administration acquires importance since recent therapeutics employ both drugs in treating insomnia or neurodegenerative diseases in the geriatric population, where baseline PK is key to understanding possible changes because of renal or hepatic failures, and accurately adjusting doses to ensure the safety of those drugs.MethodData is presented from a Phase 1 Multiple Ascending Dose (“MAD”) study (n = 10 active), on AD patients and compared to PK data for adults. A review was performed including search results from ScienceDirect, CAS, PubMed, SpringerLink, and Google Scholar, using the terms “Pharmacokinetics”, “Absorption”, “transporter*”, “intestinal”, and “elderly”. Inclusion criteria were the indexed nature of the research, and languages (English, Spanish). No temporal inclusion‐exclusion criteria were considered.ResultA dose of 2.5mg of THC reaches higher maximum plasma concentrations (Cmax = 2ng/mL), when administered together with 1.5mg of melatonin, and melatonin appears to be metabolized faster when administered with THC. When considering the relationship between the administered dose and Cmax (Cmax/dose), Cmax per dose of the co‐administered THC, 0.0008, is significantly higher than other reported PK data for oral cannabis administration 0.0003 (p<0.01).ConclusionMelatonin when administered jointly with THC could play a significant role in THC absorption and PK. We hypothesize, pending more studies, that the higher reported dose‐dependent absorption of THC may be related to the effect of melatonin on gastrointestinal transporters and efflux pumps.