bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial transcriptomics reveals neuroimmune mechanisms of Aβ clearance in immunized Alzheimer’s disease patients
Authors: van Olst Lynn , Simonton Brooke , Edwards Alex J , Forsyth Anne V , Jamshidi Pouya , Li Mengwei , Shepard Nate , Krainc Talia , Argue Benney , Zhang Ziyang , Xu Hang , Norman Jeanette , Castellani Rudolph J , Watson Thomas J , Chen Jinmiao , Nicoll James AR , Boche Delphine , Gate David 
Published: January 2025

AbstractBackgroundRecent advances in Alzheimer’s disease (AD) therapeutics involve immunization against amyloid‐β (Aβ). Post‐mortem brain analysis from the first active Aβ immunotherapy trial indicated clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain unknown.MethodHere, we utilized a novel spatial proteogenomics approach to study brain tissues from 13 AD patients immunized with Aβ. We compared these actively immunized patient brains to tissues from non‐immunized AD patients and non‐neurologic disease controls. Additionally, we used spatial proteogenomics and single‐cell RNA sequencing technologies to investigate the effects of lecanemab, a passive anti‐Aβ drug.ResultWe reveal the transcriptomic neuroimmune response in the Aβ plaque microenvironment following anti‐Aβ immunization. This response is characterized by an increase in genes associated with the TREM2‐APOE axis in microglia of the immunized AD cortex.ConclusionAltogether, our data uncover immediate and lasting neuroimmune responses in the AD brain induced by active and passive Aβ vaccination.
Association between telomere length and idiopathic normal pressure hydrocephalus: a Mendelian randomization study
Authors: Yang Feng , Cai Hanlin , Ren Meng Yi , Huang Keru , Gao Hui , Qin Linyuan , Wang Ruihan , Chen Ping Yong , Zhou Liangxue , Chen Qin 
Published: January 2025

AbstractBackgroundIdiopathic normal pressure hydrocephalus (iNPH) is highly prevalent among elderly individuals, and there is a strong correlation between telomere length and biological aging. However, there is limited evidence to elucidate the relationship between telomere length and iNPH. This study aimed to investigate the associations between telomere length and iNPH using the Mendelian randomization (MR) method.MethodThe genetic variants of telomere length were obtained from 472,174 UK Biobank individuals. Summary level data of iNPH were acquired from 218,365 individuals of the FinnGen consortium. Five MR estimation methods, including inverse‐variance weighting (IVW), MR‐Egger regression, weighted median, weighted mode and simple mode, were used for causal inference. Comprehensive sensitivity analyses were conducted to test the robustness of our results. In addition, multivariable MR was further implemented to identify potential mechanisms in the causal pathway from telomere length to iNPH.ResultGenetically determined longer telomere length was significantly associated with decreased risk of iNPH (OR = 0.44, 95% CI 0.24‐0.80; P = 0.008). No evident heterogeneity (Cochran Q = 138.11, P = 0.386) and pleiotropy (MR Egger intercept = 0.01, P = 0.514) were observed in the sensitivity analysis. In addition, multivariable MR indicated that the observed association was attenuated after adjustment for several vascular risk factors, including essential hypertension (IVW OR = 0.55, 95% CI 0.30‐1.03; P = 0.061), type 2 diabetes (IVW OR = 0.71, 95% CI 0.09‐5.39; P = 0.740) and coronary artery disease (IVW OR = 0.58, 95% CI 0.31‐1.07; P = 0.082).ConclusionOur MR study revealed a strong negative correlation of telomere length with iNPH. The causal relationship might be driven by several vascular risk factors.
Neurological, cognitive and psychiatric features of Primary Progressive Aphasia: a naturalistic study of a large cohort over 10 years
Authors: Tastevin Maud , Lavoie Monica , Laforce Robert 
Published: January 2025

AbstractBackgroundPatients with Primary Progressive Aphasias (PPAs) almost systematically inquire about the longitudinal evolution of their disease in clinics but very little research exists on the issue.MethodWe studied 82 PPA patients from the Research Chair on PPA – Fondation de la Famille Lemaire Cohort over a 10‐year span (42 logopenic, 21 non‐fluent/agrammatic and 19 semantic PPAs) and collected data from 5 domains (language, cognition, motor, psychiatric, functional) at 5 time points from onset to death. Logistical regression analyses and repeated measures ANOVAs were conducted to delineate the longitudinal profile of each variant PPA.ResultAll patients presented anomia and executive impairments over time. Language deficits tended to be more significant for lvPPA, particularly after 3 years of evolution and this group showed broader cognitive impairments. Psychiatric symptoms were more frequent in svPPA and nfvPPA, particularly after 5 years of evolution. Motor features predominantly affected patients with nfvPPA after 2 years of evolution. Overall functional abilities remained preserved the longest in svPPA (up to 5 years).ConclusionTo our knowledge, this naturalistic study on all major PPA symptoms over a 10‐year span from onset to death is the largest to date. Data from this study can help clinicians better inform and prepare their patients for future challenges as well as design more focused interventions.
Associations between 10‐year depressive symptom trajectories, cognitive function, and self‐management capacity skills among older primary care patients
Authors: Vogeley Abigail , Cecil Patrick , Opsasnick Lauren , Curtis Laura M , Yoshino‐Benavente Julia , Bonham Morgan , Russell Andrea , O'Conor Rachel , Wolf Michael S , Lovett Rebecca 
Published: January 2025

AbstractBackgroundChronic depression impacts the ability to successfully manage one’s health, yet mechanisms underlying this relationship are not fully understood. Cognitive dysfunction, or impairment, may result from persistent depression. We aimed to determine whether chronic depressive symptoms, leading to poor cognition, impacted self‐management capacity among older adults with chronic conditions.MethodData from 369 older adults from Chicago, IL and participating in a longitudinal cohort study on aging was used for this analysis. The Patient‐Reported Outcomes Measurement Information System (PROMIS) Depression 8‐item survey was administered across 4 time points over 10 years; raw scores were transformed into T‐scores. Group‐based trajectory modeling was used to identify latent depressive symptom trajectory groups. The Comprehensive Health Activities Scale (CHAS) was used to measure chronic disease self‐management skills, including comprehension and recall of print, spoken, and multimedia information. A factor score representing fluid cognitive function was derived from 11 measures across 4 cognitive domains (processing speed, working memory, inductive reasoning, long‐term memory). Demographic‐adjusted multinomial linear regressions were used to assess associations between depressive symptom trajectory groups and self‐management skills, first without and then including fluid cognitive function.ResultMean participant age was 71 years (SD 5.3); most participants were female (71%) and non‐Hispanic white (54%). 86% had 2+ chronic medical conditions (mean 3.3 (SD 1.8)). Three distinct depressive symptom trajectories emerged: participants displayed either consistently minimal (42%), normative (46%), or persistently elevated (12%) symptoms. In multivariable analyses, participants in the persistently elevated group had poorer self‐management performance (β = ‐6.4; 95% CI: ‐11.1, ‐1.7; p = 0.007). Adjusting for cognitive function attenuated this association to a level of non‐significance, while a strong association emerged between cognition and self‐management skills (β = 16.1; 95% CI: 14.4, 17.8; p<0.001).ConclusionPersistent depression may reduce self‐care capacity, likely due to poorer cognitive function. Improved understanding of how depression may alter cognitive function or lead to its progressive decline, and ultimately impact self‐care capacity, may inform future health system interventions to support the management of comorbid conditions.
Linguistically‐appropriate tools to assess cognition in Mandarin speakers
Authors: Hu William T. , Chen Michelle H. , Li Mei‐Ling , Su Guibin J , Lin Feng Vankee 
Published: January 2025

AbstractBackgroundAssessment of cognition in older Chinese Americans currently relies on content‐translated instruments with limited considerations for logographic (vs. alphabetic) nature of Chinese, cultural experience (pre‐ and post‐immigration), speech rate, and multilingualism. This results in confusion between fluency tasks, systematic error in digit span, disparate familiarity with stimuli according to country of origin (e.g., Taiwan vs. China), and low overall ecological validity. Here we developed and tested new instruments on memory (logical memory & word list learning), executive function (culturally‐appropriate Trail Making Test B), and language (fluency based on character, phoneme/pinyin, and homonym) to account for these factors.MethodBilingual (Mandarin and English, n = 50) and Mandarin‐only (n = 50) speakers were recruited in the NYC/New Jersey (Rutgers) and SF Bay (Stanford) areas. Bilingual adults completed both English and Mandarin cognitive testing for correlation, while monolingual speakers completed only Mandarin testing for reliability. Instruments in simplified and traditional Chinese were available for all, and each participant additionally underwent Clinical Dementia Rating, language proficiency(Mandarin, English), and brain MRI analysis.ResultParticipants had a median age of 66 yr (range 56‐84), and monolingual participants had been in the US for less than bilingual participants (33 vs. 42 yr, p = 0.004). New Mandarin tests had very high reliability (median Cronbach’s alpha of 0.935 range 0.807‐0.969). Among bilingual participants, performance in English and Mandarin for language‐independent tests (Trail Making Test A, written Symbol Digit Substitution Test) and some language‐dependent (e.g., animal fluency, Trail Making Test B) tests had acceptable to high reliability (standardized Cronbach’s alpha 0.638‐0.838). Total learning and delayed recall of corpus‐adjusted (based on word use frequency in American English and Beijing Chinese) also had high reliability (0.681 and 0.774) between languages, while character‐guided and animal fluency in Mandarin (0.560, p = 0.004) had similar correlation as English‐based letter‐guided and animal fluency (0.600, p = 0.005). Logical memory in English was associated with English proficiency and learning of a list of English words, but not logical memory in Mandarin.ConclusionMost novel Mandarin cognitive assessments showed high inter‐language reliability in bilingual older adults, and their diagnostic validity is being prospectively tested.
Whole‐brain Cellome‐Wide Association Study (CWAS) Unveils Ultra‐Early Neurodegeneration Phenomena in a 3D Spatial Cell Atlas
Authors: Mitani Tomoki T , Yamaura Kosei , Matsumoto Katsuhiko , Yamada Rikuhiro , Susaki Etsuo A , Ueda Hiroki R 
Published: January 2025

AbstractBackgroundIn aging societies, neurodegenerative diseases, such as Alzheimer’s disease, are receiving attention. These diseases are primary targets for preemptive medicine, emphasizing the importance of early detection and preventive treatment before the onset of severe, treatment‐resistant damages. However, there is a lack of comprehensive investigation of lesions and molecular targets in the entire organ, whereas spatial identification of early‐stage lesions is potentially overlooked at the single‐cell level.MethodHere, we propose a novel approach, CWAS (whole body/organ cellome‐wide association studies), which integrates and analyzes spatio‐temporal cellular information across the entire mouse organ into a comprehensive organ cell atlas using tissue‐clearing imaging technologies [1,2].ResultIn our initial application to neurodegenerative models, we have been able to identify previously unreported neural degenerations at specific times and locations at the single‐cell level. In addition, our time‐series analysis in a mouse model of Alzheimer’s disease revealed the possible simultaneous onset of amyloid deposition and neurodegeneration, challenging the traditional amyloid hypothesis. Furthermore, we were able to identify unique multicellular inflammation networks surrounding neurodegenerative lesions in several disease models.ConclusionOur findings establish the concept of “spatial cellomics” realized through spatially precise organ mapping and integrated multiomics analysis at the single‐cell level. This approach shifts pathology, providing deeper insight into disease mechanisms and preventive strategies.References[1] Murakami TC, et al. Nat Neurosci. 2018;21(4):625‐637.[2] Matsumoto K*, Mitani TT*, Horiguchi SA, et al*. (*equal contribution) Nat Protoc. 2019;14(12):3506‐3537.
Functional Capacity in Activities of Daily Living in the Alzheimer’s Disease Continuum
Authors: Henriquez Fernando , Dominguez Carmen , Grandi Fabrissio , Campo Cecilia Gonzalez , Contreras Patricio Riquelme , Lillo Patricia , Martínez‐Pernía David , Thumala Daniela , Henriquez Rodrigo , Aboitiz Francisco , Chonchol Andrea Slachevsky 
Published: January 2025

AbstractBackgroundThe most common and prevalent dementia worldwide is Alzheimer’s disease (AD). AD is a continuum composed of Subjective Cognitive Impairment (SCD), Mild Cognitive Impairment (MCI), and Alzheimer’s Disease dementia (ADD) stage. One of the main clinical variables in patients with dementia is performance in functional capacity since its alterations are associated with poor prognosis and disease progression. Functional capacity is measured through activities of daily living (ADL), which are divided into three domains: i) Basic (BADL), ii) Instrumental (IADL), and iii) Advanced (AADL). The study aimed to characterize the performance of the different stages of the AD continuum in the ADL domains and their association with cognitive abilities.MethodA cross‐sectional study of subjects at different stages of the AD continuum was conducted: Healthy Controls (CTR) (n = 17), SCD (n = 77), MCI (n = 30), and ADD (n = 23), who were matched for age, sex, and education. ADLs were estimated using The Technology‐Activities of Daily Living Questionnaire (T‐ADLQ), which assesses the three domains and a total score. T‐ADLQ performance was compared across groups and correlated with cognitive ability instruments (ACE‐III and IFS).ResultThe results showed that patients with ADD performed worse on the BADL, IADL, and total ADLs compared to the other three groups. There were no significant differences between the CTR, SCD, and MCI on the BADL, IADL, and total ADLs. However, the AADL, in addition to differentiating the ADD patients from the other three groups, also showed differences between CTR and MCI subjects and between SCD and MCI subjects (Table 1 and Figure 1). The correlation study showed that AADL correlated significantly with global cognitive and executive function assessment (Figure 2).ConclusionAADL shows progressive functional impairment at different stages of the AD continuum, which is further associated with global cognitive and executive function performances. As one progresses to a more advanced stage of the disease continuum, the performance of ADLs, especially AADLs, worsens, which could indicate a marker of disease progression, allowing for better patient follow‐up.
Can Butyrate offer a novel approach to mitigate the pathology of AD?
Authors: Fernando Warnakulasuriya Mary Ann Dipika Binosha , Martins Ian J , Senerath Uththara , Bharadwaj Prashant , Martins Ralph N 
Published: January 2025

AbstractBackgroundOur research group is currently exploring the potential of Butyric acid (NaB), a Short Chain Fatty Acid (SCFA), as a novel therapeutic agent for Alzheimer’s disease (AD).MethodsIn our investigation using the 5xFAD mouse model of AD, we observed that NaB had significant effects on Aβ levels, as well as on associative learning and cognitive functioning. Notably, we recorded a 40% reduction in brain Aβ and a 25% increase in fear response during both cued and contextual testing. Our studies employing M17 cell models demonstrated that butyrate provides a degree of protection against Aβ‐induced toxicity. Additionally, nanoindentation studies confirmed that butyrate induces changes in cell physiology. Building on these findings, we explored the impact of butyrate on astrocytes and microglial cells concerning amyloid beta toxicity.ResultsCurrent studies with stem cells have exhibited promising outcomes, indicating that butyrate significantly alleviates amyloid beta.ConclusionsThis investigation represents the initial confirmation of butyrate as an amyloid beta inhibitor across various Alzheimer’s disease (AD) models. The subsequent steps involve determining the levels of butyrate at different stages of AD by analyzing fecal samples and conducting tests to assess its therapeutic efficacy.
Serial order and complexity of Category Fluency words in an Italian cohort of MCI individuals
Authors: De Marco Matteo , Da Ronch Chiara , Venneri Annalena , Gallucci Maurizio 
Published: January 2025

AbstractBackgroundThe Category Fluency Test (CFT) is the most widely‐used test of semantic memory (SM). A number of studies indicate that the serial order (SO) in which words are generated during the CFT can be informative of the underlying level of SM integrity. In this study, SO and item‐level complexity of CFT words were investigated for the first time in a cohort of Italian individuals with mild cognitive impairment (MCI).MethodThe CFT (category: animals) was administered to 60 MCI individuals recruited as part of the TREviso DEMentia (TREDEM) registry and to 54 matched healthy controls. Each CFT word was scored according to its graphemic length its typicality within the cohort and, as per Italian normative values, also according to its frequency of use and age of acquisition. Rank‐based correlations were calculated for each individual between SO and each item‐level feature and z‐converted for data analysis. One‐way ANOVAs were then run to compare these correlational indices between the two groups, controlling for age, education and sex.ResultA significant between‐group difference emerged from the analysis of the SO‐word length correlational index (p < 0.004). Both groups tended to generate increasingly longer words during CFT performance, but in the MCI group this increase was significantly steeper.ConclusionWhile word length does not embed any semantic information, these findings indicate that the graphemic length‐based organisation of lexical‐semantic material during recall is altered in native Italian‐speaking MCI individuals.
Sleep experiences and longitudinal brain changes in cognitively normal older adults
Authors: Choi Jung‐Min , Byun Min Soo , Yi Dahyun , Jung Joon Hyung , Sohn Bo Kyung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Lee Dong Young ,   KBASE Research Group
Published: January 2025

AbstractBackgroundDisturbed sleep has been associated with Alzheimer’s disease (AD) dementia. Nevertheless, limited information is yet available for the relationship between sleep experiences and longitudinal changes of brain pathologies related to AD. This study aimed to investigate the association between late‐life sleep experiences and the prospective changes of in vivo AD pathologies and cerebrovascular injury over 2 years in cognitively normal (CN) old adults.MethodA total of 225 CN older adults who participated in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) study between 55 and 90 years of age were included. All participants were also systematically interviewed using a structured interview form to determine sleep duration and subjective sleep quality at baseline. All of them underwent a comprehensive clinical assessment, [11C] Pittsburgh Compound B positron emission tomography (PET), [18F]fluorodeoxyglucose (FDG)‐PET, and magnetic resonance imaging at baseline and 2‐year follow‐up. A subset of participants (n = 44) also underwent [18F]AV‐1451 PET at baseline and 2‐year follow‐up. All analyses were adjusted for age, gender, education, apolipoprotein E ε4 status, vascular risk score, Hamilton Depression Rating Scale score, and use of sleep medication.ResultPoor sleep quality at baseline was significantly associated with both higher baseline global Aβ retention and its longitudinal increase over 2 years, but not with other AD neuroimaging markers including tau deposition, AD‐related neurodegeneration, and white matter hyperintensity (WMH) volume. There was no significant relationship of sleep duration with any AD neuroimaging markers and WMH volume.ConclusionOur findings suggest that poor sleep quality in late life may predict or contribute to prospective increase of brain amyloid deposition in the near future.
A nano‐ to microscale, complex and multifactorial computational model of Alzheimer’s disease
Authors: Duchesne Simon , Chamberland Éléonore , Moravveji Seyedadel , Doyon Nicolas 
Published: January 2025

AbstractBackgroundWhile individual etiological hypotheses for AD are researched, few large‐scale theoretical integrative efforts linking entities involved in these dysfunctions have been attempted. Experimentally, assessing such a global theory is logistically near impossible to achieve as the number of variables is substantial. Alternatively, computational neuroscience allows for the joint study of multiple entities at this scale, the generation of predictions, and their validation with real data. In this work, we present a theoretical computational model describing the progression of AD through an individual’s lifespan covering more than 50 different entities.MethodOur computational model is a system of 19 ordinary differential equations (cf. Figure 1). The equations describe the evolution of proteins at the nanoscale (Aβ monomers, oligomers and plaques; tau filaments and tangles, anti‐inflammatory cytokines, insulin) and cell populations at the microscale (neurons, astrocytes, macrophages, microglia). Equations were parametrized according to sex and APOE status, and initial conditions chosen from the literature. Our key outcomes of interest were the accumulation of recognized pathological markers of AD (Aβ monomers or plaques, tau filaments or tangles) and neuronal death. The model was solved in daily increments over a 50‐year lifespan.ResultsThe evolution of every variable of our model is shown in Figure 2. For the different forms of amyloid, the curves for APOE4‐negative men and women mostly overlap. This is also observed for APOE4‐positive individuals. However, it is important to note that despite the overlap, there are noticeable variations in the curves between different groups. Neuronal loss occurs earlier in individuals with an APOE4 allele regardless of sex. We obtain losses of 10.9% and 11.7%, for APOE4‐ and APOE+ women respectively, and of 10.9% and 12.1% for APOE4‐ and APOE4+ men respectively, which are commensurate with the literature. We also observe a transition to a proinflammatory state occurring around 50 years of age, with women who are APOE4+ experience this transition earlier, followed by APOE4+ men, APOE4‐ women, and finally APOE4‐ men.ConclusionComputational models represent an essential initial step toward constructing a complex, predictive framework, and hold significant potential for identifying effective therapeutic targets in the fight against AD.