bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of α5 integrin in endothelial cells ameliorates age–associated cognitive decline and increases survival in mice
Authors: II Gregory W Hall , Ismael Saifudeen , Bix Gregory J 
Published: January 2025

AbstractBackgroundLevels of inflammatory components gradually rise in tissues and blood as we age. This “inflammageing” process is often debilitating and even fatal. Cognitive impairment is one example of inflammageing’s incapacitating nature. Excessive permeation of inflammatory markers in the brain gradually erodes the blood‐brain barrier (BBB) over time. Consequently, enhanced cerebral inflammatory processes contribute to neurological senescence. Neurological inflammageing may be partly due to α5 integrin, a receptor found primarily in brain endothelial cells during brain development, cerebrovascular injury (e.g. stroke), neuroinflammation and neurodegenerative disease (e.g. ALS). We hypothesize that deletion of α5 integrin in endothelial cells helps maintain BBB integrity and leads to improved cognitive performance with age. In the past we have shown that endothelial cell selective α5 knockout (α5‐EC‐KO) mice are more resilient to ischemic stroke. Enhanced stroke recovery in α5‐EC‐KO mice is due to less α5‐related BBB deterioration and subsequently less brain edema and infiltration of peripheral inflammatory cells. Therefore, we used aged α5‐EC‐KO and wild type (WT) litter mate mice to investigate how α5 integrin influences cognitive performance and survival probability over time.Methods25‐32‐month‐old male and female α5‐EC‐KO mice and aged‐matched WT mice were used in the study. Cognitive function was analyzed using Y‐maze and open field. Additionally, Kaplan Meier curves were used to assess probability of survival.ResultsFor Y maze, results indicate a trend towards greater alteration rate and total alteration for α5‐EC‐KO mice. Open field test shows greater center time and less peripheral time for α5‐EC‐KO. WT and α5‐EC‐KO mice have nearly identical mean speed. Additionally, Kaplan‐Meier curves indicate a greater probability of survival for α5‐EC‐KO mice between the ages of 26 to 30 months. Interestingly, 26‐30 months is the average life expectancy of a lab mouse.ConclusionsObservations from Y maze and open field tests suggest that α5‐EC‐KO mice have improved spatial memory and less anxiety behavior when compared to aged‐matched WT mice. Moreover, the Kaplan‐Meier curves depict a greater probability of survival for aged α5‐EC‐KO mice. Thus, α5 integrin expression may significantly influence age‐related cognitive decline. Preliminary data suggests that inhibition of α5 integrin may improve symptoms of age‐associated cognitive impairment.
The pTau217 interactome in human Alzheimer’s disease brain tissue from APOE3 and APOE4 carriers
Authors: Kavanagh Tomas , Ponce Jackeline , Thierry Manon , Ueberheide Beatrix , Wisniewski Thomas , Drummond Eleanor 
Published: January 2025

AbstractBackgroundHyperphosphorylated tau (pTau) in Alzheimer’s disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated on up to 55 epitopes. Emerging studies suggest that phosphorylation of specific epitopes may alter the role of tau. The role of specific pTau species can be explored through protein interaction (“interactome”) studies. These provide knowledge about the role of individual pTau species and critical context for tau‐focused biomarker and drug‐discovery studies. The aim of this study was to analyse the interactome of pTau217, which biomarker studies suggest is one of the earliest accumulating tau species in AD.MethodspTau217 interactors were identified in fresh‐frozen human brain tissue from 10 cases of advanced AD using affinity purification‐mass spectrometry. Cases were balanced for ApoE ε3/ε3 and ε4/ε4 genotypes (n = 5 each) to explore if ApoE influences pTau protein interactions. Results were compared to our previous pTauS396/S404 interactome dataset generated using the same cases to determine if individual pTau species have different interactomes.Results579 proteins were significantly enriched by pTau217 co‐immunoprecipitation in comparison to control IgG (p < 0.05; fold change >1.5). Of these, 23 proteins were identified as bona fide pTau217 interactors (SAINT score > 0.65), including known pTau interactors SQSTM1 and ubiquitin. Phosphorylation analysis of tau enriched by pTau217 vs pTau396/S404 co‐immunoprecipitation confirmed enrichment of a different pools of tau, with pTau217 displaying fewer phosphorylated epitopes, hinting that pTau217 may be an earlier generated species. Despite these differences, 15 bona fide pTau217 tau interactors also interacted with pTauS396/S404 suggesting close similarities in interactomes (Fisher’s exact p = 2.3 × 10‐14). Common interactors notably included five subunits of an E3 ubiquitin ligase not previously been linked to tau or AD. 46 and 28 pTau217 interactors were identified in ApoE ε3/ε3 and ApoE ε4/ε4 cases respectively and these significantly overlapped (16 common interactors; Fisher’s exact p = 4.3 × 10‐24).ConclusionspTau217 interacts with many similar proteins to pTauS396/S404. Our results highlight a strong interaction between multiple pTau species and a novel E3 ubiquitin ligase, which may have an important role in AD and potentially tau degradation.
Disrupted Sleep at Night Is Associated with a Higher Level of Agitation Throughout the Week in People Living with Cognitive Decline
Authors: Au‐Yeung Wan‐Tai M. , Miller Lyndsey M. , Lindauer Allison , Beattie Zachary T , Mattek Nora , Steele Joel S. , Kaye Jeffrey A 
Published: January 2025

AbstractBackgroundAgitation is one of the most challenging behaviors exhibited by people with cognitive decline, causing distress in caregivers, earlier placement into long‐term care and faster disease progression. In order to better manage agitated behaviors in people with cognitive decline, it is important to identify associated factors. The MODERATE (Monitoring Dementia‐Related Agitation Using Technology Evaluation) study aims to characterize agitation using technology and identify precipitants (behavioral or environmental) of agitation.MethodPeople living in the greater Portland, Oregon, USA area were recruited into the study. The inclusion criteria were a diagnosis of mild cognitive impairment or dementia, currently residing with a family caregiver within their own home, and caregiver endorsement of symptom(s) of agitation, irritability/lability, motor disturbance, nighttime behaviors and/or disinhibition in the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q). Bed pressure mats (Emfit) were deployed as part of the ORCATECH platform in their homes, which measure participants’ sleep behaviors and their physiological signals through ballistocardiography. The weekly agitation levels of the participants were reported by their family caregivers through modified Cohen‐Mansfield Agitation Inventory‐Short Form questionnaires as part of weekly online surveys.ResultData from the first 8 participants (mean age(SD) = 70 (10)) with bed pressure mats were analyzed. A subset of bed pressure mat outputs was selected to provide a holistic picture of participants’ sleep behaviors and their physiology while avoiding multicollinearity. Monitoring period was for a mean (SD) of 315 (190) nights. An individual mixed linear model was built with each included bed pressure mat output and week as the predictors and total agitation level as the model output. After false discovery rate correction, higher duration of wake after sleep onset was a significant predictor of their weekly total level of agitation. The caveats of these results include small sample and varied follow‐up time ranging from 4‐85 weeks of observations per participant.ConclusionDisrupted sleep (measured objectively by bed pressure mat) are positively associated with participants’ weekly level of agitation. Future work with larger sample sizes is needed to confirm findings. Unobtrusive identification of behavioral factors associated with agitation can potentially help manage this challenging behavioral symptom.
Association between mediterranean‐like diet, longitudinal cognitive decline, and medial temporal atrophy over time in cognitively unimpaired older adults with or without SCD
Authors: Kuhn Elizabeth , van Lent Debora Melo , Stark Melina , Kleineidam Luca , Yakupov Renat , Peters Oliver , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Düzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Jessen Frank , Wagner Michael ,   for the DELCODE study group
Published: January 2025

AbstractBackgroundPrevious findings evaluating longitudinal cognition in relation to the MeDi diet are inconsistent, and few studies have examined it in relation to the presence/absence of subjective cognitive decline (SCD). Our current aims are to test whether adherence to the MeDi diet is associated with the risk of clinical progression, future cognitive decline, and atrophy over time in Alzheimer’s disease (AD)‐sensitive regions in cognitively unimpaired (CU) older adults with or without SCD.MethodsThis longitudinal study includes 171 controls and 228 SCD patients recruited from memory clinics in the DELCODE study. All participants underwent serial neuropsychological assessments and MRI scans for up to 7 years, and had available MeDi adherence scores based on the clustered Food Frequency Questionnaire (range: 0‐9). Clinical progression to incident‐MCI status was determined by consensus diagnosis, global cognitive decline was assessed using the PACC5 cognitive composite, and medial temporal lobe (MTL) gray matter volume was estimated using the Freesurfer longitudinal pipeline. We used multivariate Cox regression and linear mixed‐effects modeling to address our objectives. Gray matter volumes were corrected for total intracranial volume, and all analyses were adjusted for demographics.ResultsIn SCD patients, we found that higher adherence to the MeDi diet was associated with a lower risk of clinical progression to incident‐MCI (Fig. A2), and less global cognitive decline (Fig. B2), and MTL atrophy over time (Fig. C2; mainly driven by less parahippocampal and amygdala atrophy). Higher adherence to the MeDi diet was also associated with better baseline cognition and MTL volumes in these patients. This was not significant in the HC group (Fig. A1‐C1), possibly because they experienced less cognitive decline over time than the SCD group (both p<0.001; not significant for MTL atrophy). Further adjustment for kcal intake, body mass index, and physical activity yielded similar results, although sometimes only at trend levels.ConclusionIn SCD patients seeking medical help, better adherence to a MeDi diet pattern may reduce future cognitive decline and MTL atrophy. These novel data provide a rationale for dietary intervention studies in this population, and support counseling SCD patients on the benefits of MeDi (and other lifestyle factors) for cognitive health.
Abnormal cortical neural synchronization mechanisms in quiet wakefulness in patients with Symptomatic Huntington and Dementia due to Alzheimer’s disease
Authors: Jakhar Dharmendra , Tucci Federico , Noce Giuseppe , Lopez Susanna , Lizio Roberta , Percio Claudio Del , Carpi Matteo , Salamone Enrico Michele , Güntekin Bahar , Yener Görsev , De Tommaso Marina , Delussi Marianna , Babiloni Claudio 
Published: January 2025

AbstractBackgroundHuntington’s disease (HD) is a progressive neurodegenerative disorder phenotypically manifested by motor, cognitive and psychiatric symptoms (Novak and Tabrizi, 2011). These patients are also characterized by vigilance abnormalities. This has been demonstrated by electrophysiological measures (Wiegand et al., 1991). In particular, previous studies have shown that HD patients have reduced alpha amplitude (de Tommaso et al., 2003; Bellotti et al., 2004) and increased resting delta activity (Bylsma et al., 1994). These electroencephalographic changes resemble those observed in patients with Alzheimer’s dementia (Babiloni et al., 2020). To date, there have been only a few studies on the specific pathophysiological changes that are the cause of the above changes in brain rhythms. In our opinion, the comparison of these two populations could be an enrichment of the physiological model that explains the electroencephalographic changes that have been observed in HD patients.MethodClinical and EEG datasets in 21 ADD (Dementia due to Alzheimer Disease), 16 S‐HD (Symptomatic Huntington Disease) and 39 Healthy (Nold) individuals matched for demography, education, and gender were taken from an Eurasian database. The rsEEG frequency bands were individual delta, theta, alpha as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz). The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions.ResultAs core findings, we have showed that global delta source activities (and central, parietal, and occipital delta source activity) are significantly greater in S‐HD than in ADD (p<0.05 Bonferroni corrected) and that frontal and temporal alpha 2 source activities are significantly lower in S‐HD than in ADD (p<0.05 Bonferroni corrected) Showed in Figure 1.ConclusionThe present findings showed more abnormalities in delta source activities in HD patients if compared to the ADD patients, possibly related to an abnormal functioning of dopaminergic ascending neuromodulation of basal ganglia in HD subjects. Moreover, the HD peculiar alterations in alpha source activities could be related to more alterations in the cholinergic system impinging upon basal ganglia if compared with ADD patients.
Diversity in Sociodemographic and Linguistic landscape: Perspectives from Chinese American, Mexican American, and Indian Cohorts
Authors: Tee Boon Lead , Alladi Suvarna , Thanissery Nithin , Babulal Ganesh M. , O'Bryant Sid E. , Petersen Melissa , Allen Isabel Elaine 
Published: January 2025

AbstractBackgroundNearly half the world’s population is bi‐ or multilingual, where diverse interpretations of bilingualism with varying associated sociodemographic factors may lead to inconsistent conclusions in bilingualism and cognitive research and thus our study aimed to further examine this.MethodWe examined the sociodemographic features and bilingualism phenotypes among monolingual and bilingual individuals across three cohorts: Chinese American (CA) from UCSF Memory and Aging Center (n = 517), Mexican American (MA) from HABS‐HD project (n = 1,166), and Indians (ID) from National Institute of Mental Health and Neuroscience (NIMHANS) (n = 1,233), encompassing individuals with normal cognition, mild cognitive impairment (MCI), and Alzheimer’s dementia (AD). We compared group differences between monolinguals and bilinguals via Student’s t‐test for continuous variables and with Pearson’s Chi‐squared test for categorical variables. Group comparison of bilingualism phenotypes across cohort were analyzed using ANOVAs for continuous variables (with Bonferroni correction for multiple comparisons).ResultEducational disparities were significant between monolinguals and bilinguals across all cohorts (all p<0.001), with the exception of MCI (monolinguals: 8 ±1.8 years, bilinguals: 9.6 ±6.3 years, p = 0.104) and AD groups (monolinguals: 4.4 ± 6.7 years, bilinguals: 5.5 ± 6.1 years, p = 0.722) at NIMHANS. Notably, a greater prevalence of illiteracy among monolinguals emerged in the NIMHANS (monolinguals: 10%, bilinguals: 2%, p<0.001) and HABS‐HD cohorts (monolinguals: 4%, bilinguals: 2%, p = 0.034), a trend absent in the UCSF group (monolinguals: 0%, bilinguals: 0%). In HABS‐HD, monolinguals with normal cognition (p<0.001) or MCI (p = 0.019) resided in neighborhoods with greater deprivation, whereas those in NIMHANS control group indicated lower socioeconomic status in monolinguals (p<0.001), a distinction not found in UCSF. Additionally, bilinguals in the UCSF CA and NIMHANS ID cohorts were observed to speak a greater number of languages (p<0.001) that largely belonging to different language families. Naturally, when examining the maximum spoken language distance of bilingual participants, UCSF CA and NIMHANS ID bilinguals had significantly higher language distances compared to bilinguals in the HABS‐HD cohort (p<0.001).ConclusionThese findings emphasize the diverse bilingualism phenotypes and associated sociodemographic factors within distinct populations and underscore the imperative need for a comprehensive characterization of language history in bilingualism research.
Enhancing Cognitive Health in Aging through New Language Acquisition: Insights from Behavioral and Neuroimaging Studies
Authors: Saidi Ladan Ghazi 
Published: January 2025

AbstractBackgroundI will look at the impact of new language acquisition on cognitive performance and reserve in older adults, an area not extensively explored in contrast to the well‐documented cognitive benefits in lifelong bilinguals. Previous research has shown that lifelong bilingualism may enhance cognitive reserve, evidenced by better performance on specific tasks of executive function, reflecting superior cognitive control and interference management in aging (Van den Noort, et al., 2019). Drawing on the cognitive demands of language learning, which include executive functions such as inhibition, selection, and conflict management (Ghazi Saidi et al., 2013; 2017a; 2017b), we and others hypothesize that new language learning in older adults can boost these cognitive processes, which often decline with age (Albinet, et al., 2012; Lee & Chung, 2012).MethodIn the past five years, we and others have conducted a series of behavioral and neuroimaging studies to address the gap in understanding the effects of language learning later in life, particularly as a potential non‐pharmaceutical intervention to enhance cognitive health in aging. In this presentation, I will review these studies and will present our new findings.ResultsWe are others bring evidence that Language learning in older adults can enhance cognitive control, as evidenced by improved performance on domain specific tasks such as the Stroop task, as well as global cognition and is associated with functional neuroplasticity in brain areas responsible for cognitive control (Kliesch, et al.,2018; Meltzer, et al., 2023; Nilsson, et al., 2021; Bubbico, et al., 2019; Wong, et al., 2019. These results suggest that new language acquisition in monolingual older adults may improve cognitive reserve and contributes to overall cognitive health, potentially slowing the progression of cognitive decline.ConclusionThus, learning a new language may represent an accessible and cost‐effective cognitive intervention in aging, though the effectiveness is influenced by the intensity and duration of the learning experience.
The role of impaired oxidative base lesion repair in Alzheimer’s disease
Authors: Egiazarian Milena A , Abentung Andreas , Sakshaug Teri S , Karabeika Emily E , Hanumaihgari Priyanka R , Grøntvedt Gøril Rolfseng , Sando Sigrid B , Bjørås Magnar , Scheffler Katja 
Published: January 2025

AbstractBackgroundAccumulation of oxidative DNA damage and its inefficient repair is a contributing factor to Alzheimer’s disease (AD), yet the underlying mechanism remains largely unknown. Novel AD mouse models deficient for oxidative DNA damage repair were developed and characterized to better understand their impact on AD progression. In addition, vascularized cerebral organoids from AD patients were generated to translate findings to a human model of AD.MethodAD mice deficient for oxidative DNA repair enzymes were collected at different ages and amyloid β (Aβ) accumulation quantified by enzyme‐linked immunosorbent assays and immunostaining. Astrocytes and microglia numbers were quantified by immunostaining and inflammatory responses determined by gene expression analyses. DNA damage was measured by mass spectrometry and immunostaining of DNA damage marker. Behavioral analyses were performed to assess cognitive function. Cerebral organoids were fused with vessel organoids generated form AD patients and healthy controls. Vascularization and AD pathology was determined by immunostaining of specific vessel marker and mesoderm‐derived microglia, and Aβ and neuronal marker, respectively.ResultAβ accumulation was significantly altered upon loss of oxidative DNA repair in AD mice in an age‐ and sex‐dependent manner. Microglia and astrocyte number changed significantly during disease progression and were either reduced or increased dependent on the oxidative DNA repair enzyme deficiency and sex of the mice. Level of DNA damage in the brain was only moderately increased or not affected. Cognitive function was significantly impaired in AD mice deficient for oxidative DNA repair enzymes. Cerebral organoids fused with vessel organoids developed vascular structures and showed integration of microglia cells. Aβ accumulated specifically in AD patient‐derived organoids compared to healthy controls and showed signs of neurodegeneration.ConclusionThe repair of oxidative DNA damage is critical for processes associated with AD pathogenesis, in particular neuroinflammation and important to maintain cognitive function. AD patient‐derived vascularized cerebral organoids are immunocompetent and recapitulate AD pathology which will be advantageous to translate findings from mice to humans.
Multiple pathological mechanisms of Bin1 for tau aggregation and propagation
Authors: Tomita Taisuke 
Published: January 2025

AbstractBackgroundRecent genome‐wide association analysis has identified Bridging Integrator 1 (BIN1) as one of the genetic risk factors for late‐onset AD. In AD patients, single nucleotide polymorphisms in BIN1 correlate well with tau pathology, suggesting the involvement of BIN1 in the formation and propagation of tau accumulation pathology, but the molecular mechanism and point of action remain unclear.MethodTo comprehensively clarify the effects of BIN1 on two pathological events, tau aggregation and propagation, we analyzed BIN1 knockout mice.ResultUsing transgenic mice and seed injection model, we found that BIN1 knockout facilitated the cell‐autonomous tau accumulation in neurons but reduced the tau pathology induced by extra‐neuronal tau seeds. In the primary neuron‐glia co‐cultures, but not neuronal cultures, BIN1 knockout accelerated the degradation of the extracellular tau seeds. The present study suggested that BIN1 has different effects on tau metabolism in neurons and glial cells; the loss‐of‐function of BIN1 promotes the aggregation and accumulation in neurons, while BIN1 knockout enhanced the degradation mechanism of tau in glial cells.ConclusionThe present study implicates that BIN1 has different effects on tau metabolism in neurons and glial cells.