bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Canadian Multi‐Ethnic Research on Aging (CAMERA) Study: Objectives and Design
Authors: Marawi Tulip , Rai Harleen , Nyman Alexander J , Gopinath Georgia , Alexander Madeline Wood , Yep Rachel , Boshmaf Silina Z , Munoz Douglas P , Swardfager Walter , Black Sandra E , Goubran Maged , Rabin Jennifer S 
Published: January 2025

AbstractBackgroundDespite being among the fastest‐growing ethnoracial groups in Canada and the United States, individuals of Asian descent are significantly underrepresented in research on Alzheimer’s disease and related dementias (ADRD). Limited evidence suggests a lower incidence of dementia among Asian Americans compared to their White counterparts; however, there is variability in risk factors among Asian American subgroups. Understanding this heterogeneity is crucial for tailoring dementia prevention and intervention strategies in Asian populations. To address this gap, we launched the CAnadian Multi‐Ethnic Research on Aging (CAMERA) study in Toronto, Canada.MethodCAMERA is a 5‐year longitudinal observational study based at Sunnybrook Health Sciences Centre in Toronto, Canada. CAMERA aims to enroll 300 cognitively unimpaired adults aged 55‐85 who self‐identify as South Asian, Chinese, or non‐Hispanic White (n = 100/group). Participants are recruited from the greater Toronto area using culturally appropriate, community‐based participatory approaches. We formed a community advisory board (CAB) comprising community members who share the same identity, language, culture, and values as CAMERA participants. The CAB actively engages in the research process, participant recruitment, research questions, and knowledge translation. In terms of the study protocol, at baseline (Year 1), Year 3, and Year 5, participants complete clinical, cognitive, brain MRI, blood (for genetic and biomarker analysis), and language‐ and culturally neutral eye‐tracking assessments. Every year, participants complete a series of questionnaires via REDCap covering demographic, community, cultural and social, mental and physical health, and sex‐specific health factors.ResultAs of April 2024, we have enrolled 131 participants. Of those, 92 participants completed baseline Year 1 testing. Of the 92 participants, 31 (33.7%) self‐identified as South Asian, 36 (39.1%) as Chinese, and 25 (27.2%) as non‐Hispanic White. Participants have a mean age of 68.1 years (SD = 6.2), and are mostly female (62 (67.4%)).ConclusionTo our knowledge, this will be the first longitudinal cohort study that brings together sensitive brain imaging tools, novel blood‐based markers, and comprehensive cognitive data to investigate ADRD risk in understudied Asian subgroups. This research will yield currently unavailable data to inform the development of precision strategies to prevent and delay ADRD in Asian and other populations.
Sex differences in the association between depression and dementia
Authors: Jahng Anna , Kang Jaemyeong 
Published: January 2025

AbstractBackgroundSex differences in the association between depression and dementia have been reported with inconsistent results. This study aims to explore sex differences in the relationship between dementia and depression, using the history of major depressive disorder (MDD) and Centre for Epidemiological Studies Depression Scale (CES‐D‐10) as measures.MethodUtilizing data from the 8th wave of the Korean Longitudinal Study of Aging (KLoSA) conducted in 2020 with 5717 participants, we investigated the sex effect on the association between various measures of depression and history of dementia using binary logistic regression. Two depression history variables (‘Felt MDD’ and ‘Treated for MDD’ in the last two years) and one depressive symptom variable (CES‐D‐10) were used as independent variables. Subgroup analyses in each sex group were explored. All analyses were adjusted for age, education, current smoking and alcohol consumption, regular exercise, and history of cerebrovascular disease and psychiatric disorder. Additionally, Area Under the Receiver Operating Characteristic (AUROC) analyses were performed to investigate the predictive power of CES‐D‐10 for dementia.ResultNo significant differences were observed between males and females for the prevalence of ‘Felt MDD,’ ‘Treated for MDD,’ CES‐D‐10 score, and history of dementia. While significant sex (female) interaction was detected in the association between ‘Felt MDD’ and dementia (Odds Ratio [OR] 2.103, 95% Confidence Interval [CI] 1.430 – 3.094) and between CES‐D‐10 and dementia (OR 1.039, CI 1.017 – 1.061), no significant sex interaction was found in the association between ‘Treated for MDD’ and dementia (OR 1.713, CI 0.937 – 3.310). Subgroup analyses revealed a significant association between ‘Treated for MDD’ and dementia (OR 10.142, CI 2.753 – 37.358) in males. In females, ‘Felt MDD’ (OR 3.142, CI 1.296 – 7.614) and CES‐D‐10 (OR 1.092, CI 1.032 – 1.157) showed significant association with dementia. Also, CES‐D‐10 demonstrated higher AUC predicting dementia in females (0.705) compared to males (0.666) or both sexes combined (0.692).ConclusionA greater association was found between depression and dementia in the female group compared to the male group. This might imply that sex plays a role in the association between depression and dementia.
A cognitive resilience gene expression signature in excitatory intratelencephalic cortical neurons
Authors: Fish Lauren A , Telpoukhovskaia Maria , Algoo Jonathan , Hadad Niran , Gurdon Brianna , Dai Miko , Ouellette Andrew R , Neuner Sarah M , Dunn Amy R , Willcox Jon A. L. , Wu Yiyang , Dumitrescu Logan C. , Bellur Orhan , Zhang Jigang , O'Connell Kristen MS , Dammer Eric B. , Seyfried Nicholas T , Muzumdar Sukalp , Gillis Jesse , Robson Paul , Arnold Matthias , Hohman Timothy J , Philip Vivek M. , Menon Vilas , Kaczorowski Catherine C. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a devastating form of dementia, and its prevalence is rising as human lifespan increases. Our lab created the AD‐BXD mouse model, which expresses AD mutations across a genetically diverse reference panel (BXD), to identify factors that confer resilience to cognitive decline in AD. This model mimics key characteristics of human AD including variation in age of onset and severity of cognitive decline.MethodTo facilitate discovery of conserved mechanisms of resilience to AD, we generated a cross‐species single‐nuclei transcriptomic dataset from normal and AD human (ROSMAP) and AD‐BXD mouse frontal cortex tissue. We interrogated resilience‐associated gene expression signatures, validated resilience candidate genes with human reference data, and used a druggability ranking and drug repositioning pipeline to nominate drugs to promote resilience to AD. To learn more about the context of resilience gene expression, we used a hierarchical mapping algorithm to predict anatomical locations of cells expressing resilience gene signatures.ResultWe found the strongest gene expression signature associated with cognitive resilience to AD arises from excitatory layer 4/5 (eL4/5) cortical intratelencephalic neurons. This resilience signature includes genes involved in synaptic plasticity, vesicle transport, and axonal and dendritic development. We found that 27 of the 61 genes in the resilience signature are druggable and identified several candidate drugs for further investigation (Telpoukhovskaia et al., 2022). We also identified genes expressed across a continuum of cognitive performance. Our hierarchical mapping approach showed that the eL4/5 neurons expressing resilience signature genes are distributed throughout the frontal cortex, mainly in the somatomotor area.ConclusionWe identified 61 candidate resilience genes to target with new or existing drugs. We also determined that expression of resilience candidate genes occurs in eL4/5 neurons in the somatomotor region of the cortex. Ongoing projects in the lab aim to evaluate efficacy of nominated drugs and profile learning‐specific proteomes of eL4/5 neurons in resilient and susceptible AD‐BXD strains. When integrated with existing genetic, behavioral, and pathological data, our work will elucidate the cellular, molecular, and genetic mechanisms that contribute to cognitive resilience in face of neurodegenerative disease pathology.
A Literature Review of Randomized Controlled Trials for Hospice‐eligible Patients Living with Dementia and Agitation
Authors: Wang YuHsuan (Olivia) , Fritts Arianne , Molina‐Henry Doris P. , Grill Joshua D , Mintzer Jacobo , Raman Rema 
Published: January 2025

AbstractBackgroundMost hospice‐eligible patients with dementia report agitation with antipsychotics and antidepressants with major side effects predominantly used in this population to control symptoms. Little is known about current evidence on randomized controlled trials (RCTs) on reducing agitation in this population.ObjectivesWe aimed to summarize and evaluate the existing literature on RCTs aimed at reducing agitation among hospice‐eligible patients with dementia.MethodsWe conducted a literature review using the following keywords (end‐of‐life, late‐stage dementia, agitation, terminal restless, terminal delirium, randomized controlled trials) on MEDLINE, Pubmed, PyscINFO, Proquest, CINAHL, EBSCO, EMBASE, Cochrane Library, and references of previous publications. This review considered English language RCTs and review articles on RCTs that focus on interventions for reducing agitation among patients who were terminally ill, reported symptoms of agitation, and were diagnosed with dementia.ResultsThe search included published articles from January 1990 to February 2024. Forty‐four articles were identified. Of these articles, sixteen RCTs did not include terminally ill patients with dementia and agitation; seventeen did not focus on reducing agitation; four were not completed trials, two were written in German, and one could not be retrieved. Of the four relevant articles included in this review, three tested a nonpharmacological intervention and one tested a pharmacological intervention. The sample sizes in all four studies were small: ranging from 30 to 90 participants. Of the three studies that reported race, more than 75% of participants were White. None of the studies reported Latino ethnicity. Only one study could apply to the last five‐year period, but the use of agitation reduction was the secondary outcome of the study. No interventional trials with a pharmacological approach have been reported in the previous twenty years.ConclusionOur literature review identified only four RCTs conducted in hospice‐eligible patients with agitation in the last four decades with no medication being evaluated in over a decade. Research is urgently needed to identify, develop, and test treatments for end‐of‐life agitation in patients with dementia.
Infections and cognitive function, depression, and frailty: a cross‐sectional study in the Longitudinal Aging Study in India (LASI)
Authors: Gore‐Langton Georgia R , Mansfield Kathryn E , Ravi Prithvee , Doubatty Arrisonia , Alladi Suvarna , Kinra Sanjay , Warren‐Gash Charlotte 
Published: January 2025

AbstractBackgroundSome infections may be associated with poor brain health, but evidence from low and middle‐income countries (LMICs) is limited. Therefore, we aimed to investigate associations between nine infections and cognitive function, depression, and frailty in India.MethodsWe conducted a cross‐sectional study using data from Wave 1 (2017‐2019) of the Longitudinal Aging Study in India (LASI) survey of adults (≥45years) from 35 of India’s 36 states and union territories. Survey data were collected via face‐to‐face interviews and direct health measurements. We investigated the association between nine infections either self‐reported ever (periodontal disease) or in the two years before interview (jaundice/hepatitis, malaria, tuberculosis, typhoid, chikungunya, diarrhoea/gastroenteritis, dengue, urinary tract infection [UTI]), and global cognitive function, depression and frailty. We used survey‐weighted logistic regression to estimate odds ratios comparing impaired cognition, depression, or frailty in people with at least one infection (and each individual infection) to those without infection.ResultsWe included 64,682 respondents; median age 59 years (IQR:50‐67), 53.5% female. Accounting for survey weighting, thirty‐five percent (n = 23,783) of respondents reported at least one infection. After adjusting for demographic, social/environmental, lifestyle, and chronic health conditions, we saw evidence of association between having at least one infection and both depression (OR: 1.30 [95%CI: 1.23‐1.36]) and frailty (OR: 1.78 [95%CI: 1.69‐1.87]) (Figure 1). We saw strong associations between jaundice/hepatitis and frailty (OR: 2.20 [95%CI: 1.90‐2.54]), and UTIs and both frailty (OR: 3.08 [95%CI: 2.65‐3.59]) and depression (OR: 1.38 [95%CI:1.19, 1.61]). In contrast, having at least one infection was associated with reduced odds of impaired cognition (OR: 0.81 [95%CI: 0.76‐0.87]).ConclusionsOur results suggest that infections are associated with increased depression and frailty in adults ≥45 years in India. However, reported infections were associated with better cognition, which may be explained by preferential recall of infections in those with better cognition. Longitudinal studies are needed to investigate a causal link between infections and adverse brain health, and to guide interventions to reduce the burden of impaired cognition, depression, and frailty in India and LMICs more widely.
COVID‐19 Mortality Rates and Changes in Antidementia and Psychotropic Medication Use Among Nursing Home Residents
Authors: Rataj Alison C , Alcusky Matthew , Ott Brian R. , Baek Jonggyu , Liang Shiwei , Lapane Kate L 
Published: January 2025

AbstractBackgroundWe examined the relationship between nursing home (NH) COVID‐19 mortality rates and changes in antidementia and psychotropic medication initiation before and during the pandemic and explored the influence of staffing and resident factors.MethodChanges in medication initiation were collected through a nationally representative cross‐sectional Dementia Treatment Survey (2022) of NH Directors of Nursing. Outcome measures were created by collapsing a 5‐point Likert scale contrasting less/about the same vs. more initiation and less versus more/about the same initiation. NH’s peak monthly COVID‐19 death rate per 1,000 residents (05/2020‐12/2022) was calculated from the CMS COVID‐19 Nursing Home data file. Covariates were drawn from NH Compare, Provider of Service, Master Beneficiary Summary, Minimum Data Set 3.0, and Medicare administrative claims files. Adjusted odds ratios (aORs) were estimated from multivariable logistic models.ResultNHs with higher COVID‐19 death rates at the peak of the pandemic were more likely to report a decrease (aORdecrease: 2.65, 95% CI: 1.07‐6.53) and less likely to report an increase (aORincrease: 0.28, 95% CI = 0.09‐0.87) for antidementia medication initiation. No association with psychotropic medication initiation was observed. NH’s reported increased resident behavior problems during the pandemic had higher odds of psychotropic initiation (aOR = 11.25, CI = 3.86‐32.83).ConclusionIncreased COVID‐19 mortality rates were associated with decreased initiation of antidementia medication use during, compared to before the pandemic. Higher mortality reported with antipsychotic use in this population did not appear to be a factor in NHs during the pandemic. Increased behavior changes may be due to consequences of COVID‐19 (i.e., social isolation); our findings indicate that increased behavior changes were associated with more psychotropic drug use.
Automating Microinfarct Screening in Hematoxylin and Eosin‐stained Human Brain Tissues: A Machine Learning Approach
Authors: Oliveira Luca Cerny , Chauhan Joohi , Lai Zhengfeng , Cheung Samson , Villablanca Amparo , Jin Lee‐Way , DeCarli Charles S. , Chuah Chen‐Nee , Dugger Brittany N 
Published: January 2025

AbstractBackgroundMicroinfarcts, characteristic lesions of vascular dementia (VaD), are heterogenous and vary in appearance, which pose a considerable challenge for VaD grading as there is great interrater variability in microinfarct assessment. We propose a novel application of machine learning (ML) in the automated screening of microinfarcts, addressing a gap in the post‐mortem analysis of VaD in whole slide images (WSIs) from human brain.MethodOur study adapts a patch‐based pipeline with convolutional neural networks (CNNs) to automate microinfarct screening in WSIs. We compare performance and computational cost of different fields‐of‐view (FOV) for the patch‐based method. Additionally, we propose a postprocessing step and leverage multiple FOVs to mitigate false positives. This study is validated against 66 annotated WSIs (N = 40 infarcted, N = 26 un‐infarcted) from Frontal, Parietal, and Occipital white matter regions across 22 cases. Annotations are from a single trained expert, who delineated microinfarct regions and graded white matter rarefaction.ResultWe report screening performance, i.e, the ability to distinguish infarct‐positive from infarct‐negative WSIs, and detection performance, i.e, the ability to localize the microinfarct regions within a WSI. Despite the inherent challenges of the inexact boundaries of microinfarcts, our models demonstrate notable efficacy in screening WSIs for infarcts, with ResNet‐18 achieving 100% accuracy at WSI level. However, the sensitivity in detecting infarct regions is below 50%, based on Intersection over Union thresholds above 20% overlap (a performance metric used to evaluate the accuracy of object detection models). Leveraging multiple FOV improves both detection and screening performances, reducing false positives.ConclusionThis work presents a proof‐of‐concept pipeline driven by machine learning to automate microinfarct screening & detection in WSIs. This workflow provides new avenues in the automated analysis of neuropathological images of microinfarcts, bringing potential advancement in ML‐based dementia and neuropathology research.
Dysregulated Angiopoietin‐Tie signalling contributes to neurovascular dysfunction in Alzheimer’s disease
Authors: Ince Selvi , Love Seth , Miners James Scott 
Published: January 2025

AbstractBackgroundCerebral hypoperfusion and blood‐brain barrier (BBB) leakiness within the precuneus is common in early‐stage Alzheimer’s disease (AD). Pericyte‐derived angiopoietin‐1 (ANGPT‐1) activates endothelial TIE‐2 receptors promoting vascular stability whereas endothelial cell‐derived ANGPT‐2, a weak agonist or antagonist of TIE‐2, promotes BBB leakiness. Endothelial TIE‐1 also regulates TIE‐2 signalling. We recently showed elevated ANGPT2 level in mild‐cognitive impairment related to albumin, a marker of BBB leakiness, in CSF. In this study, we examined ANGPT/TIE signalling in brain tissue and microvessel‐enriched fractions (MVFs) in relation to AD progression and cerebrovascular injury.MethodWe studied parietal cortex (Brodmann area 7) from Braak tangle stage (BS) 0‐II (n = 17), III‐IV (n = 23) and V‐VI (n = 22) from cases obtained from the South‐West Dementia Brain Bank, University of Bristol. ANGPT‐1, ANGPT‐2, TIE‐1, and TIE‐2 levels in brain tissue and MVFs were measured by ELISA. CD31 level was used to adjust for endothelial content. MAG and PLP1 levels, to assess brain oxygenation and fibrinogen, to assess BBB integrity, were measured by ELISA. One‐way ANOVA with Tukey’s post hoc testing was used to compare groups and Pearson’s correlation coefficient was used to assess relationships between ANGPT/TIE, MAG:PLP and fibrinogen.ResultIn crude homogenates, ANGPT‐1 level was elevated in BSV‐VI compared to BS0‐II (p = 0.06) and BSIII‐IV (p = 0.0005). TIE‐2 was reduced in BSIII‐IV compared to BS0‐II (p = 0.004) and BSV‐VI (p = 0.001) in crude homogenates and was lower in MVFs in BSV‐VI than BS0‐II (p = 0.02). ANGPT‐2 level was higher in BSV‐VI than BSIII‐IV in brain tissue (p = 0.04). However, both ANGPT‐2 and TIE‐1 levels were unaltered in relation to BS in MVFs. Across the entire cohort, ANGPT‐2 level correlated inversely with MAG:PLP1 ratio in BSIII‐IV (p = 0.052, r = ‐0.42) but positively with MAG:PLP1 (p = 0.04, r = 0.46) and fibrinogen level (p = 0.02, r = 0.49) in BSV‐VI brains.ConclusionThe expression of the stabilising receptor, TIE‐2, was reduced in early‐stage AD and ANGPT2 expression was differentially related to perfusion and BBB leakiness dependent on disease stage. The study highlights important differences in ANGPT/TIE signalling in relation to disease stage and illustrates a complex relationship between brain, microvascular, and CSF changes that warrants further investigation.
Mechanism of tau‐mediated microglial NF‐κB inhibitor IκBα degradation in Alzheimer’s disease
Authors: Tangavelou Karthikeyan , Jiang Shanya , Mandell Michael , Bhaskar Kiran 
Published: January 2025

AbstractBackgroundMicroglia are the brain resident immune cells that function as immune surveillance and engulf and clear damage‐associated molecular patterns (DAMPs), such as misfolded and oligomeric tau (TO) relevant Alzheimer’s disease (AD) and prevent nuclear factor‐kB (NF‐kB) mediated immune‐activation. IκBα is an endogenous inhibitor of the NF‐kB subunit p50‐p65/c‐Rel protein complex. IkBα’s association is precisely regulated in microglia to prevent excessive NF‐kB activation and neuroinflammation, which is one of the hallmarks of AD.MethodsMicroglia treated with tau oligomers (TO) purified from autopsy of the human AD brain and analyzed its uptake and clearance via autophagy, proteasome, or calpain using specific inhibitors, bafilomycin‐A (BafA1), MG‐132 and PD150606, respectively. TO’s effect on NF‐kB activity (via assessing IkBα levels) was also tested in the presence or absence of these inhibitors and upon inhibition of protein translation using cycloheximide.ResultsAD‐TO induces endomembrane damage and NF‐kB activity as confirmed by increased galectin 3 puncta and luciferase reporter activity, respectively. AD‐TO impairs autophagy, confirmed by accumulation of p62, and adding BafA1 does not increase either p62 or IkBα levels. Then, to determine the role of proteasome or calpains on IkBα degradation, AD‐TO induced IκBα degradation was attempted to stabilize by either MG‐132 or PD150606. Inhibiting either proteasome or calpains does not prevent the degradation of IkBα. We identified AD‐TO induces elevated calpain activity, which is correlating with autophagy impairment, and inhibiting calpain with PD150606 restored autophagy activity as confirmed by decreased intracellular level of p62 and AD‐TO. Inhibiting the proteostasis activity with either PD150606 + BafA1 or PD150606 + BafA1 + MG‐132 induces secretion of IkBα into the culture medium.ConclusionsMicroglial endocytosed AD‐TO damages endomembrane and activate NF‐kB by constitutively degrading IkBα, which localizes in autophagosomes, and concurrent inhibition of calpains and autophagy leading to secretion of IkBα into the extracellular space.