bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving access to global neuroimaging through locally sustained technology
Authors: Harper Joshua , Evans Tavia E , Obungoloch Johnes , Adams Hieab H.H. 
Published: January 2025

AbstractBackgroundIt is estimated that at least two‐thirds of the world lacks access to neuroimaging, including Magnetic Resonance Imaging (MRI). Yet neuroimaging is one of the most informative tools for neuroscience, potentially biasing advances toward populations with access to this technology. This is evident in Alzheimer’s disease (AD) research, where genetics and environment play important roles in disease development and treatment. Recent advances in low field MRI (LFMRI) have demonstrated the utility of this affordable and portable technology, despite lower image quality. Of the existing technologies, the OSII ONE developed by the open‐source imaging initiative is the only device that has been reproduced in low resource settings using primarily local resources. Here we highlight two pilot studies in Uganda and Paraguay to build and sustain OSII ONE devices for neuroimaging studies. We present preliminary results regarding construction, sustainability, and image processing for use in AD and offer suggestions for its inclusion as a tool to increase access to neuroimaging in low‐resource populations.MethodAn OSII ONE system was reproduced in Uganda and Paraguay. In Uganda, all system components were importanted and local human resource guided by international experts was used to complete the build. In Paraguay, only key physical components not available locally were imported and all available local components (including exclusively local human resources) were used for construction.ResultWhile the Uganda build was completed more quickly (11 days in Uganda, 6 months in Paraguay), quality was maintained across sites despite difference in personnel and the use of local components in Paraguay. Both projects are maintained locally and current image processing methods could provide adequate quality for brain analysis in AD.ConclusionWe show the feasibility LFMRI in lower resource settings. Despite the reduction in image quality, valuable structural information can be obtained, extending access to rural populations. This has significant implications for the future of AD imaging in global settings especially considering recent approval of disease modifying therapies that require safety monitoring with MRI. Future work collecting paired LFMRI and conventional MRI with AD patients in South America will further demonstrate the utility of this technology in the field.
Developing a core outcome set for people living with mild cognitive impairment: Protocol for the MCI Core Outcomes Study
Authors: Gabb Victoria Grace , Woodward Natalie , Harding Sam , McNair Angus , Clayton Julie , Alderman Sophie , Barrett‐Muir Winsome , Richardson Alan , Rudd Sarah , Webb Joseph , Dooley Jemima , Coulthard Elizabeth , Turner Nicholas 
Published: January 2025

AbstractBackgroundCore outcome sets (COS) are a set of outcomes which stakeholders agree should be collected and reported as part of a minimum dataset for studies in a clinical population. COS developed collaboratively with patients and other stakeholders encourage researchers to report outcomes which are considered important by affected individuals. COS may reduce heterogeneity of outcome selection allowing for better synthesis across studies (e.g., meta‐analysis) and reduce selective reporting of positive outcomes to support more informed healthcare decisions. There is currently no approved COS for patients with mild cognitive impairment (MCI). Therefore, we are collaborating with patient and public contributors to develop a COS for people with MCI.MethodThe study will involve three stages: 1) an umbrella review, which will provide outcomes from published studies by retrieving articles from systematic and scoping reviews of interventional studies involving people with MCI; 2) interviews with stakeholders with lived experience of MCI (people living with MCI and their partners/relatives) and relevant professional stakeholders (e.g., health and social care professionals or those from relevant charitable organisations or industry) will identify additional outcomes stakeholders consider important; 3) a “long list” of possible outcomes will be curated from Stage 1 and 2 and a two‐round Delphi survey process and consensus meeting(s) will identify the final COS to be recommended.ResultThe study is ongoing. The review is at the data extraction stage. From the first 25 studies, the most common outcome measurement instruments reported so far are all related to cognitive functioning: the Mini‐Mental State Examination (9/25, 36%), Trail Making Test (6/25, 24%), and Verbal Fluency Test (6/25, 24%). Updated results will be available for the conference. Interviews are anticipated to start in mid‐2024 with the COS published in 2025.ConclusionA COS for people with MCI will identify outcomes of importance for individuals affected by MCI and improve transparent outcome reporting in interventional research to better support patient care.
Associations of Gait, Cognitive Imparment, Dementia and Obstructive Sleep Apnea inIndividuals with Down Syndrome: Preliminary Findings
Authors: da Conceição Conceição Aline de Souza Gonçalves Gomes , Cecilio Ana Paula Assunção , Sant´Ana Livea Carla Fidalgo Garcêz , Fonseca Luciana , Forlenza Orestes Vicente 
Published: January 2025

AbstractBackgroundIt is known that atipical aging in DS is related to a high risk of early dementia, with neuropathological charactheristics compatible with Alzheimer´s disease (AD). Changes in functional mobility are expected throughout the aging process, with impairments in motor performance, involving balance and gait. Growing evidence suggests that sleep disruption may also accelerate the progression to symptomatic Alzheimer’s disease (AD) in this population. Therefore, it is mandatory to assess sleep quality and diagnose sleep‐disordered breathing, especially obstructive sleep apnea (OSA), associated with DS, to improve cognition and quality of life, preventing related comorbidities.MethodWe evaluated 66 individuals with DS (≥20 years), divided into 3 groups: stable cognition, prodromal dementia, and Alzheimer’s disease. Each individual was evaluated with the Performance‐Oriented Mobility Assessment (POMA) protocol, Polysomnography, and Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities interview adapted for adults with DS (CAMDEX‐DS).ResultThe logistic regression model with the stepwise backward technique, with the initial model including age, gender, body mass index (BMI), degree of intellectual disability, and apnea‐hypopnea index (AHI), showed that gait performance in POMA are independent factors associated with the diagnosis of control and dementia (POMA p < 0.005). All cognitive domains were correlated with OSA, but only orientation had a significant correlation (p‐value 0.268). We did not find a difference in OSA scores among POMA.ConclusionThe POMA results indicate that those with AD have worse gait performance and a higher risk of falls relative to those with dementia and stable cognition. There was no evidence of correlation between gait speed and OSA, which may have been influenced by the sample size (n:17). Further longitudinal studies with larger samples are needed to confirm our results.
Association of Tau and Amyloid with Representational Similarity in the Amygdala’s Reactivity to Negative and Neutral Stimuli in Individuals at Risk for Alzheimer’s Disease
Authors: Liu Mingtong , Betthauser Tobey J. , Gresham Lauren K. , Schaefer Stacey M. 
Published: January 2025

AbstractBackgroundEmotional dysfunction is often observed in older adults at the early stage of Alzheimer’s disease. Individuals at risk for Alzheimer’s disease may show differences in emotional reactivity before they exhibit cognitive decline (Fredericks et al., 2018). It is unclear whether emotional symptoms are associated with brain changes during the development of the disease. In this study, we examined the associations of tau and amyloid burden with representational similarity in the amygdala’s reactivity to negative and neutral stimuli in individuals at risk for Alzheimer’s disease.MethodParticipants are from the Wisconsin Registry for Alzheimer Prevention (n = 81, 69% Female, 6% BIPOC). During the fMRI scans, participants viewed 30 negative, 30 neutral, and 30 positive images followed by a neutral face. Representational similarity analysis was used to calculate the similarity of the amygdala activation pattern to negative images and neutral images. Amyloid and tau burden were measured using the positron emission tomography.ResultOur results showed that greater tau burden in the entorhinal cortex is significantly related to less neural similarity in right amygdala to negative and neutral stimuli. Individual differences of tau burden in the entorhinal cortex, but not amyloid burden, significantly predict neural similarity in the right amygdala to negative and neutral stimuli when controlling for covariates, such as age, gender, and race. Neural similarity in both left and right amygdala to negative and neutral stimuli is greater in the T− group, compared to the T+ group.ConclusionGreater tau burden in the entorhinal cortex predicts less neural similarity in the right amygdala to negative and neutral stimuli, suggesting a greater differentiation of the amygdala’s response with higher tau.
The impact of locus coeruleus degeneration on pair bonding and other Alzheimer’s disease‐relevant phenotypes in monogamous prairie voles
Authors: Kelberman Michael A. , Donaldson Zoe R , Winther Kelly , Franks Emily , Weinshenker David 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) fractures social relationships, extending the burden of disease beyond the affected individual and onto caregivers and loved ones. One brain region known to be crucial in regulating social behaviors is the noradrenergic locus coeruleus (LC), a region that becomes dysfunctional as AD progresses. Unfortunately, deficits in social bonding have been relatively understudied in AD, due in part to the limited social behavioral repertoires of mouse and rat models of AD. Here, we used monogamous prairie voles, which display many human‐relevant complex social behaviors, to assess the impact of LC degeneration on social bonding and other AD‐relevant phenotypes.MethodsPrairie voles (male and female, 3 – 6 months of age) were administered the selective LC neurotoxin DSP4 or saline (i.p., administered twice separated by a week). Voles were paired a week after their last injection and tested on partner preference tests 1, 3, and 7 days post‐pairing, timepoints designed to test for the presence and duration of bond impairment. Animals were then tested on sleep latency (arousal), Y‐maze (working memory), novelty‐suppressed feeding (anxiety‐like phenotypes), and resident intruder (social behavior) tasks to assess other AD‐relevant phenotypes. Vole pairs were then separated and singly housed in separate vivariums. After 4 weeks of isolation, they were re‐tested in the same battery of behavioral tests and in a final partner preference.ResultsDSP4 administration impaired bond formation in male but not female voles, even after 7 days of cohabitation, a striking result as other manipulations that impair bond formation typically delay rather preclude bonding. Further supporting a lack of pair bonding, DSP4 treated males displayed lower levels of aggression in a resident intruder task while still co‐housed with their partner. Meanwhile, partner separation increased anxiety‐like behavior in DSP4‐treated males, suggesting an interaction with a well‐delineated social stressor. Female behavior was unaffected by DSP4 treatment. Confirmation of LC lesions with HPLC and IHC, and behavioral analysis of partner preference after separation are ongoing.ConclusionsThis study shows that LC degeneration may contribute to social behavior abnormalities observed in prodromal AD. It further suggests that LC degeneration may exaggerate behavioral deficits following the loss of a partner.
Social Engagement as a Protective Factor for Cognition in Older Adults: Examining Sex and Race Differences
Authors: Dixon Jasmine S , Amariglio Rebecca E , Howard Marjorie , Sachs Bonnie C. , Snyder Heather M , Espeland Mark A. , Baker Laura D , Papp Kathryn V 
Published: January 2025

AbstractBackgroundSocial engagement, characterized as frequency of family/friends contact and activities with others, has emerged as a protective factor for Alzheimer’s disease. However, it is unclear how social engagement protects against cognitive decline and whether there are differences across sex and racial groups. Here we determine whether: 1) greater social engagement is associated with better global cognition in older adults at risk for cognitive decline, 2) depressive symptoms and vascular risk are mediators, and 3) the associations vary by sex and race in a cognitively at‐risk but clinically unimpaired sample.MethodsWe analyzed baseline subset data from adults who self‐identified as monoracial Black (n = 340) or White (n = 1,451) participating in the U.S. POINTER clinical trial. Social engagement was measured by a composite of seven items from the modified (for cultural sensitivity) Community Healthy Activities Model Program for Seniors (CHAMPS). Vascular risk was quantified by the Framingham Risk Score and depressive symptoms on the Geriatric Depression Scale (dichotomized). Global cognition was measured using a multi‐domain cognitive composite. Linear regression models examined associations between social engagement and cognition in the whole sample (n = 1,791) and in race‐by‐sex stratified analyses. Mediation models examined vascular risk and depressive symptoms as mediators. All models were adjusted for age, education, and time of enrollment.ResultsAcross the whole sample, greater social engagement was associated with better global cognition, fewer depressive symptoms, and less vascular risk. Vascular risk, but not depressive symptoms, was a significant mediator such that greater social engagement was associated with lower vascular risk, and greater vascular risk was associated with poorer global cognition. In race‐by‐sex stratified analyses, greater social engagement was associated with better global cognition only in White women. Greater social engagement was associated with lower depressive symptoms for White women, White men, and Black women but not Black men.ConclusionsResults suggest that social engagement is a protective factor for global cognition, and against vascular risk and depressive symptoms. Vascular risk may be a modifiable biological mechanism underlying the protective influence of social engagement on cognition for older adults. The CHAMPS data suggest that White women exhibit the greatest benefit from social engagement.
The Huntington’s Disease Integrated Staging System
Authors: Long Jeffrey M ,   Huntington’s Disease Regulatory Science Consortium (HD‐RSC) Work Group
Published: January 2025

AbstractThe Huntington’s Disease Integrated Staging System (HD‐ISS) comprises a biological research definition of HD and evidence‐based staging centered on prognostic biological, clinical, and functional landmarks. It is the result of a formal consensus process within the Huntington’s Disease Regulatory Science Consortium’s Regulatory Science Forum (RSF), a working group made up of expert representatives from industry and academia. The RSF considered prognostic biomarkers, signs, and symptoms of HD, and performed empirical data analysis. It used observational data to calculate healthy‐control‐based landmark variable cut‐offs for stage classification and to internally validate the framework.The HD‐ISS starts with Stage 0, which comprises individuals with ≥ 40 CAG repeats in the huntingtin gene (HTT) before detectable indications of disease pathology. HD progression is verified by assessments of underlying pathophysiology (Stage 1), then proceeds to a detectable clinical phenotype (Stage 2) and continues to a decline in function (Stage 3). Operationally, individuals can be classified into Stages 1‐3 based on CAG‐independent thresholds of landmark assessments. Importantly, the HD‐ISS covers the entire disease spectrum starting from birth, and is unconstrained by concepts such as “manifest,” “premanifest,” or “prodromal.”The HD‐ISS allows the definition of study populations across the entire duration of the disease trajectory, including before clinical motor diagnosis. Clinical trials using the HD‐ISS can be implemented immediately. In HD‐ISS Stages 2 and 3, we have knowledge of how to enrich and what endpoints to measure. Although clinical trials in Stage 1 may require further research, that work is ongoing. While participant populations may also be defined by additional enrichment criteria as determined by the study objectives, we propose that all new clinical studies use the HD‐ISS.
A Biological Definition and Research Integrated Staging System of Neuronal α‐Synuclein Disease: Research Framework
Authors: Simuni Tanya 
Published: January 2025

AbstractThe NSD‐ISS Working Group developed a data‐driven approach to: 1) determine a biologic definition for disease; 2) establish a framework for a disease staging platform. NSD is defined by the presence of pathologic n‐asyn (S) assessed by a validated in vivo biomarker and ultimate presence of dopaminergic neuronal dysfunction (D). This biologic definition is independent of the presence of clinical features, or if present, of the specific clinical syndrome. NSD‐ISS integrates these biological anchors (S and D) and degree of functional impairment caused by motor, cognitive or other non‐motor signs. Individuals in stage 0 and 1 are free of clinical signs and can be diagnosed either by presence of fully penetrant pathogenic variants (G) in SNCA gene (Stage 0), n‐asyn alone (Stage 1A) or in combination with dopaminergic neuronal dysfunction (Stage 1B). Stage 2 is characterized by subtle clinical signs but no functional impairment, with either n‐asyn (S) alone (Stage 2A) or in combination with dopaminergic neuronal dysfunction (Stage 2B). Stages 3‐6 require the presence of both biomarkers and stage‐specific increase in severity of functional impairment. We have developed operational definitions and applied staging to PPMI and two interventional studies cohorts.ConclusionsThe NSD‐ISS provides a comprehensive biologically‐based framework essential to advance biologically‐targeted therapeutic development. The NSD‐ISS is expected to evolve as additional biomarkers emerge. We present the first data‐driven application of the NSD‐ISS, highlighting the heterogeneity of the biological stages in a phenotypically homogeneous cohort.
Sex‐Specific Causal Genes for Alzheimer’s Disease via Proteome‐Wide Association Studies
Authors: Reid Danielle M. , Belloy Michael E. 
Published: January 2025

AbstractBackgroundWomen are at higher risk of developing Alzheimer’s disease (AD). Sex differences in AD pathobiology and prevalence appear to be partially attributed to genetics, but sex‐stratified genome‐wide association studies (GWAS) of AD have demonstrated a relative paucity of associated variants, which may reflect challenges of limited power. Furthermore, these studies lack information regarding the impact on sex‐specific proteins and pathways relevant to AD, which limits clinical translation and targeted drug development. Sex‐stratified protein quantitative trait locus (pQTL) studies pose to address these limitations. We hypothesized that directly integrating brain pQTL data with the largest to date sex‐stratified AD GWAS would increase power to reveal sex‐specific AD associated genes.MethodSex‐stratified GWAS of AD from Belloy et al. 2023 included 410,276 female and 385,813 male non‐Hispanic White individuals of European ancestry. Human brain proteome data with matching genome‐wide data were available from Wingo et al. 2022 (NSubjects = 722) and 2023 (NWomen = 507; NMen = 301). Briefly, genetic variants were associated with proteins through the FUSION package to estimate effects on protein abundance and produce non‐sex‐stratified (NProteins = 2,934) and sex‐stratified protein‐specific variant weights (NProteins = 1,800 for males; NProteins = 2,463 for females). This approach retains only proteins that show significant genetic associations (i.e., protein levels displaying significant heritability). Proteome‐wide association studies (PWAS) were performed via FUSION combining sex‐stratified AD GWAS with non‐sex‐stratified and sex‐stratified protein weights (Figure‐1). Enrichment/pathway analysis for gene and disease ontology was conducted via the DOSE package (R 4.3.3).ResultSex‐matched AD PWAS identified 27 and 2 AD causal genes for females and males, respectively. Sex‐stratified AD GWAS integrating non‐stratified protein weights identified 30 causal genes in females and 7 in males. Upon filtering results of both discoveries for sex specificity, 18 female and 2 male AD causal genes were prioritized (Figure‐2). Enrichment/pathway analysis of female‐specific AD causal genes highlighted metabolic‐related health outcomes (Figure‐3).ConclusionWe performed sex‐stratified PWAS of AD and identified 18 female‐specific AD causal genes, of which 8 strikingly converged onto metabolic disorders as a putative female‐specific AD pathway. These findings increase our understanding of AD pathogenesis and may inform therapeutic target development relevant to sex‐specific precision medicine. Supporting analyses in additional proteogenomic resources are ongoing.
Quantitative multi‐parameter mapping of locus coeruleus in aging and Alzheimer’s disease
Authors: Lenzoni Sabrina , Femminella Grazia Daniela , Loane Clare , Kurt Elif , Duckett Millie , Weiskopf Nikolaus , Callaghan Martina F , Dolan Ray , Howard Robert J , Düzel Emrah , Hämmerer Dorothea 
Published: January 2025

AbstractBackgroundThe Locus Coeruleus (LC) is prominently affected by neuronal loss in the earliest stages of Alzheimer’s disease (AD). Assessing LC integrity can serve as an important early biomarker for assessing AD progression. Neuromelanin (NM) accumulates in LC neurons and NM imaging has therefore been proposed as a means of imaging the LC. As signal intensity is taken as a proxy for cell density, a quantitative imaging approach of the LC, which is less variable across sites and time is desirable. The present study used a multi‐parameter mapping (MPM) protocol optimized for LC imaging to compare weighted and quantitative maps in healthy younger, healthy older adults and individuals with AD.MethodsStructural MRI data was acquired in a group of 26 healthy young adults, 26 healthy older adults and 26 individuals with Alzheimer’s disease. Three sets of T1‐weighted, MT‐weighted, and PD‐weighted images yielded quantitative maps (R1, MTsat, PD, and R2*) in each individual within one scan session. Qualitative and quantitative methods were used to assess weighted and quantitative maps for LC imaging across groups.ResultsQualitatively, LC visibility was higher in weighted images. The LC was also apparent in R1 maps, but less clearly visible in MTsat and R2* maps (Figure 1). LC contrast ratio (with pons as reference), was reduced in Alzheimer’s disease compared to younger adults as detected by MTw scans (p = .001) and to older adults as detected by T1w (p<.001), MTw (p<.001), and PDw scans (p = .007). No group differences were detected in quantitative maps, suggesting less sensitivity to pick up typical LC integrity reductions. PD maps could not be reliably estimated in the modified setup of the MPMs.ConclusionAlthough among the quantitative maps LC was most visible in R1 images, our findings indicate that R1 maps capture the LC signal intensity less well as compared to non‐quantitative LC imaging, as suggested by a qualitative assessment of LC visibility and inability to detect known group differences. Further research should improve sensitivity of quantitative maps for LC assessment by combining sequences capturing different aspects of LC tissue properties.