EBioMedicine最新文献

{"title":"Integration of circadian rhythms and immunotherapy for enhanced precision in brain cancer treatment.","authors":"Matthias Quist, Maas van Os, Linda W van Laake, Niels Bovenschen, Sandra Crnko","doi":"10.1016/j.ebiom.2024.105395","DOIUrl":"10.1016/j.ebiom.2024.105395","url":null,"abstract":"<p><p>Circadian rhythms significantly impact (patho)physiological processes, with disruptions linked to neurodegenerative diseases and heightened cancer vulnerability. While immunotherapy has shown promise in treating various cancers, its efficacy in brain malignancies remains limited. This review explores the nexus of circadian rhythms and immunotherapy in brain cancer treatment, emphasising precision through alignment with the body's internal clock. We evaluate circadian regulation of immune responses, including cell localisation and functional phenotype, and discuss how circadian dysregulation affects anti-cancer immunity. Additionally, we analyse and assess the effectiveness of current immunotherapeutic approaches for brain cancer including immune checkpoint blockades, adoptive cellular therapies, and other novel strategies. Future directions, such as chronotherapy and personalised treatment schedules, are proposed to optimise immunotherapy precision against brain cancers. Overall, this review provides an understanding of the often-overlooked role of circadian rhythms in brain cancer and suggests avenues for improving immunotherapeutic outcomes.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105395"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study.","authors":"Louise E van Eekeren, Quirijn de Mast, Elise M G Meeder, Adriana Navas, Albert L Groenendijk, Marc J T Blaauw, Wilhelm A J W Vos, Nadira Vadaq, Jéssica C Dos Santos, Joost Rutten, Niels P Riksen, Jan van Lunzen, Gert Weijers, Mihai G Netea, André J A M van der Ven, Eric T T L Tjwa, Leo A B Joosten","doi":"10.1016/j.ebiom.2024.105407","DOIUrl":"10.1016/j.ebiom.2024.105407","url":null,"abstract":"<p><strong>Background: </strong>Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms.</p><p><strong>Methods: </strong>We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals (\"controls\") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m².</p><p><strong>Findings: </strong>Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV.</p><p><strong>Interpretation: </strong>Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories.</p><p><strong>Funding: </strong>The 2000HIV study is funded by ViiV Healthcare.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105407"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1.","authors":"Francielle T G de Sousa, Colin M Warnes, Erika R Manuli, Laurentia V Tjang, Pedro H Carneiro, Luzia Maria de Oliveira Pinto, Arash Ng, Samhita Bhat, Jose Victor Zambrana, Luiz G F A B D'Elia Zanella, Yeh-Li Ho, Camila M Romano, P Robert Beatty, Scott B Biering, Esper G Kallas, Ester C Sabino, Eva Harris","doi":"10.1016/j.ebiom.2024.105409","DOIUrl":"10.1016/j.ebiom.2024.105409","url":null,"abstract":"<p><strong>Background: </strong>Yellow fever virus (YFV) infections are a major global disease concern with high mortality in humans, and as such it is critical to identify clinical correlates of disease severity. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections.</p><p><strong>Methods: </strong>Using serum samples from laboratory-confirmed YF patients with severe (n = 39) or non-severe (n = 18) disease in a well-defined hospital observational cohort in Brazil, plus samples from healthy uninfected controls (n = 11), we investigated factors associated with disease severity and endothelial dysfunction.</p><p><strong>Findings: </strong>We found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups, as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels, TEER values, and signs of disease severity. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death.</p><p><strong>Interpretation: </strong>This study provides further evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans and suggests serum quantification of YFV NS1 and syndecan-1 as valuable tools for disease diagnosis and/or prognosis.</p><p><strong>Funding: </strong>This work was supported by the US NIH and FAPESP.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105409"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA transcriptomics in mice reveals embryonic origin of fibrosis due to maternal obesity.","authors":"Md Nazmul Hossain, Yao Gao, Xinrui Li, Liang Zhao, Xiangdong Liu, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du","doi":"10.1016/j.ebiom.2024.105421","DOIUrl":"10.1016/j.ebiom.2024.105421","url":null,"abstract":"<p><strong>Background: </strong>Over 40% of pregnant women in the USA are obese which negatively affects fetal development and offspring health. Maternal obesity (MO) leads to fibrotic infiltration in multiple tissues and organs of offspring during their adulthood although the origin and mechanisms are unclear.</p><p><strong>Methods: </strong>C57BL/6J female mice were fed a control and high-fat diet to mimic MO condition. Embryonic somatic tissues were obtained at E9.5, E11.5, and E13.5 (equivalent to 6 weeks of human pregnancy) from control (CON) and MO mice for single-cell RNA-sequencing (scRNA-seq). To explore the role of AMP-activated protein kinase (AMPK), AMPK was activated by metformin and A769662, and knocked out in embryonic mesenchymal cells (EMC) using AMPKα1 floxed mice.</p><p><strong>Findings: </strong>Using unsupervised clustering, we identified three major cell populations with fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically (by ∼125%) due to MO, supporting an embryonic origin of fibrosis in the offspring. MO induced inflammatory response and elevated expression of transforming growth factor β (TGFβ) signalling and fibrogenic genes in embryos. MO inhibited AMPK and its activation by metformin and A769662 inhibited TGFβ signalling and fibrogenesis.</p><p><strong>Interpretation: </strong>MO profoundly enhances embryonic fibrogenesis, explaining the origin of fibrosis in the offspring of mothers living with obesity. Our data underscore the importance of early intervention, before 5-6 weeks of pregnancy, in improving embryonic development, and AMPK is an amiable target for suppressing excessive fibrogenesis in MO embryos to assist increasing populations of obese mothers having healthy children.</p><p><strong>Funding: </strong>This work was funded by National Institutes of Health Grant R01HD067449.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105421"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11565040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity of the human immune response to malaria infection and vaccination driven by latent cytomegalovirus infection.","authors":"Reena Mukhiya, Wim A Fleischmann, Jessica R Loughland, Jo-Anne Chan, Fabian de Labastida Rivera, Dean Andrew, James G Beeson, James S McCarthy, Bridget E Barber, J Alejandro Lopez, Christian Engwerda, Richard Thomson-Luque, Michelle J Boyle","doi":"10.1016/j.ebiom.2024.105419","DOIUrl":"10.1016/j.ebiom.2024.105419","url":null,"abstract":"<p><strong>Background: </strong>Human immune responses to infection and vaccination are heterogenous, driven by multiple factors including genetics, environmental exposures and personal infection histories. For malaria caused by Plasmodium falciparum parasites, host factors that impact on humoral immunity are poorly understood.</p><p><strong>Methods: </strong>We investigated the role of latent cytomegalovirus (CMV) on the host immune response to malaria using samples obtained from individuals in previously conducted Phase 1 trials of blood stage P. falciparum Controlled Human Malaria Infection (CHMI) and in a MSP1 vaccine clinical trial. Induced antibody and functions of antibodies, as well as CD4 T cell responses were quantified.</p><p><strong>Findings: </strong>CMV seropositivity was associated with reduced induction of parasite specific antibodies following malaria infection and vaccination. During infection, reduced antibody induction was associated with modifications to the T -follicular helper (Tfh) cell compartment. CMV seropositivity was associated with a skew towards Tfh1 cell subsets before and after malaria infection, and reduced activation of Tfh2 cells. Protective Tfh2 cell activation was only associated with antibody development in individuals who were CMV seronegative, and a higher proportion of Tfh1 cells was associated with lower antibody development in individuals who were CMV seropositive. During MSP1 vaccination, reduced antibody induction in individuals who were CMV seropositive was associated with CD4 T cell expression of terminal differentiation marker CD57.</p><p><strong>Interpretation: </strong>These findings suggest that CMV seropositivity may be negatively associated with malaria antibody development. Further studies in larger cohorts, particularly in malaria endemic regions are required to investigate whether CMV infection may modify immunity to malaria gained during infection or vaccination in children.</p><p><strong>Funding: </strong>Work was funded by National Health and Medical Research Council of Australia, CSL Australia and Snow Medical Foundation. Funders had no role in data generation, writing of manuscript of decision to submit for publication.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105419"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protecting vulnerable populations in extreme heat - a growing and pervasive health challenge.","authors":"Zachary J Schlader, Erica Tourula, Maxime Jeanovitch Lignier","doi":"10.1016/j.ebiom.2024.105448","DOIUrl":"10.1016/j.ebiom.2024.105448","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105448"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11570735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.","authors":"Yue Zhao, Xiayan Li, Kai Wang, Gayatri Iyer, Stacey A Sakowski, Lili Zhao, Samuel Teener, Kelly M Bakulski, John F Dou, Bryan J Traynor, Alla Karnovsky, Stuart A Batterman, Eva L Feldman, Maureen A Sartor, Stephen A Goutman","doi":"10.1016/j.ebiom.2024.105383","DOIUrl":"10.1016/j.ebiom.2024.105383","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival.</p><p><strong>Methods: </strong>In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes.</p><p><strong>Findings: </strong>Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons.</p><p><strong>Interpretation: </strong>EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS.</p><p><strong>Funding: </strong>NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105383"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of Charcot-Leyden Crystal protein on mesothelioma chemotherapy: targeting eosinophils for enhanced chemosensitivity.","authors":"Mégane Willems, Malik Hamaidia, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Lea Vilanova Mañá, Roxane Terres, Majeed Jamakhani, Sophie Deshayes, Yves Brostaux, Vincent Heinen, Renaud Louis, Bernard Duysinx, Didier Jean, Eric Wasielewski, Arnaud Scherpereel, Christophe Blanquart, Luc Willems","doi":"10.1016/j.ebiom.2024.105418","DOIUrl":"10.1016/j.ebiom.2024.105418","url":null,"abstract":"<p><strong>Background: </strong>In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.</p><p><strong>Methods: </strong>The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.</p><p><strong>Findings: </strong>Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.</p><p><strong>Interpretation: </strong>This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.</p><p><strong>Funding: </strong>Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105418"},"PeriodicalIF":11.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence in radiology: where are we going?","authors":"Merih Deniz Toruner, Yuli Wang, Zhicheng Jiao, Harrison Bai","doi":"10.1016/j.ebiom.2024.105435","DOIUrl":"10.1016/j.ebiom.2024.105435","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105435"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer's disease neuropathology.","authors":"Mathilde Antoniades, Dhivya Srinivasan, Junhao Wen, Guray Erus, Ahmed Abdulkadir, Elizabeth Mamourian, Randa Melhem, Gyujoon Hwang, Yuhan Cui, Sindhuja Tirumalai Govindarajan, Andrew A Chen, Zhen Zhou, Zhijian Yang, Jiong Chen, Raymond Pomponio, Susan Sotardi, Yang An, Murat Bilgel, Pamela LaMontagne, Ashish Singh, Tammie Benzinger, Lori Beason-Held, Daniel S Marcus, Kristine Yaffe, Lenore Launer, John C Morris, Duygu Tosun, Luigi Ferrucci, R Nick Bryan, Susan M Resnick, Mohamad Habes, David Wolk, Yong Fan, Ilya M Nasrallah, Haochang Shou, Christos Davatzikos","doi":"10.1016/j.ebiom.2024.105399","DOIUrl":"10.1016/j.ebiom.2024.105399","url":null,"abstract":"<p><strong>Background: </strong>Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD).</p><p><strong>Methods: </strong>Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task).</p><p><strong>Findings: </strong>Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits.</p><p><strong>Interpretation: </strong>The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life.</p><p><strong>Funding: </strong>The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"109 ","pages":"105399"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}