Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study.

BACKGROUND Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, “la Caixa” Foundation. We thank the PESA participants and the imaging, administrative, and medical PESA teams. The PESA study is equally co-funded by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and Santander Bank (Madrid, Spain) and also receives funding from the Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI15/02019), the European Regional Development Fund (ERDF—A Way to Build Europe), and the European Social Fund (ESF—Investing in Your Future). CNIC is a Severo Ochoa Center of Excellence (CEX2020- 001041-S) and is supported by the ISCIII, the Spanish Ministry for Science and Innovation, and the Pro-CNIC Foundation. CT-P was supported by a “la Caixa” Foundation fellowship (ID 100010434, LCF/BQ/DI19/11730052). MC-C was supported by a Miguel Servet type II research contract (ISCIII, CPII21/00007) and the Fondo de Investigación Sanitaria (ISCIII, PI20/00819). We acknowledge the Sephardic Foundation on Aging and other donors of the Alzheimer’s Disease Research (grant number A2022034S), a programme of the BrightFocus Foundation, for support of this research. This work was also partially produced with the support of a 2021 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation awarded to MC-C (the Foundation takes no responsibility for the opinions, statements, and contents of this project, which are entirely the responsibility of its authors). BI was supported by the European Research Council (ERC-2018-CoG 819775-MATRIX). MS is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine; KAW2014.0363), the Swedish Research Council (2017-02869, 2021-02678, 2021-06545), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF-agreement (ALFGBG-813971, ALFGBG-965326), the Swedish Brain Foundation (FO2021-0311), and the Swedish Alzheimer Foundation (AF-740191). MS-C receives funding from the European Research Council (grant agreement number 948677), project “PI19/00155”, funded by ISCIII and co-funded by the EU, and a fellowship from “la Caixa” Foundation (ID 100010434) and from the EU’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 847648 (LCF/BQ/PR21/11840004). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018), the EU’s Horizon Europe research and innovation programme under grant agreement number 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation, USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the EU’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 860197 (MIRIADE), the EU Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915, #2022-00732), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALFagreement (#ALFGBG-715986, #ALFGBG-965240), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270), Hjärnfonden, Sweden (#FO2017-0243, #ALZ2022-0006), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer’s Association 2022–2025 grant (SG-23-1038904 QC).S

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study

BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation

Probing proton halo effects in the 8B+64Zn collision around the Coulomb barrier

Proton halo effects in the 8B+64Zn reaction at an energy around 1.5 times the Coulomb barrier have been studied at HIE-ISOLDE CERN using, for the first time, the only existing postaccelerated 8B beam. This, together with the use of a high granularity and large solid angle detection system, allowed for a careful mapping of the elastic angular distribution, especially in the Coulomb-nuclear interference region. Contrary to what is observed for the one-neutron halo nucleus 11Be on the same target in a similar energy range, the analysis of the elastic scattering angular distribution shows only a modest suppression of the Coulomb-nuclear interference peak, with no remarkable enhancement of the total reaction cross-section. Inclusive angular and energy distributions of 7Be produced in direct reaction processes have also been measured. The comparison of these data with the results of theoretical calculations for the elastic and non-elastic breakup contributions indicate that both processes are important. Overall, the experimental data suggest a 8B collision dynamics at the barrier very different from the one of neutron halo nuclei, showing only modest effects of coupling to continuum. This behaviour can be interpreted as due to the presence of the additional Coulomb interactions halo-core and halo-target together with the presence of the centrifugal barrier felt by the valence proton of 8B

Quasi-free (p,pN) scattering of light neutron-rich nuclei around N = 14

Background: For many years, quasifree scattering reactions in direct kinematics have been extensively used to study the structure of stable nuclei, demonstrating the potential of this approach. The RB3 collaboration has performed a pilot experiment to study quasifree scattering reactions in inverse kinematics for a stable C12 beam. The results from that experiment constitute the first quasifree scattering results in inverse and complete kinematics. This technique has lately been extended to exotic beams to investigate the evolution of shell structure, which has attracted much interest due to changes in shell structure if the number of protons or neutrons is varied. Purpose: In this work we investigate for the first time the quasifree scattering reactions (p,pn) and (p,2p) simultaneously for the same projectile in inverse and complete kinematics for radioactive beams with the aim to study the evolution of single-particle properties from N=14 to N=15. Method: The structure of the projectiles O23, O22, and N21 has been studied simultaneously via (p,pn) and (p,2p) quasifree knockout reactions in complete inverse kinematics, allowing the investigation of proton and neutron structure at the same time. The experimental data were collected at the R3B-LAND setup at GSI at beam energies of around 400 MeV/u. Two key observables have been studied to shed light on the structure of those nuclei: the inclusive cross sections and the corresponding momentum distributions. Conclusions: The knockout reactions (p,pn) and (p,2p) with radioactive beams in inverse kinematics have provided important and complementary information for the study of shell evolution and structure. For the (p,pn) channels, indications of a change in the structure of these nuclei moving from N=14 to N=15 have been observed, i.e., from the 0d5/2 shell to the 1s1/2. This supports previous observations of a subshell closure at N=14 for neutron-rich oxygen isotopes and its weakening for the nitrogen isotopes

A transcriptomic analysis of Echinococcus granulosus larval stages:implications for parasite biology and host adaptation

The cestode Echinococcus granulosus--the agent of cystic echinococcosis, a zoonosis affecting humans and domestic animals worldwide--is an excellent model for the study of host-parasite cross-talk that interfaces with two mammalian hosts. To develop the molecular analysis of these interactions, we carried out an EST survey of E. granulosus larval stages. We report the salient features of this study with a focus on genes reflecting physiological adaptations of different parasite stages.We generated ~10,000 ESTs from two sets of full-length enriched libraries (derived from oligo-capped and trans-spliced cDNAs) prepared with three parasite materials: hydatid cyst wall, larval worms (protoscoleces), and pepsin/H(+)-activated protoscoleces. The ESTs were clustered into 2700 distinct gene products. In the context of the biology of E. granulosus, our analyses reveal: (i) a diverse group of abundant long non-protein coding transcripts showing homology to a middle repetitive element (EgBRep) that could either be active molecular species or represent precursors of small RNAs (like piRNAs); (ii) an up-regulation of fermentative pathways in the tissue of the cyst wall; (iii) highly expressed thiol- and selenol-dependent antioxidant enzyme targets of thioredoxin glutathione reductase, the functional hub of redox metabolism in parasitic flatworms; (iv) candidate apomucins for the external layer of the tissue-dwelling hydatid cyst, a mucin-rich structure that is critical for survival in the intermediate host; (v) a set of tetraspanins, a protein family that appears to have expanded in the cestode lineage; and (vi) a set of platyhelminth-specific gene products that may offer targets for novel pan-platyhelminth drug development.This survey has greatly increased the quality and the quantity of the molecular information on E. granulosus and constitutes a valuable resource for gene prediction on the parasite genome and for further genomic and proteomic analyses focused on cestodes and platyhelminths

High rate of subclinical chikungunya virus infection and association of neutralizing antibody with protection in a prospective cohort in the Philippines.

BACKGROUND: Chikungunya virus (CHIKV) is a globally re-emerging arbovirus for which previous studies have indicated the majority of infections result in symptomatic febrile illness. We sought to characterize the proportion of subclinical and symptomatic CHIKV infections in a prospective cohort study in a country with known CHIKV circulation. METHODS/FINDINGS: A prospective longitudinal cohort of subjects ≥6 months old underwent community-based active surveillance for acute febrile illness in Cebu City, Philippines from 2012-13. Subjects with fever history were clinically evaluated at acute, 2, 5, and 8 day visits, and at a 3-week convalescent visit. Blood was collected at the acute and 3-week convalescent visits. Symptomatic CHIKV infections were identified by positive CHIKV PCR in acute blood samples and/or CHIKV IgM/IgG ELISA seroconversion in paired acute/convalescent samples. Enrollment and 12-month blood samples underwent plaque reduction neutralization test (PRNT) using CHIKV attenuated strain 181/clone25. Subclinical CHIKV infections were identified by ≥8-fold rise from a baseline enrollment PRNT titer 50 years old. Baseline CHIKV PRNT titer ≥10 was associated with 100% (95%CI: 46.1, 100.0) protection from symptomatic CHIKV infection. Phylogenetic analysis demonstrated Asian genotype closely related to strains from Asia and the Caribbean. CONCLUSIONS: Subclinical infections accounted for a majority of total CHIKV infections. A positive baseline CHIKV PRNT titer was associated with protection from symptomatic CHIKV infection. These findings have implications for assessing disease burden, understanding virus transmission, and supporting vaccine development

The Level of Protein in Milk Formula Modifies Ileal Sensitivity to LPS Later in Life in a Piglet Model

Background: Milk formulas have higher protein contents than human milk. This high protein level could modify the development of intestinal microbiota, epithelial barrier and immune functions and have long-term consequences. Methodology/Principal findings: We investigated the effect of a high protein formula on ileal microbiota and physiology during the neonatal period and later in life. Piglets were fed from 2 to 28 days of age either a normoprotein (NP, equivalent to sow milk) or a high protein formula (HP, +40% protein). Then, they received the same solid diet until 160 days. During the formula feeding period ileal microbiota implantation was accelerated in HP piglets with greater concentrations of ileal bacteria at d7 in HP than NP piglets. Epithelial barrier function was altered with a higher permeability to small and large probes in Ussing chambers in HP compared to NP piglets without difference in bacterial translocation. Infiltration of T cells was increased in HP piglets at d28. IL-1b and NF-kappa B sub-units mRNA levels were reduced in HP piglets at d7 and d28 respectively; plasma haptoglobin also tended to be reduced at d7. Later in life, pro-inflammatory cytokines secretion in response to high doses of LPS in explants culture was reduced in HP compared to NP piglets. Levels of mRNA coding the NF-kappa B pathway sub-units were increased by the challenge with LPS in NP piglets, but not HP ones. Conclusions/Significance: A high protein level in formula affects the postnatal development of ileal microbiota, epithelial barrier and immune function in piglets and alters ileal response to inflammatory mediators later in life