The teaching of architecture as a result of a misunderstood triad

[ES] El objetivo del artículo es evidenciar el origen y persistencia posterior de un modo de organizar, desde la fragmentación, la enseñanza de la arquitectura. Para ello se desarrolla un análisis de los tratados históricos generalistas destacando las diferencias, por una parte, en la estructura organizativa de los contenidos, por otra, en el enfoque de los fines y los medios de la arquitectura y, finalmente, en su interpretación de la tríada original de Vitruvio. Y es la versión de Perrault en su Abrégé de 1674 la que la tergiversa radicalmente provocando una estructura que aniquila la visión global de la arquitectura. Con él comienza la división en tres partes, construcción, distribución y decoración que influirá en todos los tratados posteriores, salvo en dos autores franceses, que ya a principios y mediados del siglo XIX, la condenaron proponiendo otras alternativas integradoras. Con todo, la fragmentación tripartita, con un claro predominio de la tercera, mantiene firmemente su presencia hasta el siglo XX, e incluso en la actualidad.[EN] The aim of this article is to show the origin and subsequent persistence of a way of organizing, from fragmentation, the teaching of architecture. To this end, an analysis of generalist historical treatises is carried out, highlighting, on one side, the differences in the organizational structure of the contents, on the other, in the approaches to the ends and means of architecture and, finally, in its interpretation of the original Vitruvian Triad. And it is the version of Perrault in his Abrégé of 1674 that radically misunderstood it, creating a structure that destroys the global vision of Architecture. With him begins the division into three parts; construction, distribution and decoration that will influence all subsequent treatises, except for two French authors, who already in the early and mid-nineteenth century rejected it by proposing other integrative alternatives. All in all, tripartite fragmentation, with a clear predominance of the third, firmly maintains its presence until the 20th century, and even today.Onecha Perez, AB.; Gonzalez Moreno-Navarro, JL.; Puntos Pérez, S. (2020). La enseñanza de la Arquitectura como resultado de una tríada tergiversada. VLC arquitectura. Research Journal. 7(2):125-155. https://doi.org/10.4995/vlc.2020.10981OJS12515572Agüera Ruiz, Antonio. Los elementos de la arquitectura por Sir Henry Wotton. Un texto crítico. Valladolid: Universidad de Valladolid, 1997.Alberti, Leon Battista. On the Art of Building in Ten Books. Translated by Joseph Rykwert, Neil Leach, and Robert Tavernor. Cambridge: MIT Press, 1988.Amico, Giovanni Biagio. 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The builder's dictionary or, gentleman and architect's companion. London: A. Bettesworth and C. Hitch; and S. Austen, 1734.González Moreno-Navarro, José Luis. "Arquitectura y construcción en tratados y manuales: un estudio sobre el proceso de desvinculación de los contenidos de construcción en los tratados de arquitectura de los siglos XVI al XIX." PhD diss., Universitat Politècnica de Catalunya, 1987.González Moreno-Navarro, José Luis. El legado oculto de Vitruvio: saber constructivo y teoría arquitectónica. Madrid: Alianza, 1993.Hearn, Fil. Ideas that shaped buildings. Massachusetts: MIT Press, 2003.Hitchcock, H. R. Architecture: nineteenth and twentieth centuries. 3rd ed. Harmondsworth: Penguin, 1968.Kruft, Hanno Walter. Geschichte der Architekturtheorie: von der Antike bis zur Gegenwart. München: C.H. Beck, 1985.Laugier, Marc-Antoine. Essai sur l'architecture. Paris: Duchesne, 1753.Le Muet, Pierre. Maniere de bastir pour touttes sortes de personnes. Paris: Melchior Tavernier, 1623.Leoncini, Giuseppe. Instruttioni architettoniche pratiche. Roma: Matteo Gregorio Rossi, 1679.Lemerle, Frédérique. "Présentation scientifique sur, Abrégé des dix livres d'Architecture." In Architectura, Textes et images en France. XVIe-XVIIe siècles. Centre d'Études Supérieures de la Renaissance. Accessed july 22, 2020. http://architectura.cesr.univ-tours.fr/Traite/Notice/PerraultCl1674.asp?param=.Leoni, Giacomo. The architecture of A. Palladio; in four books. London: John Watts, 1715.Leoni, Giacomo. The Architecture of Leon Battista Alberti in ten books. London: Thomas Edlin, 1726.Lucan, Jacques. Composition, non-composition: architecture et théories, XIXe-XXe siècles. Lausanne: Presses Polytechniques et Universitaires Romandes, 2009.Masi, Girolamo. Teoria e pratica di architettura per istruzione della gioventù specialmente romana. Roma: Antonio Fulgoni, 1788.Memmo, Andrea. Elementi d'architettura lodoliana ossia l'arte del fabbricare con solidità scientifica e con eleganza non capricciosa. Zara: Fratelli Battara, 1833.Milizia, Francesco. Principj di Architettura Civile. Finale: Jacopo de' Rossi, 1781.Morgan, Morris Hicky. Vitruvius, The Ten Books on Architecture. Cambridge: Harvard University Press, 1914.Moxon, Joseph. Mechanick Exercises: or The doctrine of handy-works: applied to the arts of smithing, joinery, carpentry, turning, bricklayery. Londres: Dan. Widwinter and Tho. Leigh, 1703.Neve, Richard. The city and country purchaser's and builder's dictionary: or, The complete builder's guide. 3rd ed. London: B. Sprint, D. Browne, J. Osborn, S. Birt, H. Lintot, and A. Wilde, 1736.Nicholson, Peter. The Principles of Architecture. London, 1795-1798.Onecha, Belen, "Una nueva aproximación al De re aedificatoria de Leon Battista Alberti: los conocimientos constructivos y sus fuentes." PhD diss., Universitat Politècnica de Catalunya, 2012.Palladio, Andrea. I Quattro libri dell'architettura. Venice: Dominico de' Franceschi, 1570.Palladio, Andrea. The Four Books of Architecture. Translated by Isaac Ware. London, 1738. With a new introduction by Adolf K. Placzek. New York: Dover, 1965.Patte, Pierre. Mémoires sur les objets les plus importans de l'architecture. Paris: Rozet, 1769.Perrault, Claude. Abrégé des dix livres d'architecture de Vitruve. Paris: Jean-Baptiste Coignard, 1674.Perrault, Claude. Mémoires pour servir à l'histoire naturelle des animaux. Paris: Impr. Royal, 1676. https://doi.org/10.5962/bhl.title.151067Perrault, Claude. An abridgment of the architecture of Vitruvius: containing a system of the whole works of that author / illustrated with divers copper plates, curiously engraved; with a table of explanation, to which is in this edition the etymology and derivation of the terms used in architecture; first done in french by Monsr Perrault ... and now englished, with additions. London: Abel Swall and T. Child, 1692.Picon, Antoine. Claude Perrault, 1613-1688 ou la curiosité d'un classique. Paris: Picard, 1988.Puntos, Sonsoles. "Los tratados de construcción históricos británicos, siglos XVII y XVIII: análisis de sus contenidos sobre técnicas de construcción y su aplicación en rehabilitación." PhD diss., Universitat Politècnica de Catalunya, Barcelona, 2015.Reynaud, Léonce. Traité d'architecture. Paris: Carilian-Goeury et V. Dalmont, 1850.Rondelet, Jean. Traité théorique et pratique de l'art de bâtir. Paris: L'auteur, 1802-1818.De San Nicolás, Fray Lorenzo. Arte y uso de arquitectura. Madrid, 1639.Sanvitali, Federico. Elementi di Architettura Civile. Brescia: Giammaria Rizzardi, 1765.Scamozzi, Vincenzo. L'idea della architettura universale. Venice: author, 1615.Serlio, Sebastiano. I sette libri dell'architettura. Venice, 1584.Smith, Korydon. Introducing architectural theory. Debating a discipline. New York: Routledge, 2012. https://doi.org/10.4324/9780203084236Da Vignola, Iacomo Barozzio. Regola delli Cinque Ordini d'Architettura. Roma, 1562.Viollet-le-Duc, Eugène-Emmanuel. "L'enseignement des arts: il y a quelque chose à faire (troisième article)." Gazette des Beaux Arts, July 1862.Vitruvii Pollionis, M. De Architectura. Opus in Libris Decem. First century BC.Ware, Isaac. A complete body of architecture. London: T. Osborne & J. Shipton, 1756.Wotton, Henry. The elements of architecture, collected by Sir Henry Wotton from the best authors and examples. London: John Bill, 1624.Yeomans, David T. "Early carpenters' manuals 1592-1820." Journal of Construction History 2 (1986)

NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

Dystonia; Parkinson's disease/Parkinsonism; Genetic linkageMalaltia de Parkinson/Parkinsonisme; Vinculació genètica; DistoniaEnfermedad de Parkinson/Parkinsonismo; Enlace genético; DistoníaThis work was supported by the Health Institute Carlos III—General Subdirectorate for Research Evaluation and Promotion (PI16/01575, PI18/01898, PI18/00147, PI19/01576), the Spanish Ministry of Economy and Competitiveness (SAF2007-60700), the Ministry of Economy, Innovation, Science and Business of the Government of Andalucía (CVI-02526, CTS-7685), the Ministry of Health and Social Welfare of the Government of Andalucía (PI-0459-2018, PE-0210-2018, PE-0186-2019) and by the Valencian Government (PROMETEO/2018/135), within the framework of the National Research and Development Plan co-funded with European Regional Development Funds. Part of the equipment employed in this study was funded by the Valencian Government and co-financed with European Regional Development Funds (OP ERDF of Valencian Community 2014-2020). I. Hinarejos has a PFIS-PhD fellowship (FI19/00072), S. Jesús has a contract “Acción B Clínicos-Investigadores” (Action B Clinicians-Researchers) contract (B-0007-2019) funded by the Ministry of Health and Family of the Government of Andalucía, and D. Macías-García has a Río Hortega contract (CM18/00142) funded by the Health Institute Carlos III

Non-destructive production of exosomes loaded with ultrathin Palladium nanosheets for targeted bioorthogonal catalysis

The use of exosomes as selective delivery vehicles of therapeutic agents, such as drugs or hyperthermia-capable nanoparticles, is being intensely investigated on account of their preferential tropism toward their parental cells. However, the methods used to introduce a therapeutic load inside exosomes often involve disruption of their membrane, which may jeopardize their targeting capabilities, attributed to their surface integrins. On the other hand, in recent years bio-orthogonal catalysis has emerged as a new tool with a myriad of potential applications in medicine. These bio-orthogonal processes, often based on Pd-catalyzed chemistry, would benefit from systems capable of delivering the catalyst to target cells. It is therefore highly attractive to combine the targeting capabilities of exosomes and the bio-orthogonal potential of Pd nanoparticles to create new therapeutic vectors. In this protocol, we provide detailed information on an efficient procedure to achieve a high load of catalytically active Pd nanosheets inside exosomes, without disrupting their membranes. The protocol involves a multistage process in which exosomes are first harvested, subjected to impregnation with a Pd salt precursor followed by a mild reduction process using gas-phase CO, which acts as both a reducing and growth-directing agent to produce the desired nanosheets. The technology is scalable, and the protocol can be conducted by any researcher having basic biology and chemistry skills in ~3 d.We gratefully acknowledge financial support from the ERC Advanced Grant CADENCE (grant no. ERC-2016-ADG-742684) and the EPSRC (Healthcare Technology Challenge award no. EP/N021134/1). M.S.-A. thanks the Spanish Government for an FPU PhD research fellowship. B.R.-R. thanks the EC (grant no. H2020-MSCA-IF-2014–658833). V.S. acknowledges the financial support of Ministerio de Ciencia, Innovación y Universidades, Programa Retos Investigación, Proyecto REF: RTI2018-099019-A-I00. M.A. acknowledges the financial support of the ERC Consolidator Grant programme (grant no. ERC-2013-CoG-614715). P.M.-D. also thanks Instituto de Salud Carlos III (PI19/01007). We also thank CIBER-BBN, an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III and by Fondo Europeo de Desarrollo Regional (Feder) ‘Una manera de hacer Europa’, with the assistance of the European Regional Development Fund. This study is also partially funded by the Aragon Government (T57_17R p) cofounded by Feder 2014–2020 ‘Building Europe from Aragon’.Peer reviewe

In Cellulo Bioorthogonal Catalysis by Encapsulated AuPd Nanoalloys. Overcoming Intracellular Deactivation

Bioorthogonal metallocatalysis has opened up a xenobiotic route to perform nonenzymatic catalytic transformations in living settings. Despite their promising features, most metals are deactivated inside cells by a myriad of reactive biomolecules, including biogenic thiols, thereby limiting the catalytic functioning of these abiotic reagents. Here we report the development of cytocompatible alloyed AuPd nanoparticles with the capacity to elicit bioorthogonal depropargylations with high efficiency in biological media. We also show that the intracellular catalytic performance of these nanoalloys is significantly enhanced by protecting them following two different encapsulation methods. Encapsulation in mesoporous silica nanorods resulted in augmented catalyst reactivity, whereas the use of a biodegradable PLGA matrix increased nanoalloy delivery across the cell membrane. The functional potential of encapsulated AuPd was demonstrated by releasing the potent chemotherapy drug paclitaxel inside cancer cells. Nanoalloy encapsulation provides a novel methodology to develop nanoreactors capable of mediating new-to-life reactions in cell

A 5-FU precursor designed to evade anabolic and catabolic drug pathways and activated by Pd chemistry in vitro and in vivo

We are grateful to the EPSRC (EP/N021134/1) for funding. T.L.B. thanks the CMVM of the University of Edinburgh (Principal's scholarship), and B.R.-R. thanks the EC (H2020MSCA-IF-2014-658833, ChemoBOOM) for financial support. A.U.-B. and D.J.B. thank Medical Research Scotland (PHD-1046-2016) for funding. We acknowledge support from the MRC Confidence in Concept scheme (MRC/CIC6/52) and EPSRC Impact Acceleration Account (PIII024).5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.UK Research & Innovation (UKRI) Engineering & Physical Sciences Research Council (EPSRC) EP/N021134/1CMVM of the University of EdinburghEuropean Commission European Commission Joint Research Centre H2020MSCA-IF-2014-658833Medical Research Scotland PHD-1046-2016UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MRC/CIC6/52 UK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) PIII02

UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival

International audienc

Human iPSC derived disease model of MERTK-associated retinitis pigmentosa

Retinitis pigmentosa (RP) represents a genetically heterogeneous group of retinal dystrophies affecting mainly the rod photoreceptors and in some instances also the retinal pigment epithelium (RPE) cells of the retina. Clinical symptoms and disease progression leading to moderate to severe loss of vision are well established and despite significant progress in the identification of causative genes, the disease pathology remains unclear. Lack of this understanding has so far hindered development of effective therapies. Here we report successful generation of human induced pluripotent stem cells (iPSC) from skin fibroblasts of a patient harboring a novel Ser331Cysfs*5 mutation in the MERTK gene. The patient was diagnosed with an early onset and severe form of autosomal recessive RP (arRP). Upon differentiation of these iPSC towards RPE, patient-specific RPE cells exhibited defective phagocytosis, a characteristic phenotype of MERTK deficiency observed in human patients and animal models. Thus we have created a faithful cellular model of arRP incorporating the human genetic background which will allow us to investigate in detail the disease mechanism, explore screening of a variety of therapeutic compounds/reagents and design either combined cell and gene- based therapies or independent approaches.This work was supported by Andalusian Health Council (PI-0324-2013), Instituto de Salud Carlos III (PI13/01331), Spanish Ministry of Economy and Competitiveness-FEDER BFU2012-36845, Instituto de Salud Carlos III RETICS RD12/0034/0010 and Academy of Finland (218050; 272808)

Cardiac Insulin Resistance in Subjects With Metabolic Syndrome Traits and Early Subclinical Atherosclerosis.

OBJECTIVE Experimental evidence suggests that metabolic syndrome (MetS) is associated with changes in cardiac metabolism. Whether this association occurs in humans is unknown. RESEARCH DESIGN AND METHODS 821 asymptomatic individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study (50.6 [46.9-53.6] years, 83.7% male) underwent two whole-body 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET-MR) 4.8 ± 0.6 years apart. Presence of myocardial 18F-FDG uptake was evaluated qualitatively and quantitatively. No myocardial uptake was grade 0, while positive uptake was classified in grades 1-3 according to target-to-background ratio tertiles. RESULTS One hundred fifty-six participants (19.0%) showed no myocardial 18F-FDG uptake, and this was significantly associated with higher prevalence of MetS (29.0% vs. 13.9%, P < 0.001), hypertension (29.0% vs. 18.0%, P = 0.002), and diabetes (11.0% vs. 3.2%, P < 0.001), and with higher insulin resistance index (HOMA-IR, 1.64% vs. 1.23%, P < 0.001). Absence of myocardial uptake was associated with higher prevalence of early atherosclerosis (i.e., arterial 18F-FDG uptake, P = 0.004). On follow-up, the associations between myocardial 18F-FDG uptake and risk factors were replicated, and MetS was more frequent in the group without myocardial uptake. The increase in HOMA-IR was associated with a progressive decrease in myocardial uptake (P < 0.001). In 82% of subjects, the categorization according to presence/absence of myocardial 18F-FDG uptake did not change between baseline and follow-up. MetS regression on follow-up was associated with a significant (P < 0.001) increase in myocardial uptake. CONCLUSIONS Apparently healthy individuals without cardiac 18F-FDG uptake have higher HOMA-IR and higher prevalence of MetS traits, cardiovascular risk factors, and early atherosclerosis. An improvement in cardiometabolic profile is associated with the recovery of myocardial 18F-FDG uptake at follow-up.The PESA study is funded by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Santander Bank. B.I. is supported by the European Commission (grant numbers 819775 and 945118), by the Spanish Ministry of Science and Innovation (PID2019- 110369RB-I00), and by the Red Madrilena de ~ Nanomedicina en Imagen Molecular-Comunidad de Madrid (S2017/BMD-3867 RENIM-CM). A.D. is an Alfonso Martin Escudero fellow and is scientifically supported by La Caixa Foundation. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacion (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/ 10.13039/501100011033).S

Phenotypic and molecular characterization of IMP-producing Enterobacterales in Spain: Predominance of IMP-8 in Klebsiella pneumoniae and IMP-22 in Enterobacter roggenkampii

Objectives: Little is known about IMP-producing Enterobacterales (IMP-Ent) in Europe. We analyzed at genomic and phenotypic level IMP-Ent isolates circulating in Spain in a 9-year period. Materials and methods: IMP-Ent isolates submitted to our reference laboratory were included. Antibiotic susceptibility was performed using microdilution method (EUCAST), and IMP-carbapenemase activity was measured with carbapenemase inhibitors, the β-CARBA method, the modified Hodge test (MHT), and the modified carbapenemase inhibition method (mCIM). All isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis. Results: Fifty IMP-Ent isolates, collected from 19 hospitals in 13 Spanish provinces, were detected: Klebsiella pneumoniae (IMP-Kpn) (24; 48%), Enterobacter roggenkampii (13; 26%), Enterobacter hormaechei (8, 16%), Klebsiella oxytoca (two; 4%), Enterobacter asburiae (one, 2%), Serratia marcescens (one; 2%) and Escherichia coli (one; 2%). All isolates were positive by the MHT and β-CARBA tests; 48 (96%) were mCIM positive; 12 (24%) and 26 (52%) displayed positive inhibition with dipicolinic (meropenem) and EDTA (ertapenem), respectively. Five IMP-carbapenemase types were identified: IMP-8 (22; 44%), IMP-22 (17; 34%), IMP-13 (7; 14%), IMP-28 (two; 4%), and IMP-15 (two; 4%), predominating IMP-8 in K. pneumoniae and IMP-22 in E. roggenkampii. IMP-28 was exclusively identified in K. oxytoca and IMP-15 in E. hormaechei. Predominant STs were ST405 (29.2%), ST15 (25%) and ST464 (20.8%) in IMP-Kpn; ST96 (100%) in E. roggenkampii and ST182 (62.5%) in E. hormachei. Colistin and amikacin were the most active non-carbapenem antibiotics against IMP-Ent. Conclusion: IMP-Ent isolates remain infrequent in Spain, although in recent years have been circulating causing nosocomial outbreaks, being IMP-8-producing K. pneumoniae and IMP-22-producing E. roggenkampii the most frequently detected in this study. Inhibition with EDTA or dipicolinic acid presented false negative results in some IMP-producing strains. Active microbiological and molecular surveillance is essential for a better comprehension and control of IMP-Ent dissemination.This research was supported by grants from the Instituto de Salud Carlos III (numbers PI18CIII/00030 and PI21CIII/00039). This research was also supported by CIBER-Consorcio Centro de Investigación Biomédica en Red (CB21/13/00095 and CB21/13/000968), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU. This work was supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16CIII/0004/0002 and REIPI RD16/0016/0007) and co-financed by the European Development Regional Fund (EDRF), “A way to achieve Europe,” Operative program Intelligent Growth, 2014–2020.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.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