Anales de la RANM

35 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 S U P L E M E N T O I SIMPOSIO · JÓVENES INVESTIGADORES Libro de Abstracts An RANM. 2021;138(03).supl01: 35 - 54 Systemic inflammatory markers like CRP or PCT were elevated in septic patients’ plasma 24h after sepsis initiation when compared to the control groups (Figure 1), indicating an inflammatory state of the septic patients. The release of IL-1β in whole blood samples and the formation of ASC specks in monocytes after NLRP3 stimulation resulted in a differential response among septic patients, identifying a group of 10 individuals with an impaired NLRP3 inflammasome activation and 4 individuals with a normal response of the NLRP3 inflammasome (Figure 2A). However, all septic patients presented a non-impaired activation of the Pyrin inflammasome (Figure 2B). Septic patients with impaired NLRP3 inflammasome had biochemical and clinical scores of disease severity above the average. Specifically, SOFA and APACHEII were higher at admission in the group with NLRP3 inflammasome impairment (Figure 2), and these indivi- duals also present worst disease progression measured as days in the critical care unit, days with mechanical ventilation and mortality (Figure 2). Plasma concentration of CRP and PCT decreased after 3 and 5 days of sepsis onset in all septic patients, indicating a gradual resolution of systemic inflammation (Figure 3A). At hospital discharge, NLRP3-immunocompromised septic patients who survived and recovered from sepsis had an improve- ment on NLRP3 activation. Non-compromised NLRP3 septic patients had normal ASC-speck formation during the course of sepsis (Figure 3B-C). This suggests that NLRP3 inflammasome impairment during sepsis is a transitory state. Our study confirms that during the initial inflamma- tory response in sepsis there is a differential response of the NLRP3 inflammasome in septic patients. The identification of NLRP3-immunocompromised septic patients was optimized in a whole blood assay and accounted for most late deaths and have the worse prognosis. Whereas, the Pyrin inflammasome response was similar in patients and suggests that Pyrin inflammasome present different regulation mechanisms inflammasome during sepsis. The impairment of the NLRP3 inflammasome in septic patients might serve as an early indication of immuno- suppression in critical patients, while the Pyrin inflam- masome emerge as a positive control of inflammasome activation. Moreover, restoration of NLRP3 inflam- masome activation in monocytes could be a good indicator of immune recovery in septic patients. Acknowledgements: This work was supported by grants to P.P. from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (grant SAF2017-88276-R; PID2020- 116709RB-I00), Fundación Séneca (grants 20859/ PI/18, 21081/PDC/19 and 0003/COVI/20), Instituto de Salud Carlos III (DTS21/00080), European Commission H2020-SC1-2020-Single-Stage-RTD (965196 - PlasticHeal) and European Research Council (grants ERC-2013-CoG 614578 and ERC-2019-PoC 899636). Laura Hurtado-Navarro was supported by the fellowship 21214/FPI/19 (Fundación Séneca, Región de Murcia, Spain). El síndrome de Down es una forma de enfermedad de Alzheimer determinada genéticamente debido al efecto de la dosis del gen de la proteína precur- sora del amiloide. Como resultado, la patología de la enfermedad de Alzheimer se desarrolla en el cerebro desde la adolescencia y, a los 40 años, todos los individuos tienen placas de amiloide y ovillos neurofibrilares compuestas por la proteína tau hiperfosforilada. El riesgo acumulado de desarro- llar demencia por enfermedad de Alzheimer supera ampliamente el 90% en la séptima década de la vida. En consecuencia, la enfermedad de Alzheimer es ahora el principal problema médico y la principal causa de muerte en esta población. Recientemente se ha puesto de manifiesto en estudios patoló- gicos y de biomarcadores que la fisiopatología y una historia natural de la enfermedad de Alzheimer es muy similar a la descrita en la enfermedad de Alzheimer esporádica y autosómica dominante. Sin embargo, el infradiagnóstico es frecuente debido a la falta de conocimiento por parte de médicos y familiares y a los desafíos diagnósticos que plantea la discapacidad intelectual asociada al síndrome de Down. Los biomarcadores, incluidos los plasmá- ticos, han mostrado resultados muy prometedores en el diagnóstico, pero actualmente solo se utilizan en escasos centros en contexto de investigación. No existen tratamientos para prevenir la enfermedad a pesar de que el síndrome de Down es probablemente la mejor población para realizar ensayos de preven- ción de la enfermedad de Alzheimer, ya que es una población única y relativamente prevalente con una etiología conocida. La investigación en síndrome de Down es fundamental para mejorar la calidad de vida y encontrar tratamientos para la enfermedad de Alzheimer que puedan beneficiar tanto al síndrome de Down como a la población en general. Down syndrome is form of genetically determined Alzheimer’s disease due to the amyloid precursor protein gene dose effect. As a result Alzheimer’s disease pathology develops in the brain since adoles- cence and by age 40 all individuals have amyloid plaques and tau neurofibrillary tangles. The lifetime risk to develop Alzheimer’s disease dementia is well over 90% by the seventh decade of life. LA ENFERMEDAD DE ALZHEIMER EN EL SÍNDROME DE DOWN: UNA FORMA DE ALZHEIMER GENÉTI- CAMENTE DETERMINADA DOWN SYNDROME ASSOC I ATED ALZHE IMER ’ S D I SEASE: A GENET I CALLY DETERMI NED FORM OF DEMENT I A Juan Fortea 1,2,3 1 Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 2 CIBERNED, Madrid, Spain 3 Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain