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MRI; Lipoproteins Ressonància magnètica; Lipoproteïnes Resonancia magnética; Lipoproteínas Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer’s disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. Methods: The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. Results: We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. Discussion: This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis. This work was funded by the Instituto de Salud Carlos III (ISCIII), (PI17/00275, PI019/00421, PI20/00465, and PI20/00334) and co-financed by the European Regional Development Fund (FEDER). The Neurovascular Research Laboratory was part of the RICORS-ICTUS-Enfermedades Vasculares Cerebrales Network, ISCIII, Spain (RD21/0006/0007). CIBERDEM (CB07/08/0016) was an ISCIII Project.

Additional file 6. Demographic and clinical characteristics of healthy controls, CAA-ICH patients, and AD patients.

Additional file 5. Univariate analysis of MFG-E8 distribution according to the demographic and neuropathological characteristics of the CAA brain cohort.

Additional file 2. Demographic characteristics and CSF parameters of controls from both cohorts.

Additional file 8. Western blot and qPCR results showing the gene silencing efficiency of the siRNA sequence targeting MFG-E8 in HBVSMCs.

Additional file 1. Domain structure and coverage of the murine MFG-E8 sequence and the peptides detected by mass spectrometry.

Additional file 4. Cause of death and patient demographic and neuropathological characteristics in cases with and without CAA.

Additional file 3. List of proteins found by mass spectrometry. Proteins are listed in decreasing order according to the number of spectral counts identified.

Introducción La hemorragia intracerebral (HIC) representa aproximadamente el 10% de los ictus. A pesar de que se asocia a una elevada tasa de morbi-mortalidad, ningún tratamiento ha demostrado ser claramente eficaz. Es por ello muy importante la identificación de factores que puedan contribuir al deterioro clínico y funcional de los pacientes con HIC. De entre los factores conocidos relacionados con una evolución clínica y pronóstico funcional desfavorables destaca el crecimiento del hematoma (CH) durante las primeras horas tras la HIC. La identificación de predictores de CH podría servir para seleccionar aquellos pacientes con alto riesgo de CH para ensayos terapéuticos en pacientes con HIC aguda. Objetivos 1) Investigar la relación entre los niveles de colesterol LDL y el CH en pacientes con HIC aguda así como su impacto en la evolución clínica y el pronóstico funcional. 2) Estudiar la relación existente entre el crecimiento ultraprecoz del hematoma (CuH), la presencia del spot sign y el CH en pacientes con HIC aguda así como el impacto del CuH en la evolución clínica y el pronóstico funcional. Metodología Estudiamos de forma prospectiva pacientes con HIC primaria supratentorial de menos de 6 horas de evolución. Se realizó una TC craneal en las primeras 6 horas y a las 24 horas. En el primer trabajo se determinó el perfil lipídico durante las primeras 24 horas mientras que en el segundo se realizó un angioTC en las primeras 6 horas así como se evaluó el CuH. Se valoró el CH a las 24 horas, así como la presencia de deterioro neurológico precoz, mortalidad a los 3 meses y pronóstico funcional desfavorable. Resultados 1) Los niveles de colesterol LDL se correlacionan de forma inversa con la cantidad de CH a las 24 horas (r=-0’31, p=0’004) así como niveles más bajos se asocian a un mayor riesgo de CH (p=0’003), deterioro neurológico precoz (p=0’012) y mortalidad a los 3 meses (p=0’029) tras una HIC. No se relacionan sin embargo con un pronóstico funcional desfavorable (p=0’875). Niveles de colesterol LDL, Background Intracerebral hemorrhage (ICH) accounts for about 10% of strokes. Despite it is associated with poor outcome and high mortality rates, no proven treatment has been consistently demonstrated to be effective to ameliorate ICH consequences. So, it is mandatory to identify factors related to outcome in patients with ICH. Hematoma growth (HG) has been shown to be an independent determinant of clinical and functional outcome in patients with acute ICH. The identification of predictors of HG may help to select patients at high risk of HG in future treatment trials in patients with acute ICH. Objectives 1) To investigate the relationship between LDL-C levels, HG, early neurological deterioration, 3-month mortality and poor long-term outcome in patients with acute ICH. 2) To investigate the relationship between ultra-early hematoma growth (uHG), spot sign and HG, as well as the impact of the uHG on early neurological deterioration, 3-month mortality and poor long-term outcome in patients with acute ICH. Methods We prospectively studied consecutive patients with primary supratentorial ICH presenting within 6 hours from symptoms onset. CT scan was recorded at baseline and at 24 hours. Lipid profile was obtained during the first 24 hours in the first study while CT angiography was done during the first 6 hours in the second study. We recorded HG at 24 hours, early neurological deterioration, 3-month mortality and poor long-term outcome. Results 1) LDL-C levels are inversely related to the amount of hematoma enlargement at 24h (r=-0.31, p=0.004). Lower LDL-C levels are associated with HG (98.1±33.7 vs. 117.3±25.8 mg/dL, p=0.003), early neurological deterioration (89.2±31.8 vs. 112.4±29.8 mg/dL, p=0.012), and 3-month mortality (94.9±37.4 vs. 112.5±28.5 mg/dL, p=0.029), but not with poor long-term outcome (109.5±31.3 vs. 108.3±30.5 mg/dL, p=0.875). LDL-C level 10.2 mL/h is the most powerful predictor of HG (OR 3.55, 95% CI 1.39–9.07, p=0.008), early neurological deterioration (OR 70.22, 95% CI 14.63–337.03, p

Introducción Debido a la elevada morbi-mortalidad asociadas a la hemorragia intracerebral (HIC) y a la inexistencia de tratamientos claramente eficaces, es muy importante la identificación de factores de riesgo que puedan contribuir tanto al crecimiento del hematoma (CH) como al deterioro clínico y funcional en estos pacientes. Sin embargo, la asociación entre la presión arterial (PA) elevada y el riesgo de CH no ha sido demostrada. Este hecho podría deberse a la necesidad tanto de realizar determinaciones de la PA más frecuentes durante la fase aguda como de estudiar otros parámetros que reflejen mejor los cambios y el curso de la PA. Objetivos 1) Investigar el impacto de los cambios y el curso de la PA en el CH en pacientes con HIC aguda. 2) Evaluar el impacto de los cambios y el curso de la PA en la evolución clínica tras una HIC aguda. 3) Investigar el impacto de los cambios y el curso de la PA en el CH en relación con la presencia de spot sign. 4) Determinar la relación entre los diferentes umbrales de PA sistólica (PAS) con el CH y la evolución clínica en pacientes con HIC aguda. 5) Determinar el beneficio de una monitorización intensiva de la PA sobre una no intensiva en la predicción evolutiva de una HIC aguda. Metodología Estudiamos de forma prospectiva pacientes con HIC primaria supratentorial de menos de 6 horas de evolución. Se realizó una TC craneal en las primeras 6 horas y a las 24 horas. Se realizó una monitorización intensiva no invasiva de la PA cada 15 minutos durante las primeras 24 horas. Se valoró el CH a las 24 horas, así como la presencia de deterioro neurológico precoz (DNP), mortalidad a los 3 meses y pronóstico funcional desfavorable. Resultados 1) La carga de PA sistólica 180 (PAS-180) predijo de forma independiente el CH (OR 1´05, 95% CI 1´010-1´097, p=0´016). 2) La carga de PAS-180 (OR 1´04, 95% CI1´001-1´076, p= 0´042)) y la variabilidad de la PAS (OR 1´2, 95% CI 1´047-1´380, p = 0´009) predijeron de forma independiente DNP. 3) El incremento máximo de PA desde la basal y las cargas de PAS y PA media máximas se correlacionaron de forma significativa al CH en el grupo con ausencia de spot sign. 4) Las cargas de PAS-170, 180, 190 y 200 se correlacionaron de forma significativa con el incremento absoluto y relativo del CH a las 24 horas. La carga de PAS-170 se correlacionó con CH y DNP, mientras que la carga de PAS-160 se asoció con la mortalidad a las 24 horas. 5) Los pacientes con un pobre control de PA a las 6 horas mediante monitorización intensiva experimentaron una mayor tasa de DNP (50%, p =0´02), mientras que aquellos que presentaron un mal control a las 24 horas mediante monitorización intensiva se asociaron con CH (p=0´024) y mal pronóstico funcional (p=0´032). Conclusiones 1) La carga de PAS-180 predice de forma independiente el CH a las 24 horas. 2) Tanto la carga de PAS-180 como la variabilidad de PAS predicen de forma independiente la aparición de DNP 3) La presencia de spot sign en la angioTC craneal no parece influir en la relación de la PA con el CH. 4) El descenso de la PAS como mínimo hasta un umbral de 160 mmHg puede ser necesario para minimizar el efecto deletéreo de la PA elevada en la evolución clínica a las 24 horas. 5) La monitorización intensiva de la PA mejora la detección de pacientes en riesgo de CH y DNP respecto a la monitorización no intensiva., Background Due to both poor outcome and high mortality rates associated with intracerebral hemorrhage (ICH), and also the absence of proven treatments, it is rather important to identify risk factors related to hematoma growth (HG) and clinical and functional outcome. Nevertheless, the relation of higher blodd pressure (BP) with the risk of HG has not been clearly demonstrated yet. More frequent BP measurements during the acute period as well as the study of other parameters that better reflect changes and course of BP may be needed. Objectives 1) To investigate the impact of BP changes and course on HG in acute ICH. 2) To evaluate the impact of BP changes and course on clinical outcome in acute ICH. 3) To investigate the impact of BP changes and course on HG in the spot-sign-positive group. 4)To determinate the association of potential systlic blood pressure (SBP) thresholds with HG and clinical outcome in patients with acute ICH. 5) To determinate efficacy of intensiva BP monitoring compared with non-intensive BP monitoring at clinical outcome in acute HIC. Methods We prospectively studied consecutive patients with primary supratentorial ICH presenting within 6 hours from symptoms onset. CT scan was recorded at baseline and at 24 hours. An automatic non-invasive BP monitoring each 15 minutes during the first 24 hours was performed. We recorded HG at 24 hours, early neurological deterioration, 3-month mortality and poor long-term outcome. Results 1) SBP 180- load independently predicted HG (OR 1.05, 95 % CI 1.010-1.097, P=0.016). 2) Both SBP 180-load (OR 1.04, 95 % CI 1.001-1.076, P=0.042) and SBP variability (OR 1.2, 95 % CI 1.047-1-380, P=0.09) independently predicted early neurological deterioration (END). 3) Higher máximum BP increases from baseline and higher Systolic BP (SBP) and Media BP (MBP) loads were significantly related to HG in the spot-sign-negative group. 4) SPB 170, 180, 190 and 200 loads were significantly correlated with the amount of both absolute anda relative hematoma enlargement at 24 hours. SBP 170 load was related to HG and END, while SBP 160 load was associated wtih mortality at 24 hours.5) Patientes with poor SBP in the first 6 hours detected in intensive BP monitoring experienced higher rate of END (50%, P=0.02). Similarly, poor SBP control within 24h was associated wtih HG (P=0.024) and poor functional outcome (P=0.032) according intensive BP monitoring. Conclusions 1) SBP 180-load independently predicts HG. 2) Both SBP 180-load and SBP variability predict END. 3) The presence of spot-sign-positive in angio-CT does not seem to influence the relation between BP and CH. 4)SBP lowering to at least less tan 160 mmHg threshold may be needed to minimize the deleteious effect of high SBP on 24-hours outcome. 5) Intensive BP monitoring improves the detection of patients in risk of CH and DNP compared with non-intensive BP monitoring.