Publicaciones: octubre 2024

Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds

Fandler-Höfler S, Eppinger S, Ambler G et al. JAMA Netw Open. 2024 Oct 1;7(10):e2439571. doi: 10.1001/jamanetworkopen.2024.39571. PMID: 39405058

https://pubmed.ncbi.nlm.nih.gov/39405058/

Background and Objectives: Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets.

Methods: Weuse the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAGcombining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component ofexpression or proteinlevels withthe genetic componen to fa trait. We use the ICH cohort from UK Biobank as replication.

Results: For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, p value = 8.91 × 10−12), 10q24.33 (OBFC1, β = −0.12, SE =0.02, p value = 1.67 ×10−8), 13q34 (COL4A2, β = 0.02, SE = 0.02, p value = 2.34 × 10−11), and 19q13.32 (APOC1, β =−0.19, SE =0.03, p value = 1.38 × 10−12; APOE, β = 0.21, SE = 0.03, p value = 2.70 × 10−11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, p value = 1.38 × 10−8); 2 genes (SH3PXD2A, Zscore = 4.83, p value = 6.67 × 10−7;andAPOC1, Z-score: = 5.11, p value = 1.60 × 10−7); and ICA1L transcript (Z-score = 6.8, p value = 9.1 × 10−12) and protein levels (Z-score = −5.8, p value = 6.7 × 10−9).

Funding: This work was supported by grants from the Institutode Salud CarlosIII (PI11/0176),Generaci´on Project,Maestro Project (PI18/01338), INVICTUS+ network, RICORSICTUS (RD21/0006/0006) together with Next-Generation EU funds that finance the actions of the Recovery and Resilience Mechanism,and the Epigenesis Project (Marat´ode TV3), FEDER funds, iBio Stroke project (AC19/00106).E. Muiño is supportedby a R´ıoHortega Contract (CM18/00198) from the Instituto de Salud Carlos III. E. Muiño is supported by the Juan Rod´es contract (JR23/00045) from Instituto de Salud Carlos III. C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). M. Lled´os is supported by a PFIS Contract (Contratos Predoctorales de Formaci´on en Investigaci´on en Salud) from the Instituto de Salud Carlos III (FI19/00309). I. Fern´andez-Cadenas (CP12/03298) is supported by a research contract from Miguel Servet Program from the Instituto de Salud Carlos III.

 

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke

Cárcel-Márquez J, Muiño E, Gallego-Fabrega C et al. Stroke. 2024 Oct;55(10):2462-2471. doi: 10.1161/STROKEAHA.124.047833. Epub 2024 Sep 24 .PMID: 39315829.

https://pubmed.ncbi.nlm.nih.gov/39315829/

Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking.

Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data.

Results: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10−8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings.

Conclusions: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Funding: This study has been funded by Instituto de Salud Carlos III (grant numbers PI18/01338, PI20/00925, PMP21/00165, and PI21/01088), Network of European Funding for Neuroscience Research (AC19/00106), RICORS-ICTUS: Red de Investigación Cooperativa Orientada a Resultados en Salud – Enfermedades Vasculares Cerebrales (RD21/0006/0006), Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CB22/05/00067), Fondo Europeo de Desarrollo Regional, NextGeneration EU, Centres de Recerca de Catalunya Programme/Generalitat de Catalunya, Marató de 3cat grant numbers: 202306-30, 202310-30 and National Institutes of Health RO1 grant Genetic Architecture of Cerebral Edema after Stroke.

The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery

Casado-Fernández L,Laso-García F, Piniella D et al.  Neurobiol Dis. 2024 Oct 15;201:106665. doi: 10.1016/j.nbd.2024.106665. Epub 2024 Sep 12. PMID: 39277144.

https://pubmed.ncbi.nlm.nih.gov/39277144/

Abstract: Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms. This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months’ follow- up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or >50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0–2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes. Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h. In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.

Funding: This work was supported by Carlos III Health Institute (ISCIII) and co-funded by the European Union (European Regional Development Fund-FEDER) under grant PI17/01922 and PI20/00243, Invictus plus network under grant RD16/0019/0005, RICORS ICTUS network under grant RD21/0006/0012 and the Next Generation EU fundig for actions in the Recovery and Resilience Mechanism, Miguel Servet under grant CPII20/00002 to MG-F; CP20/00024 to LO-O, Ministerio de Universidades, Plan de Recuperaci´ on, Transformaci´ on y Resiliencia y la Universidad Aut´ onoma de Madrid under grant CA1/RSUE/2021-00753 to DP, and the Spanish Ministry of Health- (ISCIII) under grant CM20/ 00047 to EA-L, CM23/00022 to LC-F, FI18/00026 to FL-G and FI17/ 00188 to MG-dF. We also thank the editing assistance of Morote Traducciones.

Dubbing language-therapy CINEma-based in aphasia post-stroke (DULCINEA): A feasibility randomized crossover controlled trial

Fuentes B, Jordi-Perea P, Sempere-Iborra C et al. Digit Health. 2024 Oct 10;10:20552076241288311. doi: 10.1177/20552076241288311. PMID: 39421311.

https://pubmed.ncbi.nlm.nih.gov/39421311/

Abstract: Background: Helping people recover from aphasia is among the top 10 research priorities relating to life after stroke. Objective: We aimed to evaluate the feasibility of dubbing techniques (using newly developed software) for post-stroke aphasia therapy and explore its potential efficacy. Methods: Randomised, crossover, interventional, feasibility trial that included patients with chronic post-stroke non-fluent aphasia. The intervention consisted of an individualised programme (16 sessions; 8 weeks) based on dubbing words and sentences progressively adapted to the severity of the aphasia. Patients were allocated to groups that underwent therapy within the first 3 months, or between 3 and 6 months from inclusion, each group serving as the control during the nontherapy periods. Outcomes were the pre-post differences in the Communicative Activity Log, the Boston Diagnostic Aphasia Examination, the General Health Questionnaire-12, the Stroke Aphasia Quality of Life Scale, and the Western Aphasia Battery Revised, administered by psychologists blinded to the patients’ allocation. Results: Recruitment was limited due to COVID-19 and prematurely stopped because of funding coming to an end. A total of 23 patients were randomised, 20 of whom completed the study (1 withdrew consent, and 2 dropped out). The adherence rate to the allocated group was 95.3%. No statistically significant differences were found in any of the outcomes; however, 17 (85%) patients reported subjective improvements in communication skills. Conclusions: This trial shows the feasibility of dubbing therapy (using dedicated software) for patients with post-stroke nonf luent aphasia. Although it lacks statistical power, certain effects on language and communication cannot be ignored.

Funding: This study was promoted by the Research Foundation of La Paz University Hospital, which hosted a research consortium joined by the Department of Neurology at La Paz University Hospital, the Department of Psychology at Comillas Pontifical University, and the patients’ association, Afasia Activa. This project has received funding from “la Caixa” Banking Foundation under the project code LCF/PR/HR19/52160009. The funder was not involved in any of the following processes: design of the trial, data collection, analysis, or interpretation, or writing the manuscript. BF, EdC-R, RR, GR-A, JR-P, EA and MA-L are members of the Spanish Stroke Research Network RICORS ICTUS (RD21/0006/0012) funded by the Carlos III Institute of Health and the European Union (NextGenerationEU). ‘la Caixa’ Foundation, Instituto de Salud Carlos III, (grant number LCF/PR/ HR19/52160009, RD21/0006/0012).

 

Identification of Genetic Loci Associated With Intracerebral Hemorrhage Using a Multitrait Analysis Approach

Muiño E, Carcel-Marquez J, Llucià-Carol L et al. Neurology. 2024 Oct 22;103(8):e209666. doi: 10.1212/WNL.0000000000209666. Epub 2024 Sep 19.PMID: 39298701

https://pubmed.ncbi.nlm.nih.gov/39298701/

Background and Objetives: Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets.

Methods: Weuse the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAGcombining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component ofexpression or proteinlevels withthe genetic componentofa trait. We use the ICH cohort from UK Biobank as replication.

Results: For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, p value = 8.91 × 10−12), 10q24.33 (OBFC1, β = −0.12, SE =0.02, p value = 1.67 ×10−8), 13q34 (COL4A2, β = 0.02, SE = 0.02, p value = 2.34 × 10−11), and 19q13.32 (APOC1, β =−0.19, SE =0.03, p value = 1.38 × 10−12; APOE, β = 0.21, SE = 0.03, p value = 2.70 × 10−11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, p value = 1.38 × 10−8); 2 genes (SH3PXD2A, Zscore = 4.83, p value = 6.67 × 10−7;andAPOC1, Z-score: = 5.11, p value = 1.60 × 10−7); and ICA1L transcript (Z-score = 6.8, p value = 9.1 × 10−12) and protein levels (Z-score = −5.8, p value = 6.7 × 10−9).

Funding: This work was supported by grants from the Institutode SaludCarlosIII (PI11/0176),Generaci´on Project,Maestro Project (PI18/01338), INVICTUS+ network, RICORSICTUS (RD21/0006/0006) together with Next-Generation EU funds that finance the actions of the Recovery and ResilienceMechanism,andtheEpigenesisProject(Marat´ode TV3),FEDERfunds, iBioStrokeproject(AC19/00106).E. Muiño is supportedby aR´ıoHortegaContract (CM18/00198) from the Instituto de Salud Carlos III. E. Muiño is supported by the Juan Rod´es contract (JR23/00045) from Instituto de Salud Carlos III. C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). M. Lled´os is supported by a PFIS Contract (Contratos Predoctorales de Formaci´on en Investigaci´on en Salud) from the Instituto de Salud Carlos III (FI19/00309). I. Fern´andez-Cadenas (CP12/03298) is supported by a research contract from Miguel Servet Program from the Instituto de Salud Carlos III.