Año: 2025

How epigenetics impacts stroke risk and outcomes through DNA methylation: A systematic review

Gallego-Fabrega C, Cullell N, Fernández-Cadenas I. J Cereb Blood Flow Metab. 2025 Feb 27:271678X251322032. doi: 10.1177/0271678X251322032. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/40012472/

Abstract: The impact of DNA methylation (DNAm) on epigenetics has gained prominence in recent years due to its potential influence on ischemic stroke (IS) and treatment outcomes. DNAm is reversible and a better understanding of its role in IS could help identify novel therapeutic targets. The aim of this systematic review was to compile the available data on DNAminthe risk and prognosis of IS and to explore its therapeutic potential. The review process followed the PRISMA criteria. We searched the Pubmed and Cochrane databases to identify studies that used hypothesis free methodological approaches. Of the 459 studies identified, 34 met the inclusion criteria. The studies were categorized as follows: risk of IS; outcomes; and DNAm age. Most studies used genotyping array technology rather than whole-genome sequencing. DNAm testing was mainly based on blood samples. Most studies involved European cohorts. Most of the studies were performed at a single-center with recruitment at the time of stroke. In a few studies, health status was determined longitudinally. This systematic review shows that IS patients are biologically older than expected and present characteristic DNAm patterns related to stroke risk and outcomes. These patterns could be used to develop new treatments with epidrugs.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is partially supported by the projects: COPYCTUS (PI21/01088), EPINEXO (PI20/00678), PREVICTUS (PMP21/ 00165) and RICORS-ICTUS (RD21/0006/0006, RD24/0009/ 0029 and RD24/0009/0010) from Instituto de Salud Carlos III (ISCIII, Fondos FEDER/FSE) and STOPPED-Stroke (20231030-31-32) from La Marato Foundation.

NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL

Bugallo-Casal A, Muiño E, Bravo SB, Hervella P et al. Neuromolecular Med. 2025 Feb 27;27(1):18. doi: 10.1007/s12017-025-08840-6. PMID: 40016442

https://pubmed.ncbi.nlm.nih.gov/40016442/

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It is caused by a cysteine-altering variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of Notch3. NOTCH3 pathogenic variants in EGFr 1–6 are associated with high disease severity, whereas those in EGFr 7–34 are associated with late stroke onset and increased survival. However, whether and how the position of the NOTCH3 variant directly affects the disease severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients with CADASIL with EGFr 1–6 and 7–34 pathogenic variants to evaluate whether the NOTCH3 position affects the cell phenotype and protein profile of the generated hiPSCs lines. Six hiPSCs lines were generated: two from patients with CADASIL with EGFr 1–6 pathogenic variants, two from patients with EGFr 7–34 variants, and two from controls. Notch3 aggregation and protein profiles were tested in the established six hiPSCs lines. Cell analysis revealed that the NOTCH3 variants did not limit the cell reprogramming efficiency. However, EGFr 1–6 variant position was associated with increased accumulation of Notch3 protein in pluripotent stem cells and proteomic changes related with cytoplasmic reorganization mechanisms. In conclusion, our analysis of hiPSCs derived from patients with CADASIL support the clinical association between the NOTCH3 variant position and severity of CADASIL.

Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI17/00540, PI20/01014, PI23/000890, RICORS-ICITUS RD21/0006/0003, RD21/0006/0004, RD24/0009/0 022, RD24/0009/0017 and AC23-2/00029. AC23-2/00029 (named as CADANHIS) project has been supported by the EJP RD—European Joint Programme on Rare Diseases—Joint Transnational Call 2023 for Rare Diseases Research Project (JTC 2023). The EJP RD initiative has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement N°825575. Finally, this work was supported by grants from the Instituto de Salud Carlos III, PReDICT Project (PMPER24/00021) together with Next-Generation EU funds that finance the actions of the Recovery and Resilience Mechanism.

Burden of incidental cerebral aneurysms on lifestyle and quality of life: a survey of patients in expectant management (the SPICE Study)

Rodríguez-Pardo J, García-Castro J, Gómez-Escalonilla C et al. J Neurointerv Surg. 2025 Jan 27:jnis-2024-022459. doi: 10.1136/jnis-2024-022459. Epub ahead of print. PMID: 39567189,

https://pubmed.ncbi.nlm.nih.gov/39567189/

Abstract:

Background The increasing availability of neuroimaging tests has led to a rise in the identification of incidental unruptured intracranial aneurysms (UIAs). Their management is under debate, with no consensus on their follow-up strategy, which can cause anxiety in patients. Our aim is to evaluate the impact of diagnosis and imaging follow-up on daily activities and quality of life.

Methods A multicenter cross-sectional study was carried out in patients with UIAs undergoing watchful waiting. Exclusion criteria were history of stroke, renal polycystic disease, symptomatic aneurysms, intervention or scheduled for intervention. The patients completed an anonymous 36-question survey about their habits and perceived quality of life after diagnosis through a validated questionnaire (PROMIS).

Results We obtained 73 responses from 183 patients identified in eight hospitals (40%), 68 of which were included in the study (50 women (74%), median (IQR) age 62 (55–70) years). Forty-nine patients (72%) underwent at least one imaging follow-up per year. Forty-two patients (63%) found follow-up tests reassuring and 12 (18%) experienced concern about the results. Nineteen patients (28%) reported adopting a healthier lifestyle since diagnosis, while 13 (19%) acknowledged a negative impact on their daily activities. Forty-six (68%) admitted avoiding or conditioning at least one activity or situation from a list. PROMIS scores were similar to those of the general reference population. Overall, 77% rated their quality of life as ‘good’ or better.

Conclusions The diagnosis of UIAs seems to influence the activities of the majority of patients. However, follow-up yielded more benefit in the form of healthier lifestyles than harm to daily activities, without detriment to their perceived quality of life.

Funding: Language editing has been funded by the Instituto de Salud Carlos III RICORS-ICTUS Network (RD RD21/0006/0012) endorsed by the European Union – NextGenerationEU.

Digital tool as speech and language therapy for patients with post-stroke aphasia

Ruiz Ares G, Martin Alonso M, Rigual R et al. Digit Health. 2025 Jan 29;11:20552076251314551. doi: 10.1177/20552076251314551. PMID: 39882017.

Abstract:

Introduction: New technologies could play a role in post-stroke aphasia (PSA). Our aims were to develop a digital tool; to evaluate its acceptance and usability by patients and caregivers; and to demonstrate its effectiveness in improving language skills in patients with PSA, applying it from the acute phase. Methods: The study consisted of two phases: development of a digital tool; and an interventional before-and-after study. During the first week of admission, the digital tool, VerbalizAPP®, was installed for use with the help of family/caregivers. PSA was evaluated by a summarised version of the Boston Diagnostic Aphasia Examination (sBDAE) with 0–64 points. After 3 months of using VerbalizAPP®, the sBDAE and scales to assess user satisfaction were applied. Results: Forty patients (29 men, mean age 68.3 years) were included. Aphasia description: Broca’s 12 (15.0%), Wernicke’s13 (32.5%), mixed/global 15 (37.5%) cases. Patients began using VerbalizAPP® 4.8 days (range 2–7) after stroke onset. A significant improvement in sBDAE scores was found after 3 months of VerbalizAPP® use: 35.1 (SD 17.6) versus 51.1 (SD 14.4) points; p <.001. Academic level was the only baseline parameter related to outcomes. Comfort of use scored 8.8, and complexity 2.2 points. Expectations were exceeded in 61.1%, and impression of improvement in 83.3% of cases. No adverse effects were reported, and all participants would recommend VerbalizAPP® to other patients. Conclusions: Our results show the effectiveness of VerbalizAPP® for the treatment of PSA. However, larger prospective validation studies should be conducted to recommend its widespread use.

Funding: The authors disclosed receipt of financial support for the research, authorship, and/or publication of this article from the RICORS network under grant RD21/0006/0012, Spanish Ministry of Health-Carlos III Health Institute (ISCIII) and the Next Generation EU funds (Recovery and Resilience Plan).