Perceptions of key informant neurologists before implementing anti-amyloid drugs in the Spanish departments of neurology.

BACKGROUND: A deep knowledge of the healthcare system and the organization of neurology departments is important for planning and optimizing changes to facilitate the successful implementation of anti-amyloid antibodies treatments. OBJECTIVE: We aimed to assess the necessary changes prior to introducing these therapies in our setting. METHODS: We conducted a key informant survey among heads of departments of neurology from 16 hospitals in Spain. The questionnaire comprised questions about changes in the organization and functioning of the departments of neurology with the introduction of anti-amyloid drugs, changes in diagnosis and patient care, use of diagnostic techniques, patients, families and public information, resources allocation, and research. RESULTS: Sixteen key informants completed the survey. They strongly agreed that the introduction of anti-amyloid drugs will impact the functioning of neurology services, especially in hospitals with dementia units. Consensus was reached regarding referring all Alzheimer's disease patients eligible for therapy to dementia units. There was also agreement on the need to expand the neurology services, day hospital units, extend visit durations, and hire more professionals, especially neurologists, neuropsychologists, and nuclear medicine physicians. Furthermore, consensus was achieved on increasing the use of MRI, amyloid PET, cerebrospinal fluid biomarkers, APOE genotyping, and the necessity of advancing blood biomarkers and tau tracers. CONCLUSIONS: Our study highlights the need for extensive changes within Spanish neurological departments to effectively integrate anti-amyloid antibodies. Implementing these changes is essential for the timely and equitable adoption of novel therapies.

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

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.

Plasma Levels of Neuron/Glia-Derived Apoptotic Bodies, an In Vivo Biomarker of Apoptosis, Predicts Infarct Growth and Functional Outcome in Patients with Ischemic Stroke.

Evidence demonstrating the involvement of apoptosis in the death of the potentially salvageable area (penumbra zone) in patients during stroke remains limited. Our aim was to investigate whether apoptotic processes occur in penumbral brain tissue by analyzing circulating neuron- and glia-derived apoptotic bodies (CNS-ApBs), which are vesicles released into the bloodstream during the late stage of apoptosis. We have also assessed the clinical utility of plasma neuronal and glial apoptotic bodies in predicting early neurological evolution and functional outcome. The study included a total of 71 patients with acute hemispheric ischemic stroke (73 ± 10 years; 30 women). Blood samples were collected from these patients immediately upon arrival at the hospital (within 9 h) and at 24 and 72 h after symptom onset. Subsequently, isolation, quantification, and phenotypic characterization of CNS-ApBs during the first 72 h post-stroke were performed using centrifugation and flow cytometry techniques. We found a correlation between infarct growth and final infarct size with the amount of plasma CNS-ApBs detected in the first 72 h after stroke. In addition, patients with neurological worsening (progressive ischemic stroke) had higher plasma levels of CNS-ApBs at 24 h after symptom onset than those with a stable or improving course. Circulating CNS-ApB concentration was further associated with patients' functional prognosis. In conclusion, apoptosis may play an important role in the growth of the cerebral infarct area and plasma CNS-ApB quantification could be used as a predictive marker of penumbra death, neurological deterioration, and functional outcome in patients with ischemic stroke.

Endovascular treatment in Danon disease: a case report.

BACKGROUND: Danon disease is a lysosomal storage disorder with X-linked inheritance. The classic triad is severe hypertrophic cardiomyopathy, myopathy, and intellectual disability, with different phenotypes between both genders. Ischemic stroke is an uncommon complication, mostly cardioembolic, related to intraventricular thrombus or atrial fibrillation, among others. CASE REPORT: We report the case of a 14-year-old Caucasian male patient with Danon disease who suffered from an acute ischemic stroke due to occlusion in the M1 segment of the middle cerebral artery. He underwent mechanical thrombectomy, resulting in successful revascularization with satisfactory clinical outcome. We objectified the intraventricular thrombus in the absence of arrhythmic events. CONCLUSION: To our knowledge, we report the first case of ischemic stroke related to Danon disease treated with endovascular treatment.

Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects.

Between 2.5% and 28% of people infected with SARS-CoV-2 suffer long COVID or persistence of symptoms for months after acute illness. Many symptoms are neurological, but the brain changes underlying the neuropsychological impairments remain unclear. This study aimed to provide a detailed description of the cognitive profile, the pattern of brain alterations in long COVID and the potential association between them. To address these objectives, 83 patients with persistent neurological symptoms after COVID-19 were recruited, and 22 now healthy control subjects chosen because they had suffered COVID-19 but did not experience persistent neurological symptoms. Patients and controls were matched for age, sex and educational level. All participants were assessed by clinical interview, comprehensive standardized neuropsychological tests and structural MRI. The mean global cognitive function of patients with long COVID assessed by Addenbrooke's Cognitive Examination-III screening test [overall cognitive level (OCLz) = -0.39 ± 0.12] was significantly below the infection recovered-controls (OCLz = +0.32 ± 0.16, P < 0.01). We observed that 48% of patients with long COVID had episodic memory deficit, with 27% also with impaired overall cognitive function, especially attention, working memory, processing speed and verbal fluency. The MRI examination included grey matter morphometry and whole brain structural connectivity analysis. Compared to infection recovered controls, patients had thinner cortex in a specific cluster centred on the left posterior superior temporal gyrus. In addition, lower fractional anisotropy and higher radial diffusivity were observed in widespread areas of the patients' cerebral white matter relative to these controls. Correlations between cognitive status and brain abnormalities revealed a relationship between altered connectivity of white matter regions and impairments of episodic memory, overall cognitive function, attention and verbal fluency. This study shows that patients with neurological long COVID suffer brain changes, especially in several white matter areas, and these are associated with impairments of specific cognitive functions.

Ultrasonographic study of the orbit as an early diagnostic tool in Vogt Koyanagi Harada disease (VKH): A case report.

In recent years, ultrasound has demonstrated its usefulness in the approach to vascular structures and other tissues such as the orbit, facilitating the early diagnosis of various diseases without having to rely on other more invasive or less available tests. In Vogt Koyanagi Harada syndrome, characterised by bilateral acute uveitis, ocular ultrasound is a clear example of the usefulness of ultrasonography in early diagnosis, facilitating the initiation of specific treatment to change the ominous natural history of this disease. This case shows the usefulness of the echography to make the differential diagnosis with other diseases that clinical onset could be similar than VKH, but with a different diagnostic and therapeutic approach.

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment.

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.

Increased vertebral canal diameter measured by ultrasonography as a sign of vasculitis in patients with giant cell arteritis.

Introduction: The diagnosis of giant cell arteritis (GCA) by ultrasonography including large vessels, apart from the temporal artery increases the sensibility of the study and informs about the risk of specific complications. However, there is less information about the study of these arteries, whose affection carries higher proportion of severe complications. Objectives: To describe and analyze the value of the diameter of the cervical vertebral canal of the vertebral artery (VA) as a sign of vertebral vasculitis (VV) related to GCA and estimate the risk of stroke complications. Materials and methods: Observational study of a population that includes patients with GCA with and without VA vasculitis as well as healthy subjects. We evaluated whether there were differences in VA diameter in the groups and, if so, we estimated the diagnostic capacity of the variable that best defines VA diameter using a ROC curve. Cut-off points with their associated reliability chosen thereafter. Results: There were 347 subjects included:107 with GCA of whom 37 had vertebral vasculitis, 240 healthy controls. In patients with GCA and VV, the VA diameter was increased (No GCA 3.4 mm, GCA without VV 3.6 mm, GCA with VV 5.2 mm p < 0.01). According to the ROC curves, the variable defining vertebral diameter with best diagnostic accuracy is the sum of both sides (area under the curve of 0.98). With a cut-off point of 8.45 mm, the reliability values are: sensitivity 94.1%, specificity 94.5%, PPV 82.1% and NPV 98.4%. With a cut-off point of 9.95 mm, the sensitivity is 52.9% and the specificity is 100%. Likewise, VA diameter is independently associated with the presence of stroke in the vertebrobasilar territory (OR 1.6, range 1.2-2.2). Conclusion: The VA diameter, measured as the sum of both sides, is an objectively measurable sign with very high reliability for detect vertebral vasculitis in patients with GCA. It is proposed here as a novel echographic sign, which can aid the detection of the involvement of an artery where the complications are especially serious.

Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes.

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 × 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Ulnar nerve thickness at the elbow on longitudinal ultrasound view in control subjects.

INTRODUCTION: Ulnar mononeuropathy at the elbow is the second most frequent neuropathy in humans. Diagnosis is based on clinical and electrophysiological criteria and, more recently, also on ultrasound. Cross-sectional ultrasound is currently the most valued, although longitudinal ultrasound allows assessment of the entire affected trajectory of the nerve in a single view, but always in a straight line with no changes in direction, as in the extended elbow. The main aim of this work is to propose normative values ​​for longitudinal ultrasound of the ulnar nerve at the elbow. METHODS: The neurological exploration of upper extremity, and electrophysiological and ultrasound parameters at the elbow of ulnar nerve were evaluated in 76 limbs from 38 asymptomatic subjects. RESULTS: The diameters of the nerve as well as the distal and proximal areas were larger at the proximal region of the ulnar groove, and even more so in older individuals. In most of these elderly subjects, we found a small, non-significant slowdown in motor conduction velocity at the elbow with respect to the forearm (less than 5 m/s). CONCLUSIONS: We observed a good correlation between the longitudinal and cross-sectional ultrasounds of the ulnar nerve at the elbow. Longitudinal ultrasound proved to be sensitive, reliable, simple and rapid, but its greatest contribution was allowing the visualization of the entire nerve trajectory in an integrated way, providing an image with good definition of the outline, proportions and intraneural characteristics of the nerve.

Symptoms timeline and outcomes in amyotrophic lateral sclerosis using artificial intelligence.

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative motor neuron disease. Although an early diagnosis is crucial to provide adequate care and improve survival, patients with ALS experience a significant diagnostic delay. This study aimed to use real-world data to describe the clinical profile and timing between symptom onset, diagnosis, and relevant outcomes in ALS. Retrospective and multicenter study in 5 representative hospitals and Primary Care services in the SESCAM Healthcare Network (Castilla-La Mancha, Spain). Using Natural Language Processing (NLP), the clinical information in electronic health records of all patients with ALS was extracted between January 2014 and December 2018. From a source population of all individuals attended in the participating hospitals, 250 ALS patients were identified (61.6% male, mean age 64.7 years). Of these, 64% had spinal and 36% bulbar ALS. For most defining symptoms, including dyspnea, dysarthria, dysphagia and fasciculations, the overall diagnostic delay from symptom onset was 11 (6-18) months. Prior to diagnosis, only 38.8% of patients had visited the neurologist. In a median post-diagnosis follow-up of 25 months, 52% underwent gastrostomy, 64% non-invasive ventilation, 16.4% tracheostomy, and 87.6% riluzole treatment; these were more commonly reported (all Ps < 0.05) and showed greater probability of occurrence (all Ps < 0.03) in bulbar ALS. Our results highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes. NLP holds great promise for its application in the wider context of rare neurological diseases.

Atrial fibrillation and stroke: A review and new insights.

The link between heart and brain continues to be a matter of great interest for the scientific community. One of the most established associations between the two is that the heart is a significant source of emboli and is responsible for 20-25% of all ischemic strokes. The most frequent underlying cause of cardioembolic stroke is atrial fibrillation (AF), a disease that affects almost 3 million people in the USA and 4.5 million in Europe. AF increases the risk of ischemic stroke by a factor of 3 to 5 times. It is estimated that AF is responsible for 15% of all strokes worldwide. A more comprehensive understanding of this association and development of intensive stroke prevention measures are needed, as we know that AF incidence and prevalence will increase over the coming years, becoming one of the largest epidemics and public health challenges we face.

Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis.

OBJECTIVE: There has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics. METHODS: MEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF. RESULTS: One hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing. CONCLUSIONS: Our analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF. PROSPERO REGISTRATION NUMBER: CRD42020219844.

The Added Value of Somatosensory Potential N70 in Neurological Prognosis After Coma by Acute Brain Structural Injury: A Retrospective Study.

Background: Coma after acute brain structural injury (ABI) are associated with high mortality and disability. Somatosensory evoked potentials (SSEP) N20 and N70 are used to predict prognosis. Purpose: We assessed the utility of SSEP (N20-N70) as an early indicator of long-term functional prognosis in these patients. Methods: We conducted a retrospective cohort study of patients admitted to the intensive care unit (ICU) with a diagnosis of coma after ABI (n=60). An SSEP study including N20 and N70 was performed 24-72 hours after coma onset. Functional recovery was evaluated 6 to 12 months later using the Modified Glasgow Scale (mGS). The study was approved by our local research ethics committee. Results: The absence of N20 (41% specificity=100%) or N70 (78%) was a strong indicator of a poor outcome. In contrast, the presence of N70 was an indicator of a good outcome (specificity=64.2% sensitivity=91.3%). Conclusion: SSEP N20 and N70 are useful early prognostic markers with high specificity (N20) and sensitivity (N70). N70 has potential additional value for improving the prediction of good functional outcomes in the long term.

Case report: Endovascular embolization of a cerebral pseudoaneurysm caused by SARS-CoV2 infection.

Background: Severe COVID-19 has been shown to produce convulsions, encephalitis, Guillain-Barré syndrome, or cerebrovascular disease. However, only 4 case reports described subarachnoid or brain hemorrhage caused by ruptured cerebral aneurysms or pseudoaneurysms in patients with COVID-19. Cerebral pseudoaneurysms represent <1% of all intracranial aneurysms and have been related to radiation therapy, vasculitis, rupture of true saccular aneurysms, arteriovenous malformations, and infections by bacteria and viruses, such as Epstein-Bar and Herpes virus. Case presentation: A 28-year-old Caucasian woman, with no medical history of interest and completely vaccinated against SARS-CoV-2, was admitted to Neurology due to progressive tetraparesis with areflexia, a cough, and a fever of 38°C. SARS-CoV2 PCR was positive while lumbar puncture, blood tests, and electromyogram showed criteria for Guillain-Barré syndrome. Despite the treatment, the patient developed dyspnea and tetraplegia requiring invasive mechanical ventilation. There was motor neurological improvement but a decreased level of consciousness was observed on day 13. A brain CT scan demonstrated an acute haematoma and cerebral arteriography showed a 4-mm pseudoaneurysm located in a branch of the left middle cerebral artery. Given the high risk of rebleeding, endovascular treatment was decided upon. Therefore, complete embolization of the pseudoaneurysm was carried out by using the synthetic glue N-butyl-cyanocrylate. Two days later, the patient was clinically and neurologically recovered and was discharged. Lastly, a new angiography showed no evidence of the pseudoaneurysm 3-weeks later. Conclusions: We report, for the first time, a patient suffering a severe immune reaction caused by SARS-CoV2 infection and developing a cerebral pseudoaneurysm treated with endovascular embolization without complications.

Functional and Prognostic Assessment in Comatose Patients: A Study Using Somatosensory Evoked Potentials.

Aim: The functional prognosis of patients after coma following either cardiac arrest (CA) or acute structural brain injury (ABI) is often uncertain. These patients are associated with high mortality and disability. N20 and N70 somatosensory evoked potentials (SSEP) are used to predict prognosis. We evaluated the utility of SSEP (N20-N70) as an early indicator of long-term prognosis in these patients. Methods: This was a retrospective cohort study of patients (n = 120) admitted to the intensive care unit (ICU) with a diagnosis of coma after CA (n = 60) or ABI (n = 60). An SSEP study was performed, including N20 and N70 at 24-72 h, after coma onset. Functional recovery was assessed 6-12 months later using the modified Glasgow scale (mGS). The study was approved by our local research ethics committee. Results: In the CA and ABI groups, the absence of N20 (36% of CA patients and 41% of ABI patients; specificity = 100%) or N70 (68% of CA patients and 78% of ABI patients) was a strong indicator of poor outcome. Conversely, the presence of N70 was an indicator of a good outcome (AC: specificity = 84.2%, sensitivity = 92.7%; ABI: specificity = 64.2% sensitivity = 91.3%). Conclusion: Somatosensory evoked potentials are useful early prognostic markers with high specificity (N20) and sensitivity (N70). Moreover, N70 has additional potential value for improving the prediction of good long-term functional outcomes. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [2018/01/001].

A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype.

Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10-8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.

Ischemia preconditioning induces an adaptive response that defines a circulating metabolomic signature in ischemic stroke patients.

Transient ischemic attacks (TIAs) before an acute ischemic stroke (AIS) could induce ischemic tolerance (IT) phenomena. with an endogenous neuroprotective role (Ischemic preconditioning. IPC). A consecutive prospective cohort of patients with AIS were recruited from 8 different hospitals. Participants were classified by those with non-previous recent TIA vs. previous TIA (within seven days. TIA ≤7d). A total of 541 AIS patients were recruited. 40 (7.4%). of them had previous TIA ≤7d. In line with IPC. patients with TIA ≤7d showed: 1) a significantly less severe stroke at admission by NIHSS score. 2) a better outcome at 7-90 days follow-up and reduced infarct volumes. 3) a specific upregulated metabolomics/lipidomic profile composed of diverse lipid categories. Effectively. IPC activates an additional adaptive response on increasing circulation levels of structural and bioactive lipids to facilitate functional recovery after AIS which may support biochemical machinery for neuronal survival. Furthermore. previous TIA before AIS seems to facilitate the production of anti-inflammatory mediators that contribute to a better immune response. Thus. the IT phenomena contributes to a better adaptation of further ischemia. Our study provides first-time evidence of a metabolomics/lipidomic signature related to the development of stroke tolerance in AIS patients induced by recent TIA.

Contribution of Orbital Ultrasound to the Diagnosis of Central Retinal Artery Occlusion.

We aimed to evaluate the diagnostic value of orbital ultrasound in the etiologic diagnosis of central retinal artery occlusion (CRAO). For this purpose, patients with CRAO evaluated at our center between 2011 and 2021 were reviewed. Demographic variables, vascular risk factors and ultrasound findings were collected. An orbital duplex was performed in all cases and complemented with other diagnostic explorations. We attended 36 cases of CRAO. In all patients, orbital ultrasound confirmed the diagnosis of CRAO: in 75% emboli material (spot sign) was observed in CRA and in 25% flow alteration in CRA without visible embolus. The positive spot sign (PSS) group differed from patients with negative spot sign (NSS) in terms of etiology: 8 PSS cases (29.6%) had a major cardioembolic cause, 4 (14.8%) a large vessel atheromatous disease, 15 (55.6%) an undetermined cause. Some 21 (77.8%) PSS patients had some minor cardioembolic cause, mainly calcifications of the left valves. In the NSS group, 2 (22%) were diagnosed with giant cell arteritis (GCA). In CRAO, the ultrasound spot sign could be a guide for the detection of embolic sources. Its absence makes it necessary to consider more strongly the possibility of arteritis. Furthermore, our findings suggest a key role of calcium embolism in PSS patients.

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke.

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.