Management of cognitive impairment associated with post-COVID-19 syndrome: recommendations for primary care.

Introduction: Although post-COVID-19 syndrome (PCS) with cognitive impairment is increasingly encountered in primary care, evidence-based recommendations for its appropriate management are lacking. Methods: A systematic literature search evaluating the diagnosis and treatment of cognitive impairment associated with PCS was conducted. Practical recommendations for the management of PCS-associated cognitive impairment in primary care are summarized, based on an evaluation of pharmacological plausibility and clinical applications. Results: Currently, the pathology of cognitive impairment associated with PCS remains unclear with no high-quality data to support targeted interventions. Existing treatment approaches are directed towards symptom relief where counseling on the chronicity of the disease and regular reassessments at 4- to 8-week intervals is considered reasonable. Patients should be informed and encouraged to adopt a healthy lifestyle that centers around balanced nutrition and appropriate physical activities. They may also benefit from the intake of vitamins, micronutrients, and probiotics. The administration of Ginkgo biloba extract could offer a safe and potentially beneficial treatment option. Other non-pharmacological measures include physiotherapy, digitally supported cognitive training, and, if indicated, ergotherapy or speech therapy. In most patients, symptoms improve within 8 weeks. If serious, ambiguous, or when new symptoms occur, specialized diagnostic measures such as comprehensive neurocognitive testing or neuroimaging should be initiated. Very few patients would require inpatient rehabilitation. Conclusion: PCS with cognitive impairment is a debilitating condition that could affect daily functioning and reduce work productivity. Management in primary care should adopt a multidisciplinary approach, centering around physical, cognitive, and pharmacological therapies.

Biomarkers of early SARS-CoV-2 infection before the onset of respiratory symptoms.

OBJECTIVES: Currently, limited data exist regarding the pathological changes occurring during the incubation phase of SARS-CoV-2 infection. We utilized proteomic analysis to explore changes in the circulatory host response in individuals with SARS-CoV-2 infection before the onset of symptoms. METHODS: Participants were individuals from a randomized clinical trial of prophylaxis for COVID-19 in a workers' dormitory. Proteomic signatures of blood samples collected within 7 days before symptom onset (incubation group) were compared with those collected >21 days (non-incubation group) to derive candidate biomarkers of incubation. Candidate biomarkers were assessed by comparing levels in the incubation group with both infected individuals (positive controls) and non-infected individuals (negative controls). RESULTS: The study included men (mean age 34.2 years and standard deviation 7.1) who were divided into three groups: an incubation group consisting of 44 men, and two control groups-positive (n = 56) and negative (n = 67) controls. Through proteomic analysis, we identified 49 proteins that, upon pathway analyses, indicated an upregulation of the renin-angiotensin and innate immune systems during the virus incubation period. Biomarker analyses revealed increased concentrations of plasma angiotensin II (mean 731 vs. 139 pg/mL), angiotensin (1-7) (302 vs. 9 pg/mL), CXCL10 (423 vs. 85 pg/mL), CXCL11 (82.7 vs. 32.1 pg/mL), interferon-gamma (0.49 vs. 0.20 pg/mL), legumain (914 vs. 743 pg/mL), galectin-9 (1443 vs. 836 pg/mL), and tumour necrosis factor (20.3 vs. 17.0 pg/mL) during virus incubation compared with non-infected controls (all p < 0.05). Plasma angiotensin (1-7) exhibited a significant increase before the onset of symptoms when compared with uninfected controls (area under the curve 0.99, sensitivity 0.97, and specificity 0.99). DISCUSSION: Angiotensin (1-7) could play a crucial role in the progression of symptomatic COVID-19 infection, and its assessment could help identify individuals who would benefit from enhanced monitoring and early antiviral intervention.

Low HALP (Hemoglobin, Albumin, Lymphocyte, and Platelet) Score Increases the Risk of Post-Stroke Cognitive Impairment: A Multicenter Cohort Study.

Objective: The HALP (hemoglobin, albumin, lymphocyte, and platelet) score is a novel indicator that measures systemic inflammation and nutritional status that has not been correlated with the risk of post-stroke cognitive impairment in patients with acute ischemic stroke or transient ischemic attack (TIA). Methods: Study participants were recruited from 40 stroke centers in China. The HALP score was derived using a weighted sum of hemoglobin, albumin, lymphocytes and platelets, and study participants were categorized into 4 groups of equal sizes based on quartiles cutoffs of the HALP score. The Montreal Cognitive Assessment (MoCA)-Beijing Cognitive Assessment Scale (MoCA-Beijing) was performed at 2 weeks and 12 months following stroke onset. Post-stroke cognitive impairment was considered in patients with MoCA-Beijing≤22. Multiple logistic regression methods were employed to evaluate the relationship between the HALP score and the subsequent risk of developing post-stroke cognitive impairment. Results: The study population comprised 1022 patients (mean age 61.6±11.0 years, 73% men). The proportion of individuals with MoCA-Beijing≤22 at 2 weeks was 49.2% and 32.4% at one year. Patients in the lowest quartile of HALP score (<36.56) were observed to harbor the highest risk of post-stroke cognitive impairment at 12 months post-stroke/TIA compared to those in the highest quartile (odds ratio=1.59, 95% CI=1.07-2.37, p=0.022), and lower domain scores for executive function, naming, and attention. There were no statistically significant differences between patients in the different quartiles of HALP score and HALP score at 2 weeks post-stroke/TIA. Conclusion: The HALP score is a simple score that could stratify the risk of post-stroke cognitive impairment in stroke/TIA patients to facilitate early diagnosis and interventions.

Plasma NOTCH3 and the risk of cardiovascular recurrence in patients with ischemic stroke.

BACKGROUND: Ischemic stroke patients are more prone to developing another cardiovascular event. AIM: This study aims to examine potential biological predispositions to cardiovascular recurrence in patients with ischemic stroke. DESIGN: Human and preclinical studies. METHODS: Quantitative proteomic analysis, animal stroke, atherosclerosis models and circulating endothelial cells (CECs) were employed to examine candidate biomarkers derived from an ischemic stroke cohort in Singapore. RESULTS: Proteomic analysis of pooled microvesicles of "Event" (n = 24) and without "Event" (n = 24) samples identified NOTCH3 as a candidate marker; plasma NOTCH3 were shown to be elevated in "Event" patients compared to those without "Events" and age-matched controls. In a validation cohort comprising 431 prospectively recruited ischemic stroke patients (mean age 59.1 years; median follow-up 3.5 years), men with plasma NOTCH3 (>1600pg/ml) harbored increased risk of cardiovascular recurrence (adjusted hazards ratio 2.29, 95% CI 1.10-4.77); no significant association was observed in women. Chronic renal failure, peripheral artery disease and NT-pro-brain natriuretic peptide were significant predictors of plasma NOTCH3 in men without ischemic stroke (adjusted r2=0.43). Following middle cerebral artery occlusion, NOTCH3 expression in mouse sera increased and peaked at 24 hrs, persisting thereafter for at least 72 hours. In Apoe-/- atherosclerotic mice, NOTCH3 stained the endothelium of defective arterial lining and atherosclerotic plaques. Analysis of CECs isolated from stroke patients revealed increased gene expression of NOTCH3, further supporting endothelial damage underpinning NOTCH3-mediated atherosclerosis. CONCLUSION: Findings from this study suggests that NOTCH3 could be important in cardiovascular recurrence following an ischemic stroke.

Left Ventricular Diastolic Dysfunction Is Associated with Poor Functional Outcomes after Endovascular Thrombectomy.

INTRODUCTION: With the advent of endovascular thrombectomy (ET), patients with acute ischaemic strokes (AIS) with large vessel occlusion (LVO) have seen vast improvements in treatment outcomes. Left ventricular diastolic dysfunction (LVDD) has been shown to herald poorer prognosis in conditions such as myocardial infarction. However, whether LVDD is related to functional recovery and outcomes in ischaemic stroke remains unclear. We studied LVDD for possible relation with clinical outcomes in patients with LVO AIS who underwent ET. METHODS: We studied a retrospective cohort of 261 LVO AIS patients who had undergone ET at a single comprehensive stroke centre and correlated LVDD to short-term mortality (in-hospital death) as well as good functional recovery defined as modified Rankin Scale of 0-2 at 3 months. RESULTS: The study population had a mean age of 65-years-old and were predominantly male (54.8%). All of the patients underwent ET with 206 (78.9%) achieving successful reperfusion. Despite this, 25 (9.6%) patients demised during the hospital admission and 149 (57.1%) did not have good function recovery at 3 months. LVDD was present in 82 (31.4%) patients and this finding indicated poorer outcomes in terms of functional recovery at 3 months (OR 2.18, 95% CI 1.04-4.54, p = 0.038) but was not associated with increased in-hospital mortality (OR 2.18, 95% CI 0.60-7.99, p = 0.240) after adjusting for various confounders. CONCLUSION: In addition to conventional echocardiographic indices such as left ventricular ejection fraction, LVDD may portend poorer outcomes after ET, and this relationship should be investigated further.

Hybrid immunity augments cross-variant protection against COVID-19 among immunocompromised individuals.

BACKGROUND: Immunity to SARS-CoV-2 vaccination and infection differs considerably among individuals. We investigate the critical pathways that influence vaccine-induced cross-variant serological immunity among individuals at high-risk of COVID-19 complications. METHODS: Neutralizing antibodies to the wild-type SARS-CoV-2 virus and its variants (Beta, Gamma, Delta and Omicron) were analyzed in patients with autoimmune diseases, chronic comorbidities (multimorbidity), and healthy controls. Antibody levels were assessed at baseline and at different intervals up to 12 months following primary and booster vaccination with either BNT162b2 or mRNA-1273. Immunity induced by vaccination with and without infection (hybrid immunity) was compared with that of unvaccinated individuals with recent SARS-CoV-2 infection. Plasma cytokines were analyzed to investigate variations in antibody production following vaccination. RESULTS: Patients with autoimmune diseases (n = 137) produced lesser antibodies to the wild-type SARS-CoV-2 virus and its variants compared with those in the multimorbidity (n = 153) and healthy groups (n = 229); antibody levels were significantly lower in patients with neuromyelitis optica and those on prednisolone, mycophenolate or rituximab treatment. Multivariate logistic regression analysis identified neuromyelitis optica (odds ratio 8.20, 95% CI 1.68-39.9) and mycophenolate (13.69, 3.78-49.5) as significant predictors of a poorer antibody response to vaccination (i.e, neutralizing antibody <40%). Infected participants exhibited antibody levels that were 28.7% higher (95% CI 24.7-32.7) compared to non-infected participants six months after receiving a booster vaccination. Individuals infected during the Delta outbreak generated cross-protective neutralizing antibodies against the Omicron variant in quantities comparable to those observed after infection with the Omicron variant itself. In contrast, unvaccinated individuals recently infected with the wild-type (n = 2390) consistently displayed lower levels of neutralizing antibodies against both the wild-type virus and other variants. Pathway analyses suggested an inverse relationship between baseline T cell subsets and antibody production following vaccination. CONCLUSION: Hybrid immunity confers a robust protection against COVID-19 among immunocompromised individuals.