Prophylactic corticosteroids for cardiopulmonary bypass in adult cardiac surgery.

BACKGROUND: Cardiac surgery triggers a strong inflammatory reaction, which carries significant clinical consequences. Corticosteroids have been suggested as a potential perioperative strategy to reduce inflammation and help prevent postoperative complications. However, the safety and effectiveness of perioperative corticosteroid use in adult cardiac surgery is uncertain. This is an update of the 2011 review with 18 studies added. OBJECTIVES: Primary objective: to estimate the effects of prophylactic corticosteroid use in adults undergoing cardiac surgery with cardiopulmonary bypass on the: - co-primary endpoints of mortality, myocardial complications, and pulmonary complications; and - secondary outcomes including atrial fibrillation, infection, organ injury, known complications of steroid therapy, prolonged mechanical ventilation, prolonged postoperative stay, and cost-effectiveness. SECONDARY OBJECTIVE: to explore the role of characteristics of the study cohort and specific features of the intervention in determining the treatment effects via a series of prespecified subgroup analyses. SEARCH METHODS: We used standard, extensive Cochrane search methods to identify randomised studies assessing the effect of corticosteroids in adult cardiac surgery. The latest searches were performed on 14 October 2022. SELECTION CRITERIA: We included randomised controlled trials in adults (over 18 years, either with a diagnosis of coronary artery disease or cardiac valve disease, or who were candidates for cardiac surgery with the use of cardiopulmonary bypass), comparing corticosteroids with no treatments. There were no restrictions with respect to length of the follow-up period. All selected studies qualified for pooling of results for one or more endpoints. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all-cause mortality, and cardiac and pulmonary complications. Secondary outcomes were infectious complications, gastrointestinal bleeding, occurrence of new post-surgery atrial fibrillation, re-thoracotomy for bleeding, neurological complications, renal failure, inotropic support, postoperative bleeding, mechanical ventilation time, length of stays in the intensive care unit (ICU) and hospital, patient quality of life, and cost-effectiveness. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: This updated review includes 72 randomised trials with 17,282 participants (all 72 trials with 16,962 participants were included in data synthesis). Four trials (6%) were considered at low risk of bias in all the domains. The median age of participants included in the studies was 62.9 years. Study populations consisted mainly (89%) of low-risk, first-time coronary artery bypass grafting (CABG) or valve surgery. The use of perioperative corticosteroids may result in little to no difference in all-cause mortality (risk with corticosteroids: 25 to 36 per 1000 versus 33 per 1000 with placebo or no treatment; risk ratio (RR) 0.90, 95% confidence interval (CI) 0.75 to 1.07; 25 studies, 14,940 participants; low-certainty evidence). Corticosteroids may increase the risk of myocardial complications (68 to 86 per 1000) compared with placebo or no treatment (66 per 1000; RR 1.16, 95% CI 1.04 to 1.31; 25 studies, 14,766 participants; low-certainty evidence), and may reduce the risk of pulmonary complications (risk with corticosteroids: 61 to 77 per 1000 versus 78 per 1000 with placebo/no treatment; RR 0.88, 0.78 to 0.99; 18 studies, 13,549 participants; low-certainty evidence). Analyses of secondary endpoints showed that corticosteroids may reduce the incidence of infectious complications (risk with corticosteroids: 94 to 113 per 1000 versus 123 per 1000 with placebo/no treatment; RR 0.84, 95% CI 0.76 to 0.92; 28 studies, 14,771 participants; low-certainty evidence). Corticosteroids may result in little to no difference in incidence of gastrointestinal bleeding (risk with corticosteroids: 9 to 17 per 1000 versus 10 per 1000 with placebo/no treatment; RR 1.21, 95% CI 0.87 to 1.67; 6 studies, 12,533 participants; low-certainty evidence) and renal failure (risk with corticosteroids: 23 to 35 per 1000 versus 34 per 1000 with placebo/no treatment; RR 0.84, 95% CI 0.69 to 1.02; 13 studies, 12,799; low-certainty evidence). Corticosteroids may reduce the length of hospital stay, but the evidence is very uncertain (-0.5 days, 0.97 to 0.04 fewer days of length of hospital stay compared with placebo/no treatment; 25 studies, 1841 participants; very low-certainty evidence). The results from the two largest trials included in the review possibly skew the overall findings from the meta-analysis. AUTHORS' CONCLUSIONS: A systematic review of trials evaluating the organ protective effects of corticosteroids in cardiac surgery demonstrated little or no treatment effect on mortality, gastrointestinal bleeding, and renal failure. There were opposing treatment effects on cardiac and pulmonary complications, with evidence that corticosteroids may increase cardiac complications but reduce pulmonary complications; however, the level of certainty for these estimates was low. There were minor benefits from corticosteroid therapy for infectious complications, but the evidence on hospital length of stay was very uncertain. The inconsistent treatment effects across different outcomes and the limited data on high-risk groups reduced the applicability of the findings. Further research should explore the role of these drugs in specific, vulnerable cohorts.

Adapting prescribing criteria for amyloid-targeted antibodies for adults with Down syndrome.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.

Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome.

INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

A Neuropathology Case Report of a Woman with Down Syndrome who Remained Cognitively Stable.

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.

A pathway linking pulse pressure to dementia in adults with Down syndrome.

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.