Integrated Multi-Omics Analysis of Cerebrospinal Fluid in Postoperative Delirium.

Preoperative risk biomarkers for delirium may aid in identifying high-risk patients and developing intervention therapies, which would minimize the health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults ≥ 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case-no delirium control design. We performed metabolomics and lipidomics, which were combined with our previously reported proteomics results on the same samples. Differential expression, clustering, classification, and systems biology analyses were applied to individual and combined omics datasets. Probabilistic graph models were used to identify an integrated multi-omics interaction network, which included clusters of heterogeneous omics interactions among lipids, metabolites, and proteins. The combined multi-omics signature of 25 molecules attained an AUC of 0.96 [95% CI: 0.85-1.00], showing improvement over individual omics-based classification. We conclude that multi-omics integration of preoperative CSF identifies potential risk markers for delirium and generates new insights into the complex pathways associated with delirium. With future validation, this hypotheses-generating study may serve to build robust biomarkers for delirium and improve our understanding of its pathophysiology.

Prediction of Post-Operative Delirium in Older Adults from Preoperative Cognition and Alpha Power from Resting-State EEG.

Postoperative Delirium (POD) is the most common complication following surgery among older adults, and has been consistently associated with increased mortality and morbidity, cognitive decline, and loss of independence, as well as markedly increased health-care costs. The development of new tools to identify individuals at high risk for POD could guide clinical decision-making and enable targeted interventions to potentially decrease delirium incidence and POD-related complications. In this study, we used machine learning techniques to evaluate whether baseline (pre-operative) cognitive function and resting-state electroencephalography could be used to identify patients at risk for POD. Pre-operative resting-state EEGs and the Montreal Cognitive Assessment (MoCA) were collected from 85 patients (age = 73 ± 6.4 years) undergoing elective surgery, 12 of whom subsequently developed POD. The model with the highest f1-score for predicting delirium, a linear-discriminant analysis (LDA) model incorporating MoCA scores and occipital alpha-band EEG features, was subsequently validated in an independent, prospective cohort of 51 older adults (age ≥ 60) undergoing elective surgery, 6 of whom developed POD. The LDA-based model, with a total of 7 features, was able to predict POD with area under the receiver operating characteristic curve, specificity and accuracy all >90%, and sensitivity > 80%, in the validation cohort. Notably, models incorporating both resting-state EEG and MoCA scores outperformed those including either EEG or MoCA alone. While requiring prospective validation in larger cohorts, these results suggest that prediction of POD with high accuracy may be feasible in clinical settings using simple and widely available clinical tools.

Pre-diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population-based cohort studies from the United States and the United Kingdom.

Previous studies suggest a role for inflammation in hepatocarcinogenesis. However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case-control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p < .05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (pFDR < .05). Two proteins (stem cell factor, OR per SD = 0.31, 95% CI = 0.16-0.58; tumor necrosis factor superfamily member 12, OR per SD = 0.51, 95% CI = 0.31-0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs per SD ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.

Relationship between cortical brain atrophy, delirium, and long-term cognitive decline in older surgical patients.

In older patients, delirium after surgery is associated with long-term cognitive decline (LTCD). The neural substrates of this association are unclear. Neurodegenerative changes associated with dementia are possible contributors. We investigated the relationship between brain atrophy rates in Alzheimer's disease (AD) and cognitive aging signature regions from magnetic resonance imaging before and one year after surgery, LTCD assessed by the general cognitive performance (GCP) score over 6 years post-operatively, and delirium in 117 elective surgery patients without dementia (mean age = 76). The annual change in cortical thickness was 0.2(1.7) % (AD-signature p = 0.09) and 0.4(1.7) % (aging-signature p = 0.01). Greater atrophy was associated with LTCD (AD-signature: beta(CI) = 0.24(0.06-0.42) points of GCP/mm of cortical thickness; p < 0.01, aging-signature: beta(CI) = 0.55(0.07-1.03); p = 0.03). Atrophy rates were not significantly different between participants with and without delirium. We found an interaction with delirium severity in the association between atrophy and LTCD (AD-signature: beta(CI) = 0.04(0.00-0.08), p = 0.04; aging-signature: beta(CI) = 0.08(0.03-0.12), p < 0.01). The rate of cortical atrophy and severity of delirium are independent, synergistic factors determining postoperative cognitive decline in the elderly.

Prediagnostic plasma proteomics profile for hepatocellular carcinoma.

OBJECTIVE: Proteomics may discover pathophysiological changes related to hepatocellular carcinoma, an aggressive and lethal type of cancer with low sensitivity for early stage diagnosis. DESIGN: We measured 1305 prediagnostic (median = 12.7 years) SomaScan proteins from 54 pairs of healthy individuals who subsequently developed hepatocellular carcinoma and matched non-hepatocellular carcinoma control individuals from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). RESULTS: In NHS and HPFS, we identified 56 elevated proteins in hepatocellular carcinoma with an absolute fold change of more than 1.2 and a Wald test P value less than .05 in conditional logistic regression analysis. Ingenuity pathway analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins-chitinase-3-like protein 1, growth differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin-showed strong positive associations with hepatocellular carcinoma and were thus validated by enzyme-linked immunosorbent assay (odds ratio = 2.48-14.7, all P < .05) in the NHS and HPFS and by Olink platform (hazard ratio = 1.90-3.93, all P < .05) in the UKB-PPP. Adding these 4 proteins to a logistic regression model of traditional hepatocellular carcinoma risk factors increased the area under the curve from 0.67 to 0.87 in the NHS and HPFS. Consistently, model area under the curve was 0.88 for hepatocellular carcinoma risk prediction in the UKB-PPP. CONCLUSION: However, the limited number of hepatocellular carcinoma patients in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

A choroid plexus apocrine secretion mechanism shapes CSF proteome and embryonic brain development.

We discovered that apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. The apocrine response relies on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling. It rapidly alters the embryonic CSF proteome, activating neural progenitors lining the brain's ventricles. Supraphysiological apocrine secretion induced during mouse development by maternal administration of a serotonergic 5HT2C receptor agonist dysregulates offspring cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and ultimately changes adult social behaviors. Critically, exposure to maternal illness or to the psychedelic drug LSD during pregnancy also overactivates the ChP, inducing excessive secretion. Collectively, our findings demonstrate a new mechanism by which maternal exposure to diverse stressors disrupts in utero brain development.

Successful aging after elective surgery II: Study cohort description.

BACKGROUND: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID-19 pandemic, and lay the foundation for future work using this cohort. METHODS: SAGES II is a prospective observational cohort study of community-dwelling adults age 65 and older undergoing major non-cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID-19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. RESULTS: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty-eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID-19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1-month follow-up; nearly 90% of enrolled participants completed interviews through 6-month follow-up. CONCLUSION: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers-including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource.