Age-dependent differences and similarities in the plasma proteomic signature of postoperative delirium

Oren, Rachel; Kim, Erin J; Leonard, Angela; Rosner, Bernard; Chibnik, Lori B.; Das, Sudeshna; Grodstein, Francine; Crosby, Gregory; Culley, Deborah J.

doi:10.1038/s41598-023-34447-7

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…About half of our NTT group were limb fractures, which is a risk factor for delirium, occurring in ∼10-35% of hip fractures 85,86 . Studies of peri-operative delirium have found increased plasma levels of inflammatory cytokines 87 and tau 88,89 . This means that while the NTT group enabled us to identify protein responses specific to TBI injury, compared with general injury, the NTT group may not be a fully “brain neutral” control group.…”

Section: Discussionmentioning

confidence: 99%

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

Li,

Kodosaki,

Heselgrave

et al. 2024

Preprint

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Pathophysiology and outcomes after Traumatic Brain Injury (TBI) are complex and highly heterogenous. Current classifications are uninformative about pathophysiology, which limits prognostication and treatment. Fluid-based biomarkers can identify pathways and proteins relevant to TBI pathophysiology. Proteomic approaches are well suited to exploring complex mechanisms of disease, as they enable sensitive assessment of an expansive range of proteins. We used novel high-dimensional, multiplex proteomic assays to study changes in plasma protein expression in acute moderate-severe TBI. We analysed samples from 88 participants in the longitudinal BIO-AX-TBI cohort (n=38 TBI within 10 days of injury, n=22 non-TBI trauma, n=28 non-injured controls) on two platforms: Alamar NULISA(TM) CNS Diseases and OLINK(R) Target 96 Inflammation. Participants also had data available from Simoa(R) (neurofilament light, GFAP, total tau, UCHL1) and Millipore (S100B). The Alamar panel assesses 120 proteins, most of which have not been investigated before in TBI, as well as proteins, such as GFAP, which differentiate TBI from non-injured and non-TBI trauma controls. A subset (n=29 TBI, n=24 non-injured controls) also had subacute 3T MRI measures of lesion volume and white matter injury (fractional anisotropy, scanned 10 days to 6 weeks after injury). Differential Expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin2, UCHL1, visinin-like protein1), astroglial markers (S100B, GFAP), tau and other neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid beta42, 14-3-3γ), inflammatory cytokines (IL16, CCL2, ficolin2), cell signalling (SFRP1), cell metabolism (MDH1) and autophagy related (sequestome1) proteins. Acute plasma levels of UCHL1, PSEN1, total tau and pTau231 correlated with subacute lesion volume, while sequestome1 was correlated with whole white matter skeleton fractional anisotropy and CCL2 was inversely correlated with corpus callosum FA. Neuronal, astroglial, tau and neurodegenerative proteins correlated with each other, and IL16, MDH1 and sequestome1. Clustering (k means) by acute protein expression identified 3 TBI subgroups which had differential injury patterns, but did not differ in age or outcome. Proteins that overlapped on two platforms had excellent (r>0.8) correlations between values. We identified TBI-specific changes in acute plasma levels of proteins involved in amyloid processing, inflammatory and cellular processes such as autophagy. These changes were related to patterns of injury, thus demonstrating that processes previously only studied in animal models are also relevant in human TBI pathophysiology. Our study highlights the potential of proteomic analysis to improve the classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.

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Section: Discussionmentioning

confidence: 99%

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

Li,

Kodosaki,

Heselgrave

et al. 2024

Preprint

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“…Thus, ASGR1 holds clinical potential as a target for lowering blood cholesterol levels. However, there is limited information available regarding the regional or cellular specificity of ASGR1 in the human brain, and its function in the brain remains poorly understood ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

Depression proteomic profiling in adolescents with transcriptome analyses in independent cohorts

Sokolov,

Lafta,

Nordberg

et al. 2024

Front. Psychiatry

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IntroductionDepression is a major global burden with unclear pathophysiology and poor treatment outcomes. Diagnosis of depression continues to rely primarily on behavioral rather than biological methods. Investigating tools that might aid in diagnosing and treating early-onset depression is essential for improving the prognosis of the disease course. While there is increasing evidence of possible biomarkers in adult depression, studies investigating this subject in adolescents are lacking.MethodsIn the current study, we analyzed protein levels in 461 adolescents assessed for depression using the Development and Well-Being Assessment (DAWBA) questionnaire as part of the domestic Psychiatric Health in Adolescent Study conducted in Uppsala, Sweden. We used the Proseek Multiplex Neuro Exploratory panel with Proximity Extension Assay technology provided by Olink Bioscience, followed by transcriptome analyses for the genes corresponding to the significant proteins, using four publicly available cohorts.ResultsWe identified a total of seven proteins showing different levels between DAWBA risk groups at nominal significance, including RBKS, CRADD, ASGR1, HMOX2, PPP3R1, CD63, and PMVK. Transcriptomic analyses for these genes showed nominally significant replication of PPP3R1 in two of four cohorts including whole blood and prefrontal cortex, while ASGR1 and CD63 were replicated in only one cohort.DiscussionOur study on adolescent depression revealed protein-level and transcriptomic differences, particularly in PPP3R1, pointing to the involvement of the calcineurin pathway in depression. Our findings regarding PPP3R1 also support the role of the prefrontal cortex in depression and reinforce the significance of investigating prefrontal cortex-related mechanisms in depression.

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“…Consequently, although older patients have considerably more postoperative morbidity than younger persons, and much of it is thought to be inflammation-related, we cannot say definitively that the changes are specific to older surgical patients or the specific morbidities of these procedures. However, at least in the case of postoperative delirium, which is one of the most common morbidities of geriatric surgery, the plasma proteomic signature is agedependent [56]. Third, due to the exploratory nature of the study, we purposefully chose a conservative statistical threshold for biological relevance of >1.0 log2FC, which has been used elsewhere for analyses of NanoString data.…”

Section: Discussionmentioning

confidence: 99%

Geriatric Surgery Produces a Hypoactive Molecular Phenotype in the Monocyte Immune Gene Transcriptome

Oren,

Grasfield,

Friese

et al. 2023

JCM

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Surgery is a major challenge for the immune system, but little is known about the immune response of geriatric patients to surgery. We therefore investigated the impact of surgery on the molecular signature of circulating CD14+ monocytes, cells implicated in clinical recovery from surgery, in older patients. We enrolled older patients having elective joint replacement (N = 19) or spine (N = 16) surgery and investigated pre- to postoperative expression changes in 784 immune-related genes in monocytes. Joint replacement altered the expression of 489 genes (adjusted p < 0.05), of which 38 had a |logFC| > 1. Spine surgery changed the expression of 209 genes (adjusted p < 0.05), of which 27 had a |logFC| > 1. In both, the majority of genes with a |logFC| > 1 change were downregulated. In the combined group (N = 35), 471 transcripts were differentially expressed (adjusted p < 0.05) after surgery; 29 had a |logFC| > 1 and 72% of these were downregulated. Notably, 21 transcripts were common across procedures. Thus, elective surgery in older patients produces myriad changes in the immune gene transcriptome of monocytes, with many suggesting development of an immunocompromised/hypoactive phenotype. Because monocytes are strongly implicated in the quality of surgical recovery, this signature provides insight into the cellular and molecular mechanisms of the immune response to surgery and warrants further study as a potential biomarker for predicting poor outcomes in older surgical patients.

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Age-dependent differences and similarities in the plasma proteomic signature of postoperative delirium

Cited by 3 publications

References 53 publications

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

Depression proteomic profiling in adolescents with transcriptome analyses in independent cohorts

Geriatric Surgery Produces a Hypoactive Molecular Phenotype in the Monocyte Immune Gene Transcriptome

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