Proteomic Analysis of Preoperative CSF Reveals Risk Biomarkers of Postoperative Delirium

Abstract

Objective: To analyze the proteome of preoperative cerebrospinal fluid (CSF) in older orthopedic patients with or without postoperative delirium (POD) using untargeted proteomics.Methods: A prospective cohort study was conducted. Eighty hip fracture patients aged ≥65 years were recruited. After successful spinal anesthesia, CSF was collected. The patients were divided into POD and No-POD groups based on the Confusion Assessment Method, and patients with POD were graded using the Memorial Delirium Assessment Scale (MDAS). Thirty No-POD patients were matched to 10 POD patients by age (±2 years) and Mini-Mental State Examination score (±2 scores). Label-free proteomic analysis was performed using a liquid chromatography coupled to mass spectrometry (LC-MS) workflow. Validation was performed using mass-spectrometry-based parallel reaction monitoring (PRM) for the 30 No-POD and 10 POD patients, as well as for an additional 5 POD patients. Bioinformatics were used to investigate possible relevant pathological mechanisms.Results: The incidence of POD in older orthopedic patients was 18.8% in our cohort of 80 patients. Proteomics results revealed 63 dysregulated CSF proteins, and PRM analysis validated these results. The preoperative CSF levels of both V-set and transmembrane domain-containing protein 2B (VSTM2B) and coagulation factor V (FA5) were positively correlated with MDAS scores on postoperative day 1 (r > 0.8, p < 0.05). Bioinformatic analysis revealed that several nervous-system-related pathways are relevant to POD development. Conclusion:We identified and validated several novel CSF proteins that are dysregulated in POD, and revealed several pathways that are relevant to POD development. Our results not only provide risk biomarkers for POD, but also give clues for further investigations into the pathological mechanisms of delirium. Clinical trial registration: This study was registered in the Chinese Clinical Trial Registry (ChiCTR1900021533).

Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions

“…Our research team has investigated POD biomarkers in the CSF of elderly POD patients using metabolomics and proteomics (Han et al, 2020b , c ). However, in contrast to peripheral blood sampling, CSF availability is limited.…”

“…All patients were admitted to the orthogeriatric unit. The exclusion criteria were the same as those in our previous reports (Han et al, 2020b , c ) and included (1) patients with a medical history of neurological or neurovascular diseases such as delirium, schizophrenia, dementia, or stroke. Dementia was defined as a Mini-Mental State Examination (MMSE) score of ≤ 17 for illiterate patients, ≤20 for patients with 1–6 years of education, and ≤24 for patients with 7 or more years of education (Vutskits and Xie, 2016 ); (2) patients who were unable to read or had severe visual or auditory deficits; (3) patients with a history of alcohol abuse and drug dependence; or (4) patients who were unwilling to comply with the study protocol or procedures.…”

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

“…In fact, alterations in CNS fibrinogen biology have been implicated in the pathogenesis of neurological, neurocognitive, and psychiatric disorders including multiple sclerosis [77], traumatic brain injury [78], AD [73,79], and depression [80]. Likewise, coagulation factor V, a central mediator of hemostasis, has been previously linked to delirium pathogenesis [81]. Further, plasminogen has been shown to potentiate neuroinflammation [82,83] and AD-related pathology [82], and elevated serum kininogen has been associated with depression [80].…”

Cerebrospinal Fluid Proteomic Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

“…In fact, alterations in CNS brinogen biology have been implicated in the pathogenesis of neurological, neurocognitive, and psychiatric disorders including multiple sclerosis [82], traumatic brain injury [83], Alzheimer's disease [78,84], and depression [85]. Likewise, coagulation factor V, a central mediator of hemostasis, has been previously linked to delirium pathogenesis [33]. Further, plasminogen has been shown to potentiate neuroin ammation [86,87] and Alzheimer's disease-related pathology [86], and elevated serum kininogen has been associated with depression [85].…”

“…Previously, unbiased proteomic analyses have been successfully deployed to identify novel biomarkers for mild cognitive impairment [24], AD [24][25][26], frontotemporal dementia [27,28], Parkinson's disease [29], amyotrophic lateral sclerosis [28], HIV-related cognitive impairment [30], amygdala dysfunction [31], and chronic traumatic encephalopathy [32]. Recently, they have also been applied to postoperative delirium, revealing several candidate biomarkers and patterns of CSF protein dysregulation [33]. To date, though, few other studies have utilized unbiased mass spectrometry-based proteomics to identify novel CSF protein biomarkers or pathways in older adults with perioperative neurocognitive disorders.…”