Niccolò Terrando

BACKGROUND: Postoperative increases in cerebrospinal fluid (CSF) to plasma albumin ratio (CPAR), a blood-brain barrier dysfunction marker, have been associated with postoperative delirium (POD) and prolonged hospital stay. However, the contributions of plasma versus CSF albumin changes remain unclear. AIM: To determine whether 24-hour postoperative changes in plasma and CSF albumin are independently associated with POD and hospital length of stay. METHODS: Plasma and CSF albumin concentrations were measured before and 24-hours postoperatively in older non-cardiac surgery patients. Multivariable logistic and negative binomial regression models evaluated associations between albumin changes and POD or hospital length of stay, adjusting for age, baseline cognition, surgery type, and fluid administration. RESULTS: Of 240 patients, 31 (13.3%) developed POD. From before to 24-hours after surgery, both plasma albumin (median 3.95 to 3.43 g/dL, p<0.001) and CSF albumin decreased (median 22.68 to 20.43 mg/dL, p<0.001). Greater plasma albumin decreases (per 0.43 g/dL) were independently associated with POD (OR 2.14, 95% CI 1.28-3.58; p=0.004) and longer hospital stay (mean ratio 1.44, 95% CI 1.26-1.64; p<0.001). In contrast, CSF albumin changes (per 5.8 mg/dL higher) were not associated with POD (OR 0.97, 95% CI 0.60-1.58; p=0.91) but were modestly associated with longer hospital stay (mean ratio 1.17, 95% CI 1.04-1.32; p=0.01). CONCLUSIONS: Plasma and CSF albumin decreased postoperatively, but only plasma decreases were associated with POD. These results suggest that associations between CPAR increases and POD may be due to postoperative plasma albumin decreases and highlight limitations of CPAR as a standalone marker of postoperative BBB dysfunction.

Background: Postoperative delirium is a common syndrome of acute changes in attention, cognition, and consciousness that may result from inflammation and/or neuroinflammation, but few studies have distinguished the relationships of preoperative and 24-hour postoperative systemic inflammation (i.e. in blood) versus neuroinflammation (i.e. in cerebrospinal fluid, or CSF) in postoperative delirium. Methods: We measured CSF and plasma cytokine levels before and 24-hours after non-cardiac/non-neurologic surgery in 199 patients age ≥ 60 years who were enrolled in two prospective cohort studies. Delirium was assessed with the confusion assessment method (CAM), 3-minute diagnostic interview for CAM-defined delirium, or the CAM for the Intensive Care Unit (CAM-ICU) in patients who remained intubated postoperatively and validated chart review. Cytokines were measured with immunoassays for IL-6, IL-7, IL-8, IL-10, IL-16, TARC, MCP-1, and IP-10. Associations of CSF and plasma cytokine levels with postoperative delirium were assessed with univariable and multivariable logistic regression analyses with Holm correction for family-wise error. Results: Surgery was associated with significant changes in nearly all measured CSF and plasma cytokines (p < 0.05) except plasma IL-16 and MCP-1. In multivariable analyses adjusted for preoperative Mini-Mental Status Exam (MMSE) score and surgery duration, higher preoperative CSF IL-6 (OR 1.80, 95% CI 1.18–2.75, Holm p=0.049) and CSF IL-8 (OR 1.94, 95% CI 1.22–3.06, Holm p = 0.040) levels were independently associated with postoperative delirium. Higher 24-hour postoperative CSF IL-10 was nominally associated with delirium (OR 1.57, 95% CI 1.06–2.33, p = 0.026) in a multivariable regression controlling for MMSE and surgery duration, but this association did not remain significant after multiple-comparison correction (Holm p = 0.21). No other preoperative or 24-hour postoperative CSF or plasma cytokine levels were associated with delirium (p > 0.05). Conclusions: Surgery elicited robust postoperative changes in CSF and plasma cytokines, but 24-hour postoperative cytokine elevations were not significantly associated with postoperative delirium after multiple-comparison correction. In contrast, elevated preoperative CSF IL-6 and IL-8 levels were associated with postoperative delirium independent of baseline cognitive status and surgery duration. Thus, our findings support an important role for preoperative neuroinflammation in postoperative delirium in older elective surgery patients.

Emerging studies have highlighted the vascular contributions to cognitive impairment and dementia (VCID), especially in the context of neurodegenerative disorders that cause cognitive decline (i.e., Alzheimer's disease and related dementias [ADRD]). More recent research on perioperative neurocognitive disorders, including postoperative delirium, is describing a potential role of neurovascular dysfunction in the pathogenesis of these common complications for many older adults. These findings support an expanded conceptual framework in which delirium is not simply a transient disorder of neuronal function but may represent an acute neurovascular phenotype that links systemic inflammation, blood–brain barrier injury, and VCID. Delirium is characterized by acute and fluctuating disturbances in attention, awareness, and cognition. It is a common, costly, neurologic complication in patients, especially critically ill patients, patients with chronic metabolic disorders, or older adults. In older adults, delirium is among the most consequential complications of hospitalization. A 2025 national cohort of > 5.5 million older adults undergoing major non‐cardiac surgery found that postoperative delirium was associated with markedly higher odds of death or major complications, and 30‐day mortality. These contemporary data reinforce a shift in framing: delirium should be treated as acute brain failure and as a quality target for perioperative and critical care systems, not merely as a temporary behavioral syndrome. In addition to the acute negative impacts, delirium significantly escalates the risk of persistent cognitive decline, presaging the potential onset of neurodegenerative disorders. Despite substantial research into delirium epidemiology, prevention, and control, its management is complicated by the elusive nature of its pathophysiological mechanisms. Here, we propose a vascular etiology outlook for delirium, with emphasis on the neurovascular unit as a key interface in determining the onset of this complication and potentially jump‐starting permanent brain dysfunction and ADRD.

The role of neutrophils in mediating neurovascular vulnerability has been increasingly implicated in various acute inflammatory models of neuroimmune cross

Delirium and delirium superimposed on dementia (DSD) are common complications affecting patients suffering from ongoing neurodegenerative pathologies. Peri

Pericytes play a key role in the brain where they support the blood-brain barrier (BBB). Their loss has been reported in response to systemic inflammation and neurodegenerative disease. We recently demonstrated that iPSC-derived brain pericyte-like cells (BPLCs) and brain microvascular endothelial cell (BMEC)-like cells collaboratively form a nascent, 3D basement membrane when cultured across a nanoporous membrane ¹ . Building on this, we aimed to engineer defects in the basement membrane to investigate whether pericytes could facilitate its repair. In BMEC monocultures, we observed that micropore patterns in nanomembranes created discontinuities in laminin, which destabilized barrier function. Remarkably, the addition of pericytes to the basal side of the membrane restored both laminin integrity and barrier function. Our results align with the role of pericytes as support cells for microvasculature and encourage the use of our tissue barrier platform (the µSiM) to model neurological disorders involving pericyte dysfunction and/or disruption of basement membrane.

Aging has been identified as a leading risk factor for many diseases, including neurodegenerative disorders. While cellular senescence has been linked to age-related neurodegenerative conditions, its involvement in peripheral stress-associated brain disorders is just beginning to be explored. In this study, we investigated the impact of senescent cells on peripheral stress-induced neuroinflammation using orthopedic surgery as a model. Our results demonstrate an increased accumulation of senescent cells and neuroinflammation in the aged mouse hippocampus following surgery. Intermittent treatment of the mice with the senolytic drugs dasatinib and quercetin (D/Q) showed a significant reduction in surgery-induced senescent cell burden. This reduction in senescent cell accumulation was correlated with reduced surgery-induced neuroinflammation, as evidenced by decreased glial cell activity. Consistent with these observations, we also observed reduced levels of proinflammatory senescence-associated secretory phenotype factors in circulation, following fracture surgery, in mice treated with D/Q. Overall, our findings underscore the pivotal role of cellular senescence in surgery-induced neuroinflammation and highlight the therapeutic potential of eliminating senescent cells as a potential strategy to manage peripheral stress-induced neuroinflammatory conditions.

Microglia, brain-resident innate immune cells, have been extensively studied in neurodegenerative contexts like Alzheimer’s disease. The Coronavirus disease 2019 (COVID-19) pandemic highlighted how peripheral infection and inflammation can be detrimental to the neuroimmune milieu and initiate microgliosis driven by peripheral inflammation. Microglia can remain deleterious to brain health by sustaining inflammation in the central nervous system even after the clearance of the original immunogenic agents. In this chapter, we discuss how pulmonary infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) can lead to neurovascular and neuroimmune inflammation causing the neurological syndrome of post-acute sequelae of COVID-19 (PASC). Further, we incorporate lessons from the Human Immunodeficiency Virus’ (HIV’s) effects on microglial functioning in the era of combined antiretroviral therapies (cART) that contribute to HIV-1 associated neurocognitive disorders (HAND). Finally, we describe roles for mixed lineage kinase 3 (MLK3) and leucine-rich repeat kinase (LRRK2) as key regulators of multiple inflammatory and apoptotic pathways important to the pathogenesis of PASC and HAND. Inhibition of these pathways provides a therapeutically synergistic method of treating both PASC and HAND.