What is new in delirium: A vascular etiology outlook

Abstract

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.

Highlights

• Delirium is a complex, multifactorial neurocognitive syndrome common in older adults and is associated with impaired cognitive recovery and increased risk of subsequent dementia.

• Emerging evidence implicates vascular and neuroinflammatory mechanisms in postoperative delirium, with blood–brain barrier dysfunction increasingly recognized as a key pathological feature.

• This review proposes delirium as an acute neurovascular phenotype that links systemic inflammation, neurovascular unit injury, and the chronic vascular biology traditionally associated with vascular contributions to cognitive impairment and dementia and Alzheimer's disease and related dementias.

• Further studies are needed to define how perioperative stressors, including surgery, inflammation, and anesthesia‐related physiological perturbations, affect brain barriers, immune–metabolic signaling, and long‐term perioperative brain health.

1. INTRODUCTION

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. ¹ , ² In older adults, delirium is among the most consequential complications of hospitalization. Delirium can occur across hospitalized, surgical, critical‐care, medical, and palliative settings with symptoms that reflect substantial clinical heterogeneity. Historically, delirium was defined as a strictly transient, reversible syndrome. However, accumulating research shows this acute neurological state can lead to increased mortality and other major complications, ³ including long‐term and permanent cognitive impairment, presaging the potential onset of neurodegenerative disorders such as Alzheimer's disease and related dementias (ADRD), ⁴ suggesting a fundamental change in how medical professionals should manage delirium in the clinic. Despite substantial research into delirium epidemiology, prevention, and control, its management is complicated by the elusive nature of its pathophysiological mechanisms. Studies suggest that delirium can be mediated by disorders of various pathways, including systemic and neuroinflammation, neurotransmitter imbalance, oxidative and metabolic stress, impaired cerebral perfusion, sleep/circadian disruption, altered network connectivity, and reduced cognitive reserve. ¹ , ⁵ Here, we update the vascular etiology of delirium, particularly postoperative delirium, emphasizing the neurovascular unit (NVU) as a key interface linking systemic illness, perioperative stress, neuroinflammation, and cognitive vulnerability.

This perspective review focuses on postoperative delirium (POD). POD is a subtype of perioperative neurocognitive disorders (PNDs), which refer to a spectrum of cognitive complications temporally associated with anesthesia and surgery. Within PNDs, POD is the most acute and clinically apparent phenotype, which usually occurs between hours and days after surgery. ⁶ Because the timing of surgical stress is relatively well defined, POD provides a clinically tractable model to investigate how systemic inflammation, vascular vulnerability, and blood–brain barrier (BBB)/NVU dysfunction contribute to acute brain failure and possibly longer term cognitive decline. However, it should be noted that delirium related to sepsis, hypoxia, sedatives, metabolic derangement, withdrawal, infection, terminal illness, or delirium superimposed on dementia may involve overlapping but distinct biological pathways. ²

2. AREAS OF UNCERTAINTY: DELIRIUM AS AN ACUTE NEUROVASCULAR PHENOTYPE WITHIN THE VASCULAR CONTRIBUTIONS TO COGNITIVE IMPAIRMENT AND DEMENTIA SPECTRUM

The role of vascular pathology in cognitive decline extends beyond the conventional confines of stroke‐induced deficits. Clinical evidence suggests that a broader spectrum of vascular insults, including chronic cerebral hypoperfusion, cerebral small‐vessel disease, microbleeds, and white matter lesions, contributes to cognitive impairment and forms the substrate for various types of vascular contributions to cognitive impairment and dementia (VCID). ⁷ , ⁸ These diverse vascular pathologies emphasize the role of vascular disorders in the pathogenesis of cognitive disorders, possibly including delirium. Recent empirical observations have drawn attention to alterations in the BBB after non‐neurologic surgeries, particularly pronounced in patients who develop POD.

The BBB separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS) and comprises endothelial cells, astrocytic endfeet, and pericytes that form tight junctions to regulate the bidirectional passage of substances to and from the brain. The integrity of the barrier function is crucial for maintaining CNS homeostasis. Both clinical and preclinical studies have demonstrated that BBB disruption allows neurotoxic substances, inflammatory mediators, and immune cells to infiltrate the brain parenchyma, which can contribute to the pathogenesis of delirium. ⁹

A mouse study reported age‐dependent BBB disruption after exploratory laparotomy and suggested that endothelial cell transcytosis may be particularly affected. ¹⁰ In a mouse model of postoperative delirium superimposed on dementia, Wang et al. proposed an “immunovascular” mechanism in which surgical trauma–associated molecular patterns and dysregulated innate immune responses impair the BBB, triggering delirium‐like behavior and worsening Alzheimer's disease (AD)‐related neuropathology. ¹¹ Another study using a BBB‐on‐chip model and a mouse surgical model demonstrated that POD is accompanied by impairments in BBB‐associated cells. ¹² Recent human prospective cohort studies have shed light on the association between postoperative delirium and increased cerebrospinal fluid (CSF) to plasma albumin ratio (CPAR), an indicator of BBB integrity. This ratio, when elevated, indicates BBB disruption and has been correlated with neuroinflammatory biomarkers, including interleukin (IL)‐6 and lactate within the CSF. ¹³ , ¹⁴ CPAR's diagnostic value has been established in larger cohorts, indicating its utility as a biomarker for postoperative delirium, independent of pre‐existing cognitive impairment, a well‐established risk factor for delirium. ¹⁴

Elevated systemic inflammatory markers, such as C‐reactive protein (CRP) and pro‐inflammatory cytokine, ¹⁵ have been associated with delirium episodes, possibly by disrupting BBB integrity. Systemic inflammatory mediators may activate the cerebral endothelium and contribute to BBB dysfunction; conversely, BBB opening may amplify central neuroinflammatory signaling by permitting blood‐derived proteins, inflammatory mediators, or immune cells to enter or signal across the NVU. Additionally, indirect evidence for BBB compromise is also reflected by elevated blood levels of neuronal injury markers. For example, a recent multicohort study demonstrates neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as blood‐based risk markers for postoperative delirium in older patients with hip fracture, ¹⁶ and a meta‐analysis identified associations between postoperative delirium and inflammatory/proteomic markers, including GFAP and NfL. ¹⁵ The rise in these biomarkers post‐surgery provides a potential proxy for neural damage and BBB disruption, ¹⁷ , ¹⁸ although the exact cellular source for these biomarkers remains unclear.

Among all the BBB elements, endothelial cells contribute to key properties and selective regional permeability and exhibit a critical vulnerability to systemic inflammatory processes. In delirium, endothelial dysfunction is thought to precipitate BBB opening, thereby facilitating the intrusion of harmful substances into the brain, including blood‐derived proteins such as fibrinogen. The contributors to endothelial cell distress include oxidative stress, systemic inflammatory responses, and fluctuations in hemodynamic stability, each of which can perturb cerebral homeostasis and have been implicated in the pathogenesis of delirium. ¹⁹ Systemic inflammation can directly impair BBB functions, including facilitating protein aggregation in the context of neurodegeneration, suggesting that could be causal to the delirium onset. ²⁰ Indeed, delirium pathogenesis is complex and multifactorial. It is also possible that pre‐existing or subsyndromal VCID ¹² sparks neuroinflammation and cognitive deficits by affecting barrier integrity after an insult, such as surgery.

3. CHALLENGES: VCID AS AN INTERVENTION TARGET FOR DELIRIUM

The neuroinflammatory response to systemic insults (including surgical interventions, infections, or complex inflammatory states such as sepsis) that accompanies delirium is facilitated by disruption of the BBB. Early BBB leakage in mouse models of systemic insults is evidenced by the reduction of aquaporin‐4 (AQP‐4) and the disintegration of endothelial tight junctions, ²¹ , ²² which are crucial for normal barrier function. Additionally, the upregulation of brain endothelial cell markers acutely (within 6 hours postoperatively), along with the deposition of blood‐derived fibrinogen and immunoglobulin G within the brain, underscores a rapid and localized opening of the BBB after surgery. ²¹ , ²³ , ²⁴ The relevance of these findings, irrespective of the surgery type and/or anesthetic regimen, posits that BBB dysfunction may be a common denominator in surgery‐induced cognitive decline and contribute to increased risk for subsequent VCID/ADRD (Figure 1). Conversely, pre‐existing VCID biology, including vascular stiffness, small‐vessel disease, endothelial dysfunction, and impaired neurovascular coupling, may lower the threshold for BBB disruption during systemic stress and increase an individual's susceptibility to systemic stress (for example, peripheral surgery)‐induced delirium.

FIGURE 1.

Putative vascular contributions to delirium. We highlight a putative role for VCID as a key driver of delirium by regulating the conversion from a systemic to a central inflammatory response. (A), Systemic challenges, including trauma, surgery, and infections, contribute to cytokine dysregulation. (B), Pro‐inflammatory mediators impact the NVU (including endothelial cells, pericytes, and astrocytic endfeet), causing changes in barrier permeability. (C), Peripheral immunocytes such as neutrophils and macrophages gain access to the brain parenchyma, contributing to a pro‐inflammatory milieu and acute neurotoxicity. (D), Glia, both microglia and astrocytes, respond to systemic inflammation and NVU dysfunction, contributing to the neuronal dyshomeostasis. E, Neurons become dysfunctional and potential neurodegenerative signals are triggered in the context of a vulnerable brain (i.e., delirium superimposed on dementia). Preexisting VCID (including vascular stiffness, atherosclerosis, stroke, and hypertension) is emerging as a risk factor for delirium onset and severity by facilitating neuroimmune interactions at the NVU. Thus, targeting cellular components of the NVU (endothelial cells, pericytes, astrocytes) may become attractive strategies to selectively disrupt systemic‐to‐brain signaling that contributes to delirium and by protecting the vasculature. Figure generated in BioRender. Aβ, amyloid beta; NVU, neurovascular unit; VCID, vascular contributions to cognitive impairment and dementia.

The bidirectional interplay among inflammation and vascular factors in delirium still requires further study. It has been challenging to model the complex interactions at the BBB and how VCID contributes to these perioperative complications. Experiments using microphysiological systems (MPSs) are beginning to clarify relationships among inflammation, neurodegeneration, and the brain vasculature. A recent innovation uses an in vitro barrier model, referred to as MPS featuring a nanoporous silicon membrane (µSIM‐on‐chip), in which structural defects in the basement membrane (3 µm and 5 µm micropores) can be engineered to understand how pericytes can restore barrier function. ²⁵ MPSs are now being applied to study the vascular underpinnings of delirium and to test potential immunoregulatory compounds. ¹² Unlike clinical biomarker studies, this in vitro system enables controlled interrogation of human BBB cellular responses to defined inflammatory stimuli. These microfluidic 3D culture platforms, constructed from the primary culture of human cells, enable a closer examination of the BBB's response to inflammatory stimuli. For instance, IL‐1β, a cytokine known to increase after systemic surgical stress, has been shown to reduce endothelial tight junction integrity, disrupt astrocyte–endothelial interactions, and increase pericyte activity markers. ¹² The BBB‐on‐chip, including the use of human pluripotent stem cells, offers novel tools to study preventive and interventional therapies for delirium that target VCID and BBB opening. Understanding the complex interactions at the barrier may offer novel targets for preventive strategies against postoperative delirium and subsequent long‐term cognitive impairment.

4. TAKE‐HOME MESSAGES

The interplay between vascular pathology and delirium is gaining traction from recent preclinical and clinical studies. The evidence pointing to BBB dysfunction as a central component of delirium's pathophysiology is compelling and underscores the need for a paradigm shift in prevention and management strategies for delirium.

Current challenges in delirium research include identifying early biomarkers for delirium, elucidating the molecular pathways through which BBB impairments contribute to delirium, and developing interventions that preserve vascular and cognitive functions. Addressing these will require multidisciplinary approaches to bridge the gap between fundamental science and clinical practice. Such efforts hold the promise for designing accurate strategies to effectively treat this complex syndrome and improve the clinical outcomes and societal burdens related to this often neglected complication of systemic illness and injury.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Supporting information

Supporting Information