Abstract
Postoperative cognitive dysfunction (POCD) is common in geriatric trauma patients and involves complex underlying mechanisms. Most existing studies have focused on isolated risk factors, with limited attention to how these factors interact. In this perspective article, we propose a dual-pathway theoretical model—central nervous system vulnerability and peripheral stress amplification—to reframe the understanding of POCD pathogenesis. In older adults, POCD rarely stems from a single cause. Instead, it arises from a “second hit” process, in which pre-existing central nervous system vulnerabilities (e.g., neurodegenerative pathology and reduced cognitive reserve) interact with perioperative peripheral stressors (e.g., trauma, surgical stress, and anesthetic exposure) through interfaces such as the blood–brain barrier and neuroimmune circuits. Guided by this dual-pathway framework, future research should move from isolated risk factor screening toward dynamic, multidimensional, and individualized risk stratification, and explore sequential intervention strategies that target both pathways.
1 Introduction
1.1 Clinical challenges of postoperative cognitive dysfunction (POCD) in geriatric trauma
As the global population ages, more older trauma patients undergo surgery (). POCD is a common central nervous system complication in this group, marked by declines in attention, memory, and executive function (Newfield, 2009; Wu et al., 2023). The reported incidence of perioperative neurocognitive disorders in older surgical patients varies widely, from about 10% to 40%, depending on surgery type, perioperative stress intensity, and baseline cognitive vulnerability (; Zhao et al., 2024). In geriatric trauma populations, this risk may be even higher because trauma-related systemic inflammation, hemodynamic instability, and the urgency of emergency surgery often coexist with pre-existing neurodegenerative and cerebrovascular conditions (; Subramaniyan and Terrando, 2019). Beyond prolonging hospitalization and increasing long-term mortality, POCD significantly reduces quality of life and frequently leads to dependence on long-term care (Nilsson et al., 2025; Suraarunsumrit et al., 2024). Given its insidious onset and lack of specific treatments, the high incidence and poor prognosis of POCD pose a major clinical challenge in geriatric trauma surgery, placing substantial burdens on health care systems and society ().
1.2 Limitations of existing risk factor research
Previous studies have identified multiple risk factors for POCD, including advanced age, low preoperative cognitive reserve, surgical trauma intensity, anesthetic type, perioperative stress, and systemic inflammation (Rundshagen, 2014). However, this body of research remains largely fragmented (Rundshagen, 2014; Tang et al., 2025). First, how these factors interact and relate to one another has not been systematically integrated (). Second, most analytical models do not account for the unique pathophysiological context of older adults—such as age-related susceptibility to neuroinflammation, multisystem degeneration, and the compounded effects of multiple chronic conditions—as a unified framework (). This “factor-listing” approach limits the development of precise risk prediction models and hinders the translation of mechanistic insights into effective interventions.
1.3 Need for a dual-pathway framework
To address these limitations, this perspective article proposes a “dual-pathway framework” as an integrated theoretical model. This framework conceptualizes POCD pathogenesis along two interrelated but mechanistically distinct pathways. The first, the “neuroinflammation-dominant pathway,” emphasizes how surgery-induced systemic inflammation is transmitted to the CNS and leads to microglial overactivation, which impairs synaptic plasticity (Skvarc et al., 2018; Subramaniyan and Terrando, 2019). The second, the “neural reserve depletion pathway,” focuses on how aging and comorbidities reduce cognitive reserve, impair cerebrovascular function, and exhaust the compensatory capacity of neural networks, making older individuals especially vulnerable to exceeding cognitive thresholds under perioperative stress (; Stern, 2012). These two pathways interact synergistically across molecular, cellular, and circuit levels, jointly determining the onset and progression of POCD (; Figure 1).
FIGURE 1
1.4 Article structure and perspective
This perspective article first examines the theoretical foundations and empirical evidence underlying the dual-pathway framework. It then details the mechanistic features of each pathway and their specific manifestations in the geriatric trauma population, followed by a discussion of their potential interactions and clinical implications. Our central perspective is that advancing the understanding of POCD requires shifting from a “factor-summation” approach to a “mechanism-integration” perspective—one that places POCD within the interactive context of aging and perioperative stress. Such an integrated framework is essential to overcoming current research bottlenecks and providing a theoretical basis for precision strategies in perioperative brain protection.
2 Pathway I: central nervous system vulnerability—endogenous susceptibility basis
This section addresses the intrinsic characteristics of the aging central nervous system that predate surgery and trauma. These features determine an individual’s baseline sensitivity to perioperative insults and constitute the susceptibility foundation for POCD.
2.1 Structural and functional brain aging
Normal aging entails substantial structural and functional brain alterations (). Neuroimaging studies frequently reveal preoperative changes in older adults, including white matter hyperintensities, global brain atrophy, and reduced hippocampal volume (). These findings reflect neuronal loss and diminished white matter integrity (Liu et al., 2017). Aging of the neurovascular unit is another hallmark of brain aging (), characterized by increased blood–brain barrier (BBB) permeability, attenuated vascular reactivity, and impaired perivascular clearance under physiological conditions (). Such changes render the aged brain more vulnerable to microenvironmental disturbances when confronted with surgical trauma and anesthetic exposure (; ). In addition to structural and vascular aging, older adults often exhibit a decline in autonomic regulation (; Olivieri et al., 2024). Specifically, impairment of the vagus nerve–mediated cholinergic anti-inflammatory pathway—manifested by reduced acetylcholine release and weakened α7 nicotinic acetylcholine receptor signaling—diminishes endogenous anti-inflammatory control, thereby heightening susceptibility to excessive systemic and neuroinflammatory responses during perioperative stress (; ; Zhang et al., 2023; Zorbaz et al., 2022).
2.2 Pathological comorbidities and subclinical neurodegeneration
Beyond physiological aging, older patients frequently harbor subclinical or overt neurodegenerative pathology. Alzheimer’s disease–related changes, such as amyloid-β deposition and hyperphosphorylated tau accumulation, are common even in the absence of dementia (Terrando et al., 2011). This pathological burden sensitizes the brain to perioperative inflammatory stress, amplifies neuroinflammatory responses, and accelerates cognitive decline (Liu et al., 2022; Subramaniyan and Terrando, 2019). Mechanistically, amyloid-β accumulation promotes a proinflammatory microglial phenotype by engaging pattern-recognition receptors and inflammasome-related signaling, thereby enhancing the release of interleukin-1β, tumor necrosis factor-α, and reactive oxygen species under perioperative conditions (Seplovich et al., 2025; Wang et al., 2020). Concurrently, hyperphosphorylated tau disrupts synaptic integrity and mitochondrial function, rendering neurons more vulnerable to inflammatory and metabolic insults (Seplovich et al., 2025; Wu et al., 2021). A bidirectional pathophysiological relationship has been identified: experimental evidence shows that surgery-induced systemic inflammation can, in turn, accelerate tau phosphorylation and exacerbate amyloid-β-related neurotoxicity, perpetuating a vicious cycle that drives persistent postoperative cognitive decline in susceptible older individuals (; Yu et al., 2021). Concomitantly, cerebrovascular conditions—such as microinfarcts, atherosclerosis, and cerebral small vessel disease—impair cerebral autoregulation (; Ren et al., 2025). This disruption compromises the dynamic balance between oxygen supply and metabolic demand under stress (Ren et al., 2025), further reducing the brain’s resilience to perioperative insults.
2.3 Cognitive reserve and neural compensatory mechanisms
Cognitive reserve denotes the brain’s capacity to sustain cognitive function despite neuropathological damage (Stern, 2012). Proxy indicators such as years of education, occupational attainment, and participation in cognitively stimulating activities are commonly used to estimate cognitive reserve (Stern, 2012). Epidemiological evidence demonstrates a clear inverse association between greater cognitive reserve and the incidence of POCD (). At the network level, aging is linked to diminished functional connectivity within resting-state networks, particularly the default mode network (), manifesting as reduced intra-network connectivity and increased inter-network dedifferentiation (). This loss of network flexibility impairs the brain’s ability to reconfigure functional connections and maintain cognitive performance under stress, thereby heightening susceptibility to perioperative cognitive decompensation ().
3 Pathway II: peripheral stress amplification—exogenous triggers and aggravating factors
This section examines the systemic stress responses induced by traumatic injury and perioperative management, how these responses are converted into central nervous system injury signals, and how they initiate or exacerbate POCD in the context of pre-existing vulnerability.
3.1 Dual insults of trauma itself
Trauma imposes a dual insult on older patients. The first component is acute blood loss and hypoperfusion. Traumatic hemorrhage can sharply reduce effective circulating volume and lower cerebral perfusion pressure, markedly increasing the risk of secondary cerebral ischemia and hypoxia (). This risk is especially pronounced in older individuals with pre-existing cerebral small vessel disease or impaired autoregulation, in whom even mild hemodynamic disturbances may produce occult brain injury (). The second component is the systemic inflammatory response syndrome triggered by tissue damage (Lord et al., 2014). Extensive soft tissue contusion or bone fracture activates the innate immune system, releasing large quantities of proinflammatory cytokines and establishing a systemic inflammatory state that primes the central nervous system for a secondary insult ().
3.2 Neurotoxicity and immunomodulation associated with anesthesia and surgery
Anesthesia and surgical procedures act as independent stressors. Regarding anesthetics, volatile agents and certain intravenous drugs may exert neurotoxic effects on the aged brain (Safavynia and Goldstein, 2019; Wu et al., 2025), involving mitochondrial dysfunction, neuronal apoptosis, and suppressed neurogenesis (Safavynia and Goldstein, 2019; Wu et al., 2025). Preclinical studies have identified specific underlying mechanisms, demonstrating that volatile anesthetics such as isoflurane and sevoflurane can induce calcium dysregulation, mitochondrial oxidative stress, and activation of apoptosis-related signaling pathways in aged neurons (Osman et al., 2023; Qin and Deng, 2026). In vulnerable aging brains, anesthetic exposure has also been associated with increased amyloid-β production, tau hyperphosphorylation, impaired hippocampal neurogenesis, and disrupted synaptic plasticity (; Terrando et al., 2011). Although the clinical translation of these findings remains under investigation, the convergent evidence suggests that anesthetic-associated neurotoxicity may interact synergistically with pre-existing neurodegenerative vulnerability, thereby worsening perioperative neurocognitive impairment (; Qin and Deng, 2026). Regarding surgical factors, surgical trauma elicits sterile inflammation by releasing damage-associated molecular patterns such as high-mobility group box 1 and activating the complement cascade (; Saxena et al., 2021; Terrando et al., 2016). These inflammatory signals are subsequently transmitted to the central nervous system through a compromised BBB or via neural–immune pathways (Safavynia and Goldstein, 2019). Collectively, these factors increase the inflammatory burden on the central nervous system.
3.3 Perioperative stress–immune–metabolic dysregulation
The perioperative stress response extends beyond inflammatory pathways to encompass widespread neuroendocrine and metabolic disturbances. The hypothalamic–pituitary–adrenal axis becomes overactivated following trauma and surgical stimulation, leading to abnormally elevated cortisol levels or disruption of its normal circadian rhythm (). Prolonged or excessive glucocorticoid exposure can directly damage brain regions subserving cognition by inhibiting hippocampal neuronal plasticity, promoting dendritic atrophy, and reducing neurogenesis (McEwen, 1998). In addition, postoperative pain acts as a persistent stressor. Persistent postoperative pain activates peripheral and central inflammatory signaling pathways, thereby contributing to neurocognitive dysfunction (; Qin and Deng, 2026). Sustained nociceptive stimulation increases the release of proinflammatory mediators—including interleukin-1β, interleukin-6, prostaglandins, and tumor necrosis factor-α—which in turn promote microglial activation and synaptic dysfunction in cognition-related brain regions (Kong et al., 2024). Concurrently, chronic pain-related stress disrupts hippocampal neuroplasticity, impairs long-term potentiation, and alters functional connectivity within memory-related neural networks (Liu et al., 2024; Meng et al., 2025). Thus, inadequate postoperative pain control may act not only as a physiological stressor but also as a neuroinflammatory amplifier, directly contributing to the development of postoperative cognitive dysfunction. Opioid analgesics, although effective for pain relief, possess immunomodulatory properties that may suppress cellular immunity and interfere with the resolution of inflammation (; Sacerdote, 2006), creating a complex balance between adequate analgesia and appropriate immune regulation. The combined dysregulation of the stress–immune–metabolic network represents the peripheral mechanism that amplifies central nervous system injury ().
4 Interaction mechanisms of dual pathways: from parallelism to convergence
This section forms the core of the present perspective article. It demonstrates that central nervous system vulnerability (Pathway I) and peripheral stress amplification (Pathway II) do not operate independently. Rather, they interact through multiple biological interfaces to jointly drive the onset and progression of POCD.
4.1 Interface 1: the BBB—coupling vulnerability with permeability
The BBB is the critical interface between the central nervous system and the peripheral circulation. Age-related BBB vulnerability, as delineated in Pathway I—including reduced expression of tight junction proteins, diminished pericyte coverage, and structural alterations of the basement membrane—provides the structural basis for peripheral inflammatory signals to enter the central nervous system (Montagne et al., 2015; Sweeney et al., 2018). Superimposed on this susceptibility, the systemic inflammatory response following trauma (Pathway II) further compromises BBB integrity (Varatharaj and Galea, 2017). Proinflammatory cytokines and damage-associated molecular patterns can downregulate tight junction proteins such as claudin-5 and occludin, increase vascular permeability, and establish a vicious cycle of vulnerability substrate and inflammatory injury (; Yang et al., 2017). This cycle facilitates the entry of peripheral inflammatory mediators into the brain parenchyma.
4.2 Interface 2: neuroimmune interactions—microglial priming and hyperactivation
Microglia, the intrinsic immune cells of the central nervous system, play a central role in the interplay between the two pathways. Aging-related changes accumulating through Pathway I—including amyloid deposition, tau pathology, and chronic low-grade inflammation—shift microglia into a primed state (; Perry and Holmes, 2014), characterized by morphological alterations, elevated basal cytokine expression, and a lowered threshold for immune activation. When peripheral stress signals from Pathway II (such as surgical trauma or systemic inflammation) reach the central nervous system via the BBB or other routes, primed microglia mount an exaggerated response (; Terrando et al., 2010), releasing substantial quantities of proinflammatory cytokines (e.g., interleukin-1β, tumor necrosis factor-α) and generating a central inflammatory storm (Terrando et al., 2010). This storm can directly impair cognitive function by disrupting synaptic plasticity, particularly by inhibiting long-term potentiation in neural circuits essential for learning and memory (Yirmiya and Goshen, 2011).
4.3 Interface 3: the autonomic nervous system—an amplifier of stress signals
The autonomic nervous system serves a key regulatory role in the bidirectional transmission of central and peripheral stress signals. The vagus nerve–mediated cholinergic anti-inflammatory pathway constitutes an intrinsic mechanism for limiting excessive inflammation (Pavlov and Tracey, 2012; Tracey, 2002). As discussed in Pathway I, the age-related decline of this regulatory pathway weakens endogenous anti-inflammatory capacity and heightens vulnerability to excessive neuroinflammatory responses under perioperative stress. Concurrently, sympathetic overactivation can lead to reduced heart rate variability, increased blood pressure fluctuations, and impaired cerebral autoregulation (Thayer et al., 2010). These changes further destabilize cerebral perfusion, rendering vulnerable brain regions more susceptible to ischemic and hypoxic injury under stress (). Thus, within the dual-pathway framework, the autonomic nervous system functions not only as a physiological regulator but also as a dynamic interface that amplifies the transmission of stress signals between peripheral inflammatory responses and central nervous system vulnerability.
4.4 Integrated model
Bringing together the aforementioned interaction interfaces, an integrated model of POCD pathogenesis can be proposed. Central nervous system vulnerability (Pathway I) establishes the background susceptibility state, characterized by compromised BBB integrity, primed microglia, and reduced autonomic regulatory capacity (Skvarc et al., 2018; Subramaniyan and Terrando, 2019). Peripheral stress amplification (Pathway II) provides the triggering force, delivering multidimensional insults through systemic inflammation, hemodynamic fluctuations, and neuroendocrine disturbances (; Safavynia and Goldstein, 2019). The two pathways converge through three key interfaces—the BBB, microglia, and the autonomic nervous system—ultimately leading to synaptic dysfunction, neuronal injury, and clinically evident cognitive decline (). This model emphasizes the mechanistic progression from parallelism to convergence and offers an integrated theoretical framework for the prevention and intervention of POCD (Supplementary Table 1).
5 Clinical implications and future directions: precision management based on the dual-pathway framework
Building on the dual-pathway interaction model, the clinical management of POCD can shift from the identification of isolated risk factors toward mechanism-guided precision management. This section focuses on risk stratification, intervention strategies, and future research priorities.
5.1 Risk stratification: from static assessment to dynamic monitoring
Traditional risk prediction models for POCD rely primarily on static preoperative variables and often fail to capture dynamic perioperative changes (). The dual-pathway framework provides a more comprehensive approach to risk stratification. During the preoperative phase, assessment should emphasize central nervous system vulnerability (Pathway I) (Silbert et al., 2015). Neuroimaging techniques may be used to quantify white matter hyperintensity burden, cerebral atrophy, and hippocampal volume. In addition, emerging biomarkers, including serum neurofilament light chain and glial fibrillary acidic protein, may help reflect neuroaxonal injury and astrocyte activation, respectively (Safavynia and Goldstein, 2019).
During the perioperative period, dynamic monitoring should focus on the degree of peripheral stress amplification (Pathway II). This includes serial assessment of systemic inflammatory markers, such as interleukin-6 and C-reactive protein, as well as regional cerebral oxygen saturation, which may provide real-time information regarding inflammatory burden and cerebral oxygen balance (; Vacas et al., 2013). Integrating baseline vulnerability assessment with dynamic stress monitoring may improve individualized risk stratification and facilitate the early identification of high-risk patients (Figure 2).
FIGURE 2
5.2 Redefining intervention strategies
The dual-pathway framework provides a hierarchical strategy for POCD prevention and management. For Pathway I (enhancing resilience), the primary objective is to improve central nervous system reserve capacity and tolerance to perioperative stress. Potential approaches include preoperative cognitive prehabilitation, optimized control of cerebrovascular risk factors such as hypertension and hyperglycemia, and interventions aimed at slowing subclinical neurodegenerative progression (; ). For Pathway II (reducing peripheral insult), the focus is to minimize the intensity and duration of peripheral stress responses. Strategies may include minimally invasive surgical techniques to reduce tissue injury, multimodal analgesia to decrease opioid exposure and related immunomodulatory effects, and the use of anesthetic agents with potential organ-protective properties, such as dexmedetomidine, to attenuate neuroinflammatory responses (Kotekar et al., 2014; Su et al., 2016).
At the interaction interfaces (blocking pathological convergence), therapeutic strategies should target key biological mediators involved in pathway integration. Current translational research is exploring BBB protectants and modulators of microglial polarization, such as minocycline, with the aim of interrupting the pathological convergence between central vulnerability and peripheral stress amplification (Subramaniyan and Terrando, 2019).
5.3 Unresolved questions and future perspectives
Although the dual-pathway framework provides an integrated perspective for POCD research, several important questions remain unresolved. First, the causal relationships among the major components of the two pathways require further validation. Future investigations should combine multimodal imaging techniques, including positron emission tomography-magnetic resonance imaging, with high-dimensional multi-omics analyses to clarify the temporal and mechanistic relationships among vulnerability characteristics, stress-signal amplification, and cognitive decline (; ).
Second, the relationship between POCD and long-term postoperative cognitive disorders, including Alzheimer’s disease and related dementias, remains incompletely understood (; ). Risk prediction models based on the dual-pathway framework may help address this issue by integrating multidimensional perioperative data, including preoperative vulnerability profiles, perioperative stress exposure, and responses at key interaction interfaces (; ; Roseborough et al., 2023). Such models may improve prediction of the transition from transient POCD to persistent cognitive impairment and facilitate earlier intervention. Progress in these areas may help shift POCD management from an experience-based clinical approach toward a mechanism-driven precision medicine paradigm.
6 Summary
Postoperative cognitive dysfunction in geriatric trauma patients is not caused by a single factor but results from the interaction between intrinsic vulnerability and extrinsic perioperative stress within the biological context of aging. Intrinsic vulnerability is primarily reflected in central nervous system susceptibility, including structural brain aging, accumulation of pathological comorbidities, and depletion of cognitive reserve. Extrinsic stressors involve peripheral stress amplification, including trauma-related injury, the neuroimmunomodulatory effects of anesthesia and surgery, and dysregulation of perioperative stress–immune–metabolic networks. These processes converge at key biological interfaces, including the BBB, microglia, and the autonomic nervous system, ultimately contributing to cognitive decline.
From a future clinical perspective, the dual-pathway framework may support a paradigm shift in perioperative neurocognitive protection. Rather than focusing solely on anesthetic management, this model advocates an integrated strategy that combines brain health preservation with regulation of perioperative stress responses throughout the surgical period. Along the temporal dimension, this approach emphasizes the coordination of preoperative vulnerability assessment, intraoperative stress modulation, and postoperative rehabilitation. Along the mechanistic dimension, it targets both enhancement of central resilience and reduction of peripheral insult. Together, these concepts provide a theoretical foundation for individualized diagnostic and therapeutic strategies aimed at the precise prevention and management of POCD.
Statements
Data availability statement
The original contributions presented in the study are included in this article/Supplementary material, further inquiries can be directed to the corresponding authors.
Author contributions
X-dW: Conceptualization, Data curation, Methodology, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. JX: Conceptualization, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. T-tQ: Conceptualization, Methodology, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. C-jY: Conceptualization, Data curation, Methodology, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing. X-yL: Conceptualization, Data curation, Investigation, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. YQ: Conceptualization, Data curation, Investigation, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the Scientific Research Innovation Team of Inner Mongolia Medical University (YKD2022TD032), the Clinical Medical Research and New Technology Promotion Program of the Inner Mongolia Medical Doctor Association (YSXH2024KYF064), and the Inner Mongolia Autonomous Region Science and Technology Program (2025KJHZ0013). The funders had no role in the design, execution, or writing of this study.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnagi.2026.1841750/full#supplementary-material
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Summary
Keywords
blood–brain barrier, cognitive reserve, geriatric trauma, neuroinflammation, perioperative management, peripheral stress amplification, postoperative cognitive dysfunction
Citation
Wang X, Xue J, Qiao T, Yang C, Li X and Qiu Y (2026) Risk factors for postoperative cognitive dysfunction in geriatric trauma: a dual-pathway perspective. Front. Aging Neurosci. 18:1841750. doi: 10.3389/fnagi.2026.1841750
Received
29 March 2026
Revised
27 May 2026
Accepted
29 May 2026
Published
17 July 2026
Volume
18 - 2026
Edited by
Allison B. Reiss, New York University, United States
Reviewed by
Yang Yang, Sichuan University, China
Updates
Copyright
© 2026 Wang, Xue, Qiao, Yang, Li and Qiu.
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*Correspondence: Xiao-yan Li, xiao-yanli@outlook.comYi Qiu, tough88410@21cn.com
† These authors have contributed equally to this work
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