Published online Nov 27, 2026. doi: 10.4240/wjgs.119120
Revised: January 30, 2026
Accepted: March 2, 2026
Published online: November 27, 2026
Processing time: 296 Days and 21.6 Hours
Postoperative cognitive dysfunction, a legacy term broadly corresponding to the postoperative spectrum within the contemporary perioperative neurocognitive disorders framework, is a frequent and clinically consequential complication after gastrointestinal (GI) cancer surgery in older adults. Preoperative depression is increasingly recognized as a high-impact risk factor, yet its biological links to peri
Core Tip: Postoperative cognitive dysfunction (POCD) is a frequent yet underappreciated complication in elderly patients undergoing gastrointestinal tumor surgery. This editorial highlight emerging evidence that preoperative depression represents a biologically active vulnerability state that predisposes patients to POCD through synergistic neuroinflammatory activation and cholinergic dysfunction. By integrating findings on interleukin-6-mediated inflammation and impaired cholinergic regulation, the article reframes POCD as a disorder of perioperative brain resilience. This perspective supports earlier risk identification and mechanism-based preventive strategies to preserve cognitive health in aging surgical populations.
- Citation: Wang G, Pan SJ. Preoperative depression as a neuroimmune-cholinergic vulnerability state for postoperative cognitive dysfunction after gastrointestinal cancer surgery. World J Gastrointest Surg 2026; 18(11): 119120
- URL: https://www.wjgnet.com/1948-9366/full/v18/i11/119120.htm
- DOI: https://dx.doi.org/10.4240/wjgs.119120
This editorial refers to "Retrospective analysis cognitive function changes in elderly depressive patients after gastrointestinal tumor surgery and exploration of cholinergic mechanism" by Li et al, 2026; https://dx.doi.org/10.4240/wjgs.v18.i3.115910.
Postoperative cognitive dysfunction (POCD) - a term historically used to describe postoperative cognitive decline and broadly corresponding to the postoperative spectrum within the contemporary perioperative neurocognitive disorders (PND) framework - has emerged as a major and increasingly consequential complication among elderly patients undergoing major oncologic surgery[1]. In the context of gastrointestinal (GI) tumor surgery, postoperative cognitive impairment extends beyond transient postoperative confusion; it is associated with delayed functional recovery, impaired treatment compliance, prolonged hospitalization, and diminished long-term quality of life[2]. As global surgical oncology practice shifts toward an older and more comorbid population, perioperative neurocognitive outcomes are no longer a marginal postoperative concern but a central determinant of postoperative resilience and survivorship[3].
Despite its clinical importance, postoperative cognitive impairment remains mechanistically heterogeneous and incompletely understood. Contemporary evidence suggests that postoperative neurocognitive disorders arise from a convergence of perioperative stressors - including surgical trauma, anesthesia exposure, metabolic perturbation, and inflammatory activation - superimposed upon pre-existing neural vulnerability[4]. Among these processes, systemic and neuroinflammation have been most consistently implicated, with inflammatory mediators capable of disrupting blood-brain barrier integrity, activating microglia, and impairing synaptic plasticity[5]. However, inflammation alone fails to account for the marked interindividual variability in postoperative neurocognitive outcomes, indicating that patient-specific biological susceptibility plays a decisive role.
Preoperative depression represents one such susceptibility factor that has been persistently underrecognized in perioperative risk assessment. Depression is highly prevalent among elderly patients with cancer and is independently associated with cognitive impairment, immune dysregulation, and adverse postoperative outcomes[6,7]. Importantly, depression is not merely a psychological construct; it is accompanied by reproducible biological alterations, including chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and neurotransmitter imbalance[8]. These changes may prime the brain for exaggerated vulnerability to perioperative insults, yet depression has traditionally been treated as a secondary or confounding variable contributor to postoperative neurocognitive outcomes within the PND spectrum[9].
Of particular mechanistic interest is the cholinergic system, which occupies a unique position at the interface of cognition and immunity. Cholinergic neurotransmission is essential for attention, learning, and memory, and simultaneously serves as a key regulator of systemic inflammation through the cholinergic anti-inflammatory pathway[10]. Disruption of cholinergic signaling has been implicated in cognitive aging, delirium, and neurodegenerative disorders[11], and emerging evidence suggests that depressive states are likewise characterized by impaired cholinergic tone[12]. When compounded by perioperative exposure to anticholinergic agents and surgical stress, this vulnerability may substantially amplify the risk of postoperative cognitive decline[13].
Parallel to cholinergic dysfunction, inflammatory mediators - most notably interleukin (IL)-6 - have been increasingly linked to postoperative cognitive outcomes. IL-6 exerts pleiotropic effects on the central nervous system, influencing synaptic transmission, neuroplasticity, and microglial activation[14]. Elevated perioperative IL-6 levels have been associated with both acute delirium and longer-term cognitive impairment, positioning IL-6 as a critical molecular bridge between peripheral immune activation and central cognitive dysfunction[15]. The interaction between inflammation and cholinergic signaling therefore represents a biologically coherent, yet insufficiently explored, pathway through which depression may modulate risk for postoperative neurocognitive impairment within the PND spectrum[16].
Within this conceptual framework, the recent retrospective study by Li et al[17] published in World Journal of Gastrointestinal Surgery, provides timely and clinically meaningful insights. By focusing specifically on elderly patients with preoperative depression undergoing GI tumor surgery, the authors move beyond descriptive epidemiology to propose a mechanistically informed framework in which depression-associated inflammatory activation and cholinergic impairment are jointly associated with POCD[17]. Their findings suggest that POCD should be understood not solely as a consequence of surgical insult, but as the result of a dynamic interaction between perioperative stressors and pre-existing neuroimmune vulnerability.
This editorial contextualizes the work of Li et al[17] within the evolving landscape of perioperative neuroscience and surgical oncology. It argues that postoperative neurocognitive impairment in elderly GI cancer patients, within the contemporary PND framework, should be reframed as a disorder of neuropsychiatric-immune-cholinergic integration, and that preoperative depression represents a biologically actionable risk state rather than a passive comorbidity, with important implications for risk stratification and perioperative optimization[6,18]. Importantly, this article is intended as an invited editorial commentary rather than a systematic or narrative review. Its purpose is to interpret and contextualize the findings of Li et al[17] within an emerging neuroimmune-cholinergic framework, to integrate relevant biological plausibility from the existing literature, and to generate testable hypotheses for future investigation. No attempt is made to provide comprehensive evidence synthesis, formal literature appraisal, or causal inference beyond the constraints of the original retrospective study.
The objective of this editorial is to provide a critical, mechanistically informed interpretation of the recent retrospective study by Li et al[17], which investigates postoperative cognitive changes in elderly patients with preoperative depression undergoing GI tumor surgery. Beyond summarizing the reported associations, these editorial aims to reframe the study’s findings within a broader conceptual model of perioperative brain vulnerability, integrating neuropsychiatric, inflammatory, and neurotransmitter-based mechanisms[4,6].
First, this editorial seeks to clarify the role of preoperative depression as a biologically active risk state, rather than a passive comorbidity. While depression has long been recognized as prevalent among elderly cancer patients, its contribution to POCD has often been treated as secondary or confounded by age and comorbidity[7,9]. By examining Li et al’s data[17] through a mechanistic lens, this editorial emphasizes depression as a condition characterized by chronic immune activation and altered neuromodulatory tone, which may prime the brain for exaggerated cognitive injury in response to surgical stress[8,12].
Second, the editorial aims to critically examine the dual-pathway framework proposed by Li et al[17], in which systemic inflammation - indexed by IL-6 - and cholinergic-related alterations - reflected by reduced peripheral cholinesterase activity - act as convergent biological pathways statistically linked to POCD. Rather than viewing these pathways in isolation, this editorial highlight their biological interdependence: Inflammatory signaling can impair cholinergic neurotransmission, while reduced cholinergic tone weakens endogenous anti-inflammatory control[10,16]. Framing these processes as an interacting network provides a more coherent explanation for why patients with depression exhibit heightened postoperative cognitive vulnerability.
Third, these editorial aims to position the study’s findings within the evolving field of perioperative brain health, with direct implications for clinical decision-making. By linking mechanistic insights to modifiable perioperative factors - such as anesthetic exposure, anticholinergic drug use, and preoperative mental health optimization - the editorial seeks to bridge the gap between observational research and actionable clinical strategies[13,18]. This approach underscores the potential for mechanism-based risk stratification and targeted prevention of POCD in high-risk populations.
Ultimately, the objective of this editorial is to use Li et al’s work[17] as a foundation for a conceptual shift in how POCD is understood and managed in elderly GI cancer patients. By integrating depression-related neurobiology with immune and cholinergic pathways, the editorial advances a unified framework that supports more precise, interdisciplinary, and preventive approaches to perioperative cognitive care[6,18].
The study by Li et al[17] offers a substantive advance in the understanding of postoperative neurocognitive outcomes within the contemporary PND framework by shifting attention from procedure-centered explanations toward a patient-centered, biologically integrated model of perioperative cognitive vulnerability. Their findings suggest that POCD in elderly patients undergoing GI tumor surgery is not merely the downstream consequence of surgical stress or anesthetic exposure, but rather the manifestation of a pre-existing susceptibility state in which depression-related neuroimmune and neurotransmitter dysregulation plays a decisive role[19].
A central observation of the study is the high incidence of POCD (36.84%) among elderly patients with preoperative depression[17]. This magnitude is clinically meaningful and reinforces the concept that cognitive outcomes after surgery are strongly conditioned by baseline brain resilience[20]. Importantly, Li et al[17] demonstrate that the association between depression and POCD persists after adjustment for conventional risk factors such as age, operative duration, and medication exposure. These finding challenges traditional perioperative risk models that prioritize demographic and procedural variables while underweighting neuropsychiatric vulnerability as a determinant of postoperative brain function[21].
The mechanistic contribution of this work lies in its identification of two interdependent biological pathways - systemic inflammation and cholinergic-related alterations - that together are statistically consistent with the observed association between preoperative depression and postoperative cognitive outcomes[17]. Elevated postoperative IL-6 emerged as a key inflammatory signal associated with POCD.
IL-6 is highlighted in this editorial primarily because it is a commonly reported perioperative cytokine that is highly responsive to surgical trauma and tissue injury, and is frequently used in the perioperative neuroinflammation literature as an accessible index of acute systemic inflammatory activation. In addition, IL-6 has pleiotropic relevance to neurocognitive vulnerability through its associations with acute-phase signaling, endothelial and vascular responses, and neuroimmune communication, making it a practical representative inflammatory signal for conceptual framing in the context of the biomarkers reported by Li et al[17].
At the same time, perioperative inflammation is intrinsically multidimensional. Other cytokines and inflammatory mediators (e.g., IL-1β, tumor necrosis factor-α, IL-8), acute-phase proteins (e.g., C-reactive protein), and cellular immune dynamics may contribute to postoperative neurocognitive outcomes and could confound or modify observed associations when not jointly modeled. Moreover, perioperative factors such as intercurrent infection, postoperative complications, anesthetic or analgesic exposure, transfusion, and baseline comorbidity burden can substantially influence cytokine trajectories. Accordingly, the IL-6 signal should be interpreted as part of a broader inflammatory network rather than as a singular or causal pathway.
Biologically, IL-6 is a pleiotropic cytokine with well-established effects on synaptic function, neuronal energy metabolism, and microglial activation[22]. Its perioperative elevation may reflect a state in which peripheral immune activation is associated with central neuroinflammatory processes, potentially compromising cognitive networks essential for attention and memory in vulnerable patients[23].
Equally important is the study’s demonstration of a cholinergic-related signal, indexed by reduced peripheral cholinesterase activity, as an independent mediator of POCD risk[17]. The cholinergic system occupies a unique position at the intersection of cognition and immunity. Beyond its canonical role in attentional modulation and memory processing, cholinergic signaling exerts tonic inhibitory control over inflammatory responses through the cholinergic anti-inflammatory pathway[24]. Depression-associated reductions in cholinergic tone may therefore have dual consequences: Diminished cognitive signaling capacity and weakened endogenous regulation of inflammation[25]. In the perioperative setting, this dual vulnerability may substantially amplify susceptibility to POCD.
Interpretation of cholinesterase activity requires important caution. Cholinesterase measures obtained from peripheral blood primarily reflect systemic enzymatic activity (e.g., acetyl-cholinesterase and/or butyryl-cholinesterase) and are influenced by multiple physiological factors, including hepatic synthetic function, nutritional status, acute-phase/inflammatory responses, perioperative hemodilution, and medication exposure. Accordingly, peripheral cholinesterase activity should be interpreted as an indirect proxy related to cholinergic biology rather than a direct readout of central cholinergic neurotransmission or synaptic acetylcholine signaling. The mechanistic inferences discussed here therefore remain biologically plausible but not definitive, and future studies would benefit from incorporating more direct assessments of cholinergic signaling (e.g., pharmacologic anticholinergic burden metrics, neurophysiological markers, or central biomarkers where feasible) alongside longitudinal cognitive testing.
A particularly novel aspect of analysis is the demonstration that inflammatory and cholinergic pathways explain overlapping yet distinct components of the observed association between depression and POCD[17]. This finding supports a synergistic, network-based model, rather than a linear or unidirectional pathway. In such a model, inflammatory signaling may be associated with reduced cholinergic tone, while impaired cholinergic signaling further disinhibits inflammatory cascades, creating a self-reinforcing loop that culminates in postoperative cognitive decline[26]. This integrative perspective helps reconcile previously fragmented findings in the POCD literature and aligns with emerging concepts of perioperative brain injury as a failure of adaptive neuroimmune regulation[27].
From a broader conceptual standpoint, this work advances the field by reframing postoperative neurocognitive outcomes within the PND framework as a disorder of neuropsychiatric-immune-neurotransmitter coupling, rather than an isolated postoperative complication[19]. It suggests that depression defines a biological phenotype characterized by heightened inflammatory reactivity and reduced neuromodulatory reserve, rendering the brain less capable of maintaining cognitive homeostasis in the face of surgical stress[28].
Several limitations merit consideration. The retrospective design precludes definitive causal inference, and the temporal sequencing of depressive severity, inflammatory activation, and cholinergic impairment cannot be fully delineated. Moreover, cognitive assessment at an early postoperative time point may not capture longer-term trajectories of cognitive recovery or decline[29]. Nonetheless, these limitations do not diminish the conceptual value of the study; rather, they underscore the need for prospective, longitudinal investigations incorporating repeated cognitive testing and dynamic biomarker profiling[30]. In addition, reliance on a limited set of inflammatory biomarkers (e.g., IL-6) and incomplete capture of perioperative inflammatory drivers may introduce residual confounding, further highlighting the importance of multidimensional inflammatory profiling in future studies.
Depression-related measurement and treatment heterogeneity also warrant consideration. In retrospective perioperative cohorts, depression may be identified using different assessment tools, thresholds, and time points relative to surgery, introducing heterogeneity in case definition and misclassification risk. Moreover, depression severity, duration, and chronicity are rarely captured in sufficient granularity, yet these dimensions may differentially influence inflammatory activation, neurobiological vulnerability, and postoperative cognitive trajectories.
In addition, exposure to antidepressant medications and other perioperative psychotropic agents represents an important potential confounder. Antidepressants may exert independent effects on inflammatory signaling, neurotransmitter systems, sleep architecture, and perioperative cognitive outcomes, while perioperative medication adjustments or polypharmacy may further modify risk. These factors were not fully accounted for in the available data and may contribute to residual confounding. Future prospective studies should incorporate standardized depression assessments, severity stratification, and detailed psychotropic medication profiling to more precisely delineate the relationship between depression, neuroimmune alterations, and POCD.
In summary, Li et al’s study[17] meaningfully enriches the current understanding of POCD by integrating depression, inflammation, and cholinergic dysfunction into a coherent mechanistic framework. By positioning preoperative depression as an active biological determinant of postoperative cognitive outcomes, the study challenges prevailing paradigms and provides a compelling rationale for more nuanced, mechanism-driven approaches to perioperative brain health in elderly patients undergoing GI tumor surgery.
The findings of Li et al[17] carry potentially important implications for future perioperative practice for the perioperative management of elderly patients undergoing GI tumor surgery. By demonstrating that preoperative depression operates as a biologically active vulnerability state associated with increased risk of POCD - rather than a passive psychosocial comorbidity - the study compels a reorientation of perioperative care toward mechanism-informed, patient-centered brain health strategies[19].
Current perioperative risk stratification models largely emphasize chronological age, surgical complexity, and anesthetic exposure[21]. Li et al’s work[17] highlights a critical limitation of this approach: It overlooks latent neurobiological vulnerability. Preoperative depression, as shown in this study, reflects a state of altered immune signaling and impaired neuromodulatory reserve that substantially lowers cognitive resilience to surgical stress[28]. Accordingly, routine preoperative depression screening may be considered as part of future risk stratification frameworks for elderly GI cancer patients, not only to identify psychological distress but to flag patients at elevated biological risk for POCD[31].
A particularly compelling implication of this work is the positioning of depression as a modifiable perioperative risk factor[19]. Unlike age or tumor stage, depression is potentially reversible. Timely intervention - through pharmacological treatment, structured psychotherapy, or combined approaches - may attenuate inflammatory activation and partially restore cholinergic balance prior to surgery[32]. In line with this concept, emerging perioperative intervention studies have demonstrated that integrated psychological and behavioral strategies can modulate immune responses and improve postoperative recovery trajectories in GI cancer patients[33].
The identification of cholinergic dysfunction as a mediator of POCD has immediate relevance for perioperative medication management[17]. Elderly patients with depression may be uniquely sensitive to anticholinergic burden, whether from anesthetic adjuncts, perioperative medications, or postoperative symptom control[13,24]. These findings support a more deliberate, individualized approach to anesthesia planning - prioritizing agents and techniques that minimize cholinergic disruption and cognitive side effects[34].
The association between elevated postoperative IL-6 and POCD underscores perioperative inflammation as a central therapeutic target[22,23]. While routine anti-inflammatory prophylaxis cannot yet be recommended, Li et al’s findings[17] justify closer monitoring of inflammatory trajectories in high-risk patients and encourage future trials of targeted immunomodulatory strategies[26,35]. Importantly, this perspective reframes inflammation not merely as a marker of surgical stress, but as an actionable pathway through which cognitive outcomes may be modified.
Collectively, these implications argue for a transition toward a multidisciplinary perioperative brain health framework, integrating surgery, anesthesia, geriatrics, psychiatry, and neurology[27,31]. Prevention of PND cannot rely on isolated interventions; it requires coordinated strategies that address mental health status, immune regulation, neurotransmitter integrity, and postoperative cognitive surveillance as interdependent components of care. Li et al’s study[17] provides a biologically grounded justification for such integration and highlights its potential to improve not only cognitive outcomes, but overall functional recovery and quality of life in elderly surgical patients[33].
In summary, the clinical significance of this work lies in its ability to move PND prevention upstream, from postoperative recognition to preoperative anticipation and intervention[19]. By operationalizing depression, inflammation, and cholinergic dysfunction as modifiable perioperative targets, the study outlines a conceptual roadmap for future investigation and intervention development to safeguard cognitive health in elderly patients undergoing GI tumor surgery.
The work by Li et al[17] represents a substantive conceptual advance in the understanding of POCD in elderly patients undergoing GI tumor surgery. By systematically linking preoperative depression, systemic inflammatory activation, and cholinergic dysfunction, the study moves beyond traditional perioperative risk models and provides a biologically coherent explanation for why certain patients experience disproportionate cognitive decline after surgery.
A key message emerging from this analysis is that POCD should be reconceptualized as a manifestation of pre-existing neurobiological vulnerability, rather than an unavoidable by-product of surgical or anesthetic exposure. Preoperative depression, as demonstrated in this study, reflects a state of altered neuroimmune homeostasis characterized by heightened inflammatory reactivity and reduced neuromodulatory reserve. When superimposed on the physiological stress of surgery, this vulnerability substantially increases the likelihood of postoperative cognitive impairment. This reframing elevates depression from a contextual comorbidity to a central biological determinant of perioperative brain outcomes.
Equally important is the study’s demonstration that inflammatory signaling and cholinergic dysfunction operate as interacting, partially mediating pathways, rather than isolated mechanisms. This integrative perspective provides a more nuanced understanding of POCD pathogenesis and reconciles previously fragmented observations in the literature. It suggests that effective prevention of POCD will require strategies capable of restoring neuroimmune balance and preserving cholinergic integrity, rather than focusing exclusively on procedural modification or postoperative symptom management.
From a clinical standpoint, these insights support a shift toward anticipatory, mechanism-based perioperative care. Identifying depression-related neurobiological risk before surgery opens opportunities for targeted intervention, including mental health optimization, individualized anesthetic planning, and future anti-inflammatory or neuromodulatory therapies. Such an approach aligns with the principles of precision medicine and emphasizes proactive preservation of cognitive function as a core surgical outcome.
Looking forward, Li et al’s findings[17] highlight several priorities for future research. Prospective, longitudinal studies are needed to validate these mechanistic pathways, clarify their temporal dynamics, and determine whether modifying depression, inflammation, or cholinergic function can meaningfully alter cognitive trajectories after surgery. The development of reliable biomarkers to identify high-risk patients and monitor intervention response will be critical to translating this framework into routine practice.
In summary, this study advances perioperative neurocognitive research by positioning postoperative cognitive outcomes within the contemporary PND framework at the intersection of mental health, immune regulation, and neurotransmitter function. By doing so, it provides both a compelling conceptual framework and a clear clinical impetus for redefining perioperative brain health strategies in elderly patients undergoing GI tumor surgery. As an editorial, this article does not seek to establish definitive mechanistic causality or clinical recommendations. Rather, it aims to provide a conceptual synthesis that highlights preoperative depression as a neuroimmune-cholinergic vulnerability state and to frame Li et al’s findings[17] as hypothesis-generating. Definitive validation of these pathways and their clinical modifiability will require prospective, longitudinal, and interventional studies.
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