The Role of Inflammation in Postoperative Cognitive Dysfunction

Aim of review: Postoperative cognitive dysfunction (POCD) is a common complication following surgery, especially in the elderly population. Surgery exposes patients to extensive trauma, blood loss, and tissue injury, all of which contribute to an inflammatory response. In recent years, inflammation has been shown to be a key contributor to the pathogenesis of cognitive decline and neuroinflammatory processes, both in animal models and initial clinical observations.Method: We review the recent literatures on the proposed mechanisms whereby peripheral trauma leads to cognitive impairments and some of the new neuroprotective strategies that may be implemented to prevent neuroinflammation and POCD.Recent findings: Changes in pro-inflammatory cytokines, alarmins, macrophage activation and blood-brain barrier (BBB) dysfunction have been proven to be related to the pathogenesis of cognitive decline using a variety of models, reagents, and technologies. Strategies to harness these pathways through anti-inflammatory and pro-resolving strategies show remarkable effects in modulating neuronal function, synaptic plasticity, glia activity and memory processes.Summary: Further studies are needed to better identify the patients at higher risk for cognitive decline in the postoperative period and which interventions may be suitable for translation and new clinical trials.  Citation: Guo-Xun Xu, Ting Yang, Niccolo Terrando. The role of inflammation in postoperative cognitive dysfunction. J Anesth Perioper Med 2014; 1: 97-103. doi: 10.24015/JAPM.2014.0015This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.


C
ognitive disorders, encompassing changes in acute mental status and prolonged cognitive impairments, are often seen following hospitalization and largely contribute to functional impairment worldwide, especially with a steady increase in the geriatric population (1,2).Much progress in the field of postoperative cognitive decline has happened over the last decade, with several studies contributing to a better understanding on the pathogenesis of this phenomenon at both the preclinical and clinical levels.

Overview on Postoperative Cognitive Dysfunctions
The initial observation that memory and learning disabilities may occur following surgery and anesthesia has long been known, as referred to as "insanity" by George Savage in 1887.We can now divide the field of postoperative cognitive decline into two main categories: postoperative delirium (POD) and longerterm postoperative cognitive dysfunction (POCD) (3).Delirium is a more evident and severe form of cognitive failure that meets defined criteria in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV).POD affects up to 50% of elderly patients, costing more than US $164 billion per year in the USA and over $182 billion per year in EU (4).POCD is a more subtle dysfunction affecting one or more cognitive domains following surgery and anes- thesia, including short and long-term memory, attention, concentration, mood, language comprehension, abstract thinking, executive functioning, social integration, and orientation (5).Despite no standardized diagnostic criteria, POCD has become an apparent complication in the perioperative care setting, especially amongst elderly patients.Both POD and POCD are associated with poorer outcome in the patients, including higher mortality, more comorbidities, increased length of hospitalization, possible permanent dementia, and severely affected overall quality of life (6).
In 1998, a seminal paper from the International multicenter study on POCD (ISPOCD) reported an incidence of cognitive impairments of 25% at 1 week and 9.9% at 3 months after noncardiac surgery (7).The study also identified risk factors, including advanced age, occurrence of postoperative infections and exposure to multiple operations as key contributors to the prolonged cognitive deficits.The association between advanced age and surgical procedure has been established by several studies thereafter, with overall incidences of POCD ranging from 12.7% (8) up to 46.1% after 1 year (9,10).
Apart from noncardiac surgery, especially orthopedic surgery, POCD is a frequent complication of cardiac procedures (11).Long-term cognitive dysfunctions in patients after coronary artery bypass grafting (CABG) are common, with incidence up to 42% at five years after hospital discharge (12).Ablation for atrial fibrillation (AF) is also associated with a 13% to 20% prevalence of POCD in patients with AF at longterm follow-up (13).Cerebral micro-emboli caused by the cardiac procedures were initially considered to lead to brain injury and neuropsychological deficits, however, the observation from high-intensity transient signals (HITS) in transcranial Doppler recordings showed no evident correlation between cerebral micro-emboli and POCD (14,15).
The mechanisms whereby surgical procedures and general anesthesia contribute to cognitive decline are currently poorly understood.Anesthetics may be responsible for modifications in the body that outlast their elimination, suggesting a possible role for anesthesia per se in modulating memory function (16).Anesthetics "cocktails", in-cluding ketamine, nitrous oxide, propofol, midazolam, barbiturates, and isoflurane have been found to be associated with markers of neuroapoptosis and long-term cognitive impairments in the developing and adult brain (17,18).Hallmarks of neurodegenerative processes such as beta-amyloid (Aβ) aggregation and tau protein phosphorylation have been detected to be related to anesthesia exposure, suggesting that some anesthetic agents may increase the risk of Alzheimer's disease (AD) in vulnerable individuals (19,20).Recently, markers of AD have been found to be altered after anesthesia and surgery, highlighting the possible role of cerebrospinal fluid (CSF) biomarkers in predicting POCD in different surgical settings (21)(22)(23).In a randomized study from the ISPOCD study group, no significant difference was found in the incidence of cognitive dysfunction at 3 months after either general or regional anesthesia (24).To date, the role of anesthesia and other factors contributing to POCD remain controversial due to underpowered studies with several methodological limitations (25).
To overcome some of these problems, animal models have been introduced in order to better understand the multifactorial origin of cognitive decline following surgery, anesthesia and comorbidities.This review will focus on the growing evidence highlighting a role of inflammation, as caused by surgical trauma, in the pathogenesis of cognitive decline.In this setting, we will discuss the mechanisms whereby pro-inflammatory mediators affect the brain and how novel neuroprotective strategies may be implemented in the clinic to possibly limit the occurrence of postoperative cognitive complications.

Surgery, Neuroinflammation and POCD
Inflammation is an evolutionary conserved critical response to any type of injury, for example infection or trauma, and is necessary to restore function in a tissue or organ (26).Release of soluble mediators, including pro-inflammatory cytokines, chemokines and oxidative stress may however impact on remote organs including the central nervous system (CNS) overall contributing to "sickness behaviour", whose symptoms include fever, decreased food intake, somnolence, hyperalgesia, and general fatigue (27).Accumu- lating evidence from animal models and clinical studies suggests a key role of surgical trauma in modulating the brain and CNS function, leading to cognitive decline, neuroinflammation and neurodegeneration (28)(29)(30)(31)(32)(33)(34).Some of the most recent proposed mechanisms in the pathogenesis of POCD are discussed herein: Systemic Cytokines and Immune-to-Brain Signaling Surgical procedures expose the patients to significant damages (i.e.blood loss, tissue trauma, bone reamings, device implanting, ischemia-reperfusion injury etc.) that contribute to inflammation.This ensuing sterile inflammatory response is clinically similar to sepsis, even though not mediated by infective agents (35).Sterile inflammation may actually activate similar downstream signaling pathways as pathogens, for example through release of damage-associated molecular patterns (DAMPs) and cytokines.These soluble mediators trigger a systemic inflammatory response through the activation of different pattern recognition receptors (PRRs), including toll-like receptors (TLRs), cytokine receptors interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α and oxidative stress pathways (36).Animal models of perioperative cognitive decline have been studied to assess the causal relationship between soluble mediators including TNFα (29), IL-1β (28,32,37), IL-6 (38), high mobility group box-1 (HMGB-1) (39, 40) and memory dysfunction after surgery and critical illness.In a recent meta-analysis, Peng et al. showed that POCD was correlated with the concentrations of systemic inflammatory markers, with IL-6 and S-100β as highly predictive biomarkers (41).Notably, changes in systemic proinflammatory cytokines are also found in human samples and some of these soluble mediators may serve as novel biomarkers to predict poor cognitive outcome in patients at risk (42)(43)(44).
Peripheral immune signals may reach the brain and cause neuroinflammation by activating a neuronal, cellular and humoral response (Figure 1) (45).Nerve conduction, for example via afferent vagal projections to the brainstem, represents a fast processor that sense peripheral inflammatory molecules and conveys information directly to the brain (46).Activation of the inflammatory reflex limits ongoing systemic inflammatory processes by modulation of alpha7 nicotinic acetylcholine receptor (nAChR) signaling and suppression of nuclear factor (NF)-κB in bone marrow-derived cells (47).A key role of cholinergic signaling has been proposed in POD (48) and recent evidence from animal models suggests an involvement of neuronal signaling and the inflammatory reflex in preventing neuroinflammation and cognitive decline (30,49).
The brain has been historically considered an immuno-privileged organ given the presence of the blood brain barrier (BBB) but the systemic pro-inflammatory milieu can negatively impair its function by direct proteolytic actions on the tight junctions (TJs), thus allowing more of these molecules and peripheral cells to enter the brain (50).It is now established that peripheral injury increases levels of cytokines including TNF-α, IL-1β, IL-6, S-100β and these molecules can exert effects on the BBB, alone or in combination.TNFα is rapidly released after orthopedic surgery and is a strong inducer of endothelia dysfunction and BBB opening (29).IL-1β exposure induces endo- thelial barrier dysfunction through activation of protein kinase C (PKC), phosphorylation of zonaoccludens (ZO)-1, and downregulation of claudins (51,52).Peripheral cytokines, including alarmins like HMGB-1, mediate and facilitate the migration of macrophages into the brain parenchyma through activation of TNFα/NF-κB signaling pathway and impairing BBB function, which may consequently affect memory and cognitive function (30,53).HMGB-1 has recently been shown to be associated with BBB dysfunction after abdominal surgery and its effect on macrophages have been proven to be related to the processes of surgery-induced cognitive decline and long-term neurocognitive function after sepsis (39,40,54).Aside from a direct effect of pro-inflammatory cytokines on the endothelium, comorbidities including advanced age, systemic diseases, and infections can further impact on the BBB integrity and permeability (55).Drugs, including anesthetic agents, and toxins accumulation due to decreased efflux through permeability glycoprotein (P-gp), basement membrane disruption, and decreased nutrient transport may also contribute to BBB damage (55).
Overall, impairments to the neurovascular unit result in disrupted CNS microenvironment, with systemic molecules including fibrinogen, cytokines, and alarmins contributing to neuronal damage and neuroinflammation (56).Yet, the crosstalk between systemic inflammation, endothelial function and neuroinflammation remains unclear and further studies are needed to understand how immune-to-brain signaling can be effectively modulated after surgery.

Neuroinflammation and CNS Function
The transduction of peripheral inflammation into the brain results in neuroinflammation, a process that affects glia function and overall neuronal homeostasis (57).Microglia activation is a hallmark of brain pathology.These cells are responsible to actively sense changes in brain homeostasis, for example the presence of inflammatory molecules, becoming reactive and mounting macrophage-type innate immunity within the CNS (58).Microglia have been referred to as a "double-edged sword": they can not only exert protective function by releasing neurotrophic and anti-inflammatory molecules but also contribute to a pro-inflammatory milieu, de novo cytokine production, and neurodegenerative processes once activated (59).It is well established that several substances can activate microglial cells, for instance, lipopolysaccharide (LPS), Aβ, interferon (IFN)γ, ATP and some pro-inflammatory cytokines (60).Centrally released cytokines, including TNFα, IL-1β, and IL-6, have also been implicated in processes of synaptic formation and scaling, long-term potentiation (LTP), and neurogenesis (61).Recent studies have highlighted some of the possible mechanisms whereby surgery and the ensuing inflammatory response contribute to cognitive decline, including changes in synaptic plasticity (62,63), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking (64), and N-methyl-D -aspartate receptor (NMDA) subtype 2B (NR2B) expression (65).
Although many studies reported microglia activation after surgery and anesthesia exposure, especially in older animals, the exact role of microglia in the pathogenesis of POCD remains elusive and no evidence of neuroinflammation in humans exists.Recently, monocytes and macrophages have been found in the brain parenchyma after peripheral surgery, suggesting a possible role for these cells in mediating the neuroinflammatory response (30,53).Similar neuropathology with macrophage infiltration and defective phagocytosis has been highlighted in the brain of AD patients (66) and this may be mediated by changes in BBB permeability during the neurodegenerative process (67).Changes in BBB permeability and function have been reported in several models of surgery-induced cognitive decline, including orthopedic (30), cardiac (68) and abdominal (54) surgery-induced cognitive decline, suggesting a role of endothelial and other glia cells contributing to cognitive decline.
As key cellular components of the BBB, astrocytes have been found to be related to several neurological conditions.Astrogliosis is characterized by cellular hypertrophy and hyperplasticity, accompanying an elevation of expression of markers like glial fibrillary acidic protein (GFAP) and S100β (69).Disrupted BBB can affect astrocytes function leading to astrogliosis and perturbing neuronal homeostasis (70).Furthermore, mitochondria in astrocytes directly  Surgery has been shown to engage the innate immune system and activate a cascade of pro-inflammatory mediators, including alarmins, cytokines and eicosanoids.These molecules exert effects on the humoral and neuronal signaling overall contributing to the neuroinflammatory response.These processes are mediated not only by activation of resident microglia but also by infiltration of peripheral cells into the brain parenchyma via a disrupted BBB.This pro-inflammatory milieu and glia dysfunction impair neuronal activity and synaptic plasticity, impinging on processes of long-term potentiation, neurotransmission, and receptor function at the synapse.In combination, these pathological hallmarks contribute to learning and memory impairments following surgical trauma.
participates in the metabolic changes associated with astrogliosis and neuroinflammation via iN -OS-mediated NO production and subsequent dynamin-related protein 1 (Drp1) activation (71).TNFα, IL-1, IL-6, IFNγ, bone morphogenetic proteins (BMPs) and Notch signaling molecules are all potent activators of astrogliosis and activated astrocytes subsequently release comprehensive cytokine and chemokine secretome [e.g., IL-1β, TNF-α, monocyte chemotactic protein-1 (MCP1)], which closely link to NF-κB activation and might affect short-term memory processes at the synapses (72)(73)(74).Overall, it is evident that POCD is a classic multifactorial condition with many factors contributing to the memory dysfunction and several targets being affected both systemically and centrally (Figure 2).

Neuroprotective Strategies and Future Directions
Neuroinflammation has become the hallmark of cognitive decline and several neurodegenerative processes (75).Significant efforts have been devoted to define strategies to limit, and possibly prevent, neuroinflammation and ensuing cognitive decline after trauma.Anti-inflammatory therapies have shown promising effects in limiting memory decline after surgery in several preclinical models.Targeting of the systemic pro-inflammatory milieu with selective antibody strategies or general anti-inflammatories has provided insights on how trauma contributes to POCD pathophysiology.
Release of pro-inflammatory cytokines and alarmins is a timely event with defined kinetic and resolution indices (76).Pre-emptive targeting of early-released cytokines like TNFα, HMGB-1, and IL-1β limit the perpetuation of the inflammatory cascade and protect the CNS from neuroinflammation and cognitive decline (28)(29)(30)39).Administration of broadly used antiinflammatory agents including minocycline (77), non-steroidal anti-inflammatory drugs (NSAIDs) and more selective cyclooxygenase (COX) inhibitors (78,79) have shown beneficial effects in preventing microglia activation and memory decline.Antioxidants may also attenuate some of the processes associated with cognitive decline (80), including tissue damage and apoptosis resulting from ischemia-reperfusion injury (81).It has become apparent that cytokines are necessary and sufficient for disease pathogenesis (82) and inflammation in POCD has gained more attention both from preclinical mechanistic studies and clinical researches.Endogenous control of inflammatory process is therefore of considerable interest to modulate cognitive dysfunction and unresolved inflammation (83).
Resolution of inflammation is now regarded as an active process involving a class of specialized pro-resolving lipid mediators (SPM), which exert potent stereoselective actions during acute inflammation and restore homeostasis (84,85).Resolvins, protectins and maresins are three families of SPM biosynthesized from omega-3 essential eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that display evident antiinflammatory and pro-resolving effects (86).Omega-3 supplementation has been shown to increase SPM production in the blood (87,88), demonstrating the presence of these mediators in human samples.Recently, resolvins like AT- Different agents of relevance to the perioperative care setting and ageing population may also be used to effectively jumpstart resolution.Atorvastatin and pitavastatin reduce the levels of oxidative stress and activation of cytokines in the CNS (94).These drugs also protect synaptic networks and prevent subsequent worsening of cognitive function (95)(96)(97).Statins may also redirect microglial activation and promote an anti-inflammatory phenotype, thereby reducing the clinical occurrence of delirium and attenuating neuroinflammation (98).In line with these mechanisms, preoperative administration of statins has been associated with the reduced risk of postoperative delirium after cardiac surgery with cardiopulmonary bypass, and ongoing statin therapy is associated with a lower daily risk of delirium in critically ill patients (99,100).Although some clinical evidence supports the use of statins in reducing cognitive impairment, double-blind randomized placebo-controlled clinical trials are required to validate these findings.
Recently, a crosstalk between SPM and the in-flammatory reflex has been shown (101) and stimulation of the cholinergic anti-inflammatory pathway through activation of alpha7 nAChR significantly attenuated macrophage infiltration in the CNS after surgery, increasing production of anti-inflammatory cytokines like IL-10 (30).
To modify the pro/anti-inflammatory balance, anesthetic agents including isoflurane may contribute to resolution of inflammation (102) and noble gases like xenon effectively prevented surgery-induced memory dysfunction by modulating heat shock protein 72 (HSP72) expression in the hippocampus (97).
Overall, modulation of pro-resolving processes after surgery may offer a safe and effective treatment to prevent postoperative cognitive dysfunctions in our patients, but it remains of paramount importance to further develop better tools to predict POCD in patients at risk, including validated blood/CSF biomarkers, neuroimaging (fMRI, PET) and omic-tools (lipidomic, metabolomic) to add on standardized neuropsychological assessment.These approaches are becoming more mature amongst the neurodegenerative field, with blood tests acquiring more validity in detecting preclinical AD in patients (103).Similarly, in the perioperative care it will be necessary to spearhead novel preclinical investigations and large multicenter clinical studies in order to better understand and treat postoperative cognitive disorders.
The author thanks Dr. Ralph E Harding for critical reading of the manuscript and grants from the European Society of Anaesthesiology and Karolinska Institutet Foundations.
No other potential conflict of interest relevant to this review was reported.
Thanks also to the collaborators and investigators contributing to this field whose publications were not cited due to size limitations.
Xu et al.

Figure 1 .
Figure 1.Immune-to-Brain Signaling after Surgery.Surgery induces changes in brain cytokines, including transcription and translation in selective regions such as hippocampus.From the periphery, cytokines and other pro-inflammatory mediators can penetrate the brain via the circumventricular organs (CVOs) and choroid plexus, which lack a patent BBB.Cytokines, chemokines and matrix metalloproteinases (MMPs) can directly disrupt the barrier by affecting tight junctions (TJs) integrity and allowing blood-derived molecules like fibrinogen and monocytes-derived macrophages to enter the brain parenchyma.Through more regulated processes, cytokines can be actively transported across the brain endothelium, thus gaining access to the CNS and contributing to microglia activation and de-novo synthesis of other cytokines.At last, peripheral afferents such as the vagus nerve bypass the BBB interface and signal to brain physiological and inflammatory changes due to systemic injury.

Figure 2 .
Figure 2. Proposed Mechanisms for Neuroinflammation and POCD.Surgery has been shown to engage the innate immune system and activate a cascade of pro-inflammatory mediators, including alarmins, cytokines and eicosanoids.These molecules exert effects on the humoral and neuronal signaling overall contributing to the neuroinflammatory response.These processes are mediated not only by activation of resident microglia but also by infiltration of peripheral cells into the brain parenchyma via a disrupted BBB.This pro-inflammatory milieu and glia dysfunction impair neuronal activity and synaptic plasticity, impinging on processes of long-term potentiation, neurotransmission, and receptor function at the synapse.In combination, these pathological hallmarks contribute to learning and memory impairments following surgical trauma.