Introduction

Underlying conditions that are associated with persistent inflammation produce conditions likely to result in an exacerbated neuroinflammatory response to surgery thereby causing various forms of exaggerated cognitive decline, termed the perioperative neurocognitive disorders (PND). The variety of clinical scenarios associated with persistent inflammation include advanced age, metabolic syndrome, contiguous infection, depression, and additional surgical procedures, each of which increase the risk of PND (1–4).

Advanced Age

The aging population and improvements in anesthesia and surgery have led to an increase in the number of elderly patients undergoing surgery. At the time of this writing, the number of major surgical interventions requiring anesthesia exceeds 230 million worldwide (5) and the prevalence of surgical interventions in patients over 65 years old is increasing faster than any other demographic group (5). Unfortunately, persistent cognitive impairments can develop as a side effect of these surgical procedures (6) and the incidence of postoperative delirium is significantly higher in elderly patients. It is estimated that up to 50% of elderly patients suffer from delirium after surgery (7). The occurrence of delirium increases the risk of PND, and therefore, it is likely that the various forms of postoperative central nervous system dysfunction will become increasingly common.

An international multicenter study of POCD (ISPOCD) demonstrated memory impairments in more than a quarter of the patients 1 week after noncardiac surgery and in 10% after 3 months in patients older than 60 years (4). Follow-up studies have shown a similar incidence with some reports describing cognitive decline persisting for up to 1 year after surgery (8). Large observational studies reported that 10% to 15% of surgical patients over 60 years old experience POCD for more than 3 months (9,10).

Although the pathogenesis of PND is considered multifactorial (6,11), inflammation has been shown to be the pivotal factor in its pathogenesis (see Chapter 9). In addition to the local and systemic inflammatory responses, surgery is associated with CNS infiltration and activation of bone marrow-derived monocytes together with activation of the primary brain immune cells, microglia, that cumulatively increase levels of pro-inflammatory cytokines in the brain (12–15). The resulting neuroinflammation may decrease neuronal function and cognitive function (12,16), as it has been associated with development of PND both in preclinical models and in humans (12,13,17–21). Frequent immunologic challenges and their failure to resolve results in a chronic low-grade inflammatory condition (22–25). Moreover, aging has also been associated with a chronic low-grade increase in systemic and CNS inflammatory markers (22,24,25), particularly in the microglia. This has been characterized as a “primed” microglial phenotype, which exhibits an up-regulated number of cytokine receptors, a hypertrophic cell body, and a heightened reactivity to inflammatory stimuli (22,26).

While never formally studied, it is conceivable that the pathogenesis of this low-grade inflammatory state associated with advanced age may be due to a failure to resolve inflammation. Neuroinflammation after surgery is likely to include a pro-inflammatory phase and pro-resolving phase, and the switch of these two phases is mediated by both neural and humoral pathways (27,28). The humoral factors, such as resolvins and lipoxins, derived from polyunsaturated fatty acids (PUFAs), are novel lipid mediators that promote the resolution of inflammation. D-series resolvins play protective roles in both acute and chronic inflammatory diseases, such as peritonitis, ischemia/reperfusion injury, and sepsis. Resolvins both limit the infiltration of polymorphonuclear leukocytes and enhance macrophage phagocytosis by transducing signaling mechanisms that originate at specific receptors on human polymorphonuclear leukocytes, monocytes, and macrophages. Lipoxins were the first mediators recognized to have both anti-inflammatory and pro-resolving actions (29). They are capable of attenuating the pro-inflammatory response by inhibiting macrophage NF-κB activity and polarizing macrophages into an M2 phenotype (30–32). Dietary supplementation with PUFAs in patients with metabolic syndrome (MetaS) corrects many of the metabolic derangements (33) as well as the pro-inflammatory markers (34).

With respect to the resolving inflammatory state mediated by neural factors, damage-associated molecular patterns (DAMPs) activate the efferent arc of the inflammatory reflex via NF-κB, termed the cholinergic anti-inflammatory pathway. At the splenic nerve terminus of the neural cholinergic reflex, vagal outflow releases adrenergic agonists rather than the usual cholinergic neurotransmitters; these catecholamines activate β2 adrenergic receptors on CD3 T lymphocytes that are capable of synthesizing and releasing acetylcholine needed to mediate inhibition of macrophage NF-κB activity by signaling through the α7 subtype of nicotinic acetylcholine receptors (α7 nAChR). Ultimately, it inhibits synthesis and release of pro-inflammatory cytokines from circulating immunocompetent cells (27,35,36). The neural cholinergic reflex is very important in resolving the inflammatory pathogenesis of several diseases including sepsis (37), rheumatoid arthritis (38), and colitis (39). Furthermore, the cholinergic anti-inflammatory pathway also modulates the function of T regulatory cells (40), which influences the production of anti-inflammatory cytokines (IL-4 and IL-10) (41) and alternative macrophage activation that promotes the resolution of inflammation (42). IL-4 is responsible for polarizing macrophages from the pro-inflammatory classically activating (M1) to the reparative alternatively activating (M2) phenotype. In the mouse models of type II diabetes, there is a relative lack of T regulatory cells and an imbalance of M1/M2 macrophages, which might contribute to persistent low-grade inflammation (43).

A well-described problem in advanced age is vagal hypotonia (44). Given the importance of vagal stimulation (37), it is plausible that this is the primary reason for the persistent low-grade vagal hypotonia inflammation that is seen in patients with advanced age.

Hovens et al. found that after the symptoms of mycoplasma infection had subsided, aged rats still showed neuroinflammation, alterations in exploration and anxiety-related behavior, and impaired spatial learning and memory, which lasted for at least 2 weeks after rats had recovered (cognitive and behavioral changes) (45). In addition, the aged rats exhibited more severe postoperative cognitive impairment. Systemic cytokine levels and microglial activation in the hippocampus are increased for up to 2 weeks after surgery, indicating prolonged neuroinflammation (45).

Metabolic Syndrome

About a quarter of American adults suffer from MetaS and almost half of patients undergoing cardiac surgeries have MetaS (3,46). Recent studies demonstrated that patients having MetaS are more likely to develop PND along with other postoperative complications (3,46). Although the precise definition and diagnostic criteria of MetaS are in dispute (47), it is generally accepted that it includes visceral obesity, insulin resistance, dyslipidemia, and hypertension; one or more of these elements of MetaS will increase the potential for postoperative complications, including PND, and result in a higher postoperative mortality rate (2,3,48). Cerebrovascular accidents (without residual deficit), which occur with increased frequency in patients with MetaS, are also associated with an increased risk for PND (2).

MetaS was shown to exacerbate postoperative cognitive decline, as well as postoperative systemic and neuroinflammation in rodent models (2,3,49,50). Formal studies of the factors involved revealed that there is a deficiency in the organisms ability to resolve inflammation (49,50). Abnormalities of the switching mechanism may cause a nonresolving chronic inflammatory state that creates the pathophysiologic mechanisms for persistent cognitive decline. It has been shown that MetaS will contribute to exaggerated and persistent PND in a rat model of tibia fracture (49), which might result from dysfunctional resolution of inflammation in these MetaS rats (50).

Studies have shown the importance of this reflex for resolving DAMP-induced neuroinflammation, and cognitive decline. There is evidence indicating that stimulation of the α7 nAChR in macrophages inhibited NF-κB activity which in the quiescent state precludes postoperative memory impairment by preventing migration of monocytes into the hippocampus (51). Su et al. found that MetaS rats have defects in the complicated cholinergic anti-inflammatory pathway during dysregulated inflammation resolution, including (1) decrease of an α7 nAChR-expressing CD11b/c+ cells, leading to hyporesponsiveness to the inhibitory actions of α7 nAChR agonist, thus increasing NF-κB activity and TNF-α production; (2) reduction of β2AR-induced IL-10 release and the number of Tregs that could impair M2 macrophage polarization; and (3) decrease of β2AR-expressing CD3+ lymphocytes, causing the failure of splenic α7 nAChR-expressing CD11b/c+ cells to attenuate NF-κB activation. All of these changes will contribute to persistent PND (50).

In addition, the pro-inflammatory adipokines might derive from pathologic metabolism in adipose tissue (52), while production of adiponectin is reduced in MetaS (36). Adiponectin can rectify the up-regulated NF-κB activity in morbid obesity (53). A recent study showed that there is less anti-inflammatory and more pro-inflammatory macrophages in the stromal-vascular fraction and adipocyte fractions separated from epididymal fat pads excised from MetaS rats 5 months after surgery, which may contribute to the impairment in the resolution of systemic and neuroinflammation as well as cognitive decline as long as 5 months following surgery.

Preoperative exercise eliminates the exaggerated cognitive decline in MetaS rats, by normalizing dysregulated inflammation resolution and rectifying the abnormal microbiome, which may provide an opportunity to improve surgical outcome in the high-risk patients with MetaS.

Infection

Inflammatory events may cause prolonged alterations in the immune system (54,55) as well as depression-like behavior and cognitive impairments in rodents (56,57,58).

Furthermore, some human observational studies have found that lifetime inflammatory events, such as cytomegalovirus infection, repeated increase of IL-6, and general infectious burden were associated with increased pro-inflammatory cytokine production and vulnerability to mental health problems (16,59–61).

Aged rats that experienced an infection before surgery showed a decreased performance in location recognition and spatial learning (54,55). In addition, other authors have reported similar effects in rodents while inflammation was present at the time of surgery. The effects of a prior infection on PND pathogenesis might possibly result from changes in immune functioning similar to those seen in aging (62). By administering the mice with a low dose of LPS 2 hours before surgery, Fildalgo et al. (63) found that this led to an exacerbated inflammatory response as well as a more severe impairment of contextual fear memory after surgery.

In a broader perspective, it is hypothesized that the sum of inflammatory events during life-span may determine immune reactivity and thereby the vulnerability to detrimental side effects of immune challenges with aging. In humans this may include not only recurrent infections or trauma, but also chronic diseases, stress, and choice of life styles, such as smoking or a high fat intake. However, the extent to which these factors may predispose patients to PND is still largely unknown. Therefore, future studies should further dissect out the effects of repeated exposure to inflammatory events during aging on susceptibility to postoperative cognitive impairment.