Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies

Abstract

Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant clinical, social and financial impacts for patients and their communities. The underlying pathophysiology is becoming increasingly understood, with the role of neuroinflammation and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review aims to describe the putative mechanisms by which surgery-induced inflammation produces cognitive sequelae, with a focus on identifying potential novel therapies based upon their ability to modify these pathways.

Full text

Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis
and novel therapies.
*David R. Skvarc a, c, dskvarc@deakin.edu.au
Michael Berk c, d, e, mikebe@barwonhealth.org.au
Linda K. Byrne a, linda.byrne@deakin.edu.au
Olivia M. Dean c, d, e, olivia.dean@barwonhealth.org.au
Seetal Dodd c, d, seetald@barwonhealth.org.au
Matthew Lewis a, f, m.lewis@cgmc.org.au
Andrew Marriott b, c, d, e, amarri@barwonhealth.org.au
Eileen M. Moore b, c, eileenmo@barwonhealth.org.au
Gerwyn Morris g, activatedmicroglia@gmail.com
Richard S. Paged, h, Richard.page@deakin.edu.au
& Laura Gray d, l.gray@deakin.edu.au
*Corresponding author: dskvarc@deakin.edu.au
A. School of Psychology, Deakin University, Melbourne, Australia. B. Department of
Anaesthesia, Perioperative Medicine & Pain Management, Barwon Health, Geelong,
Australia. C. Deakin University, Innovations in Mental and Physical Health and Clinical

Treatment (IMPACT) Strategic Research Centre, Barwon Health, Geelong, Australia. D.
Deakin University, School of Medicine, Geelong, Australia. E. Orygen, The National Centre of
Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute of
Neuroscience and Mental Health, the University of Melbourne, Parkville, Australia. F. Aged
Psychiatry Service, Caulfield Hospital, Alfred Health, Caulfield, Australia. G. Tir Na Nog. H.
Department of Orthopaedics, Barwon Health, Geelong, Australia.

Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis
and novel therapies.
Abstract
Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant
clinical, social and financial impacts for patients and their communities. The underlying
pathophysiology is becoming increasingly understood, with the role of neuroinflammation
and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review
aims to describe the putative mechanisms by which surgery-induced inflammation produces
cognitive sequelae, with a focus on identifying potential novel therapies based upon their
ability to modify these pathways.
Abbreviations
AD, Alzheimer’s disease; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
ApoE, apolipoprotein E; BBB, Blood brain barrier; BDNF, brain-derived neurotrophic factor;
CNS; Central nervous system; CRP, C-reactive protein; GABA, gamma-aminobutyric acid;
HMGB1; High-mobility group 1 box; IL, Interleukin; NAC, N-acetylcysteine; NADPH,
nicotinamide adenine dinucleotide phosphate; NMDA, N-Methyl-D-aspartate; POCD, Post-
Operative Cognitive Dysfunction; TNF-α; Tumour necrosis factor alpha.
Keywords
Cognition, Post-operative cognitive dysfunction, biomarkers, neuroinflammation, oxidative
stress

1. Introduction
Cognitive dysfunction following a surgical procedure can have a significant impact upon
patients’ health, function and wellbeing. Post-Operative Cognitive Dysfunction or Decline
(POCD) is a controversial condition that is the subject of much debate, but is purported to
encompass acute or persistent deficits in attention, concentration, learning and memory
following surgery that are not attributable to an overt complication or insult arising from the
procedure (Niccolò Terrando et al., 2011; Tsai, Sands, & Leung, 2010). POCD is distinct from
delirium (Tsai, Sands, & Leung, 2010), which describes an acute fluctuating and transient
disturbance to perception and cognition that is not attributable to a pre-existing
neurocognitive disorder (European Delirium Association and American Delirium Society,
2014). The definition of POCD varies markedly across studies but is typically inferred from a
comparison of pre-operative to post-operative cognitive function. The investigation of
POCD typically has focussed on an acute phase, lasting up to the time of discharge, and a
more prolonged cognitive deficit that can occur months to years following the surgical event
(Tsai, Sands, & Leung). In the absence of a DSM or ICD classification or biological marker, the
condition has been defined by consensus as “a spectrum of postoperative central nervous
dysfunction both acute and persistent” (Tsai, Sands, & Leung).
POCD can occur in between 25% to 40% of elderly patients at the point of discharge, and
the long-term impact of this is marked by a significantly higher mortality rate as compared
to age and sex matched controls without POCD (Moller et al., 1998; Monk et al., 2008).
These changes persist for some time, with 25% of patients over 65 years of age displaying
evidence of POCD at 7 days following hip replacement surgery (M.-H. Ji et al., 2012; LI, XI,
AN, DONG, & ZHOU, 2012) and 25% of patients displaying significant impairments in

executive functions and/or memory functions 3 months following surgical intervention
(Price, Garvan, & Monk, 2008). The consequences for such patients can be significant; a
longitudinal follow up of 700 patients diagnosed with POCD 3 months following surgery
revealed a significantly higher rate of death and disability leading to loss of employment and
a greater reliance on social security (Steinmetz, Christensen, Lund, Lohse, & Rasmussen,
2009).
Bedford (1955), first described post-operative symptoms consistent with POCD. Since then
there has been a concerted effort to determine aetiological factors that underpin the
cognitive dysfunction. The majority of the early work has focused on factors specific to
cardiac surgery but no aetiological factors conclusively emerged. Subsequent work reported
that in the medium term similar numbers of people undergoing non-cardiac surgery develop
POCD (Evered, Scott, Silbert, & Maruff, 2011) which has necessitated a broader examination
of possible underlying causes. Increased attention has been focused on inflammatory
markers. Preclinical studies suggest that neuroinflammation and oxidative events are key
mechanisms underpinning the development of POCD (Cibelli et al., 2010; N. Terrando et al.,
2010). This has also been shown in replicated clinical studies, with patients also displaying
elevated levels of pro-inflammatory cytokines in both the systemic circulatory and central
nervous systems following surgery associated with the degree of cognitive decline
(Beloosesky et al., 2007; Buvanendran et al., 2006). However, despite the strengthening
evidence supporting this aetiological model, there has been minimal translation into
therapeutic development, with no established preventive or ameliorating therapies. This
review will explore the pathophysiology of POCD focussing on the aetiological role of
neuroinflammatory and oxidative processes. Such mechanisms suggest potential therapies
acting on such targets, including N-acetyl cysteine, whose capacity to act as an anti-oxidant,

anti-inflammatory and modifier of glutamate signalling, hypothetically could prove effective
in ameliorating the pathways involved.
2. Aetiology of POCD
2.1. Surgery induced inflammation
Current theories regarding the mechanisms underlying cognitive dysfunction following
surgery highlight the role of inflammation and immune activation. Surgery itself induces
inflammatory processes; both localised and systemic expression of pro-inflammatory
cytokines and related signalling molecules (Kohl & Deutschman, 2006; Reikerås, 2010).
Tissue damage following surgery provokes the release of IL-1 and TNF-α from endothelial
cells and phagocytes, triggering a cascade (Mannick, Rodrick, & Lederer, 2001; Menger &
Vollmar, 2004) of downstream signalling events (E. Lin, Calvano, & Lowry, 2000). Elevated
levels of IL-1 and TNF α induce the later production of IL-6, whose levels correlate positively
with the extent of tissue trauma(Mannick, Rodrick, & Lederer, 2001; Menger & Vollmar,
2004).
Copious pre-clinical data from animal models supports the association of immune system
activation following surgery with the development of cognitive decline (Cibelli et al., 2010;
N. Terrando et al., 2010; Niccolò Terrando et al., 2010, 2011). Multiple, although relatively
small-scale, clinical studies have reported correlations between circulating peripheral
inflammatory markers and cognitive dysfunction after surgery. Li et al observed higher
serum levels of IL-6 in patients developing POCD (LI et al., 2012), and similarly, Hudetz et al
documented impaired memory in patients with high IL-6 or high C-reactive protein (CRP), a
marker of the acute-phase inflammatory response (Hudetz, Gandhi, Iqbal, Patterson, &

Pagel, 2010). The latter study also observed persistent decrements of cognitive function in
the high-IL-6 group 1 month after surgery. A meta-analysis of clinical data showed that
elevated peripheral inflammatory markers were indeed associated with POCD, and that this
relationship was strongest for IL-6 (L. Peng, Xu, & Ouyang, 2013). Further support for the
role of Il-β, TNF-α and other pro-inflammatory cytokines in the genesis of cognitive
dysfunction following surgery is provided by a number of animal experiments. These
preclinical studies revealed that surgical trauma is associated with prolonged activation of
macrophages with the capacity of maintaining elevated levels of cytokines and that those
levels correlate with the severity of cognitive dysfunction as measured in several domains,
especially in memory and learning (Cibelli et al., 2010; Rosczyk, Sparkman, & Johnson, 2008;
Niccolò Terrando et al., 2011).
Insights into the interaction between inflammation and cognitive function can also be drawn
from other inflammatory states. Associations between elevated circulating inflammatory
markers and cognitive dysfunction have been documented in numerous clinical populations,
such as in viral and bacterial infection (Cvejic, Lemon, Hickie, Lloyd, & Vollmer-Conna, 2014),
HIV infection (Yuan et al., 2015), following chemotherapy (Ganz et al., 2013), in sickle-cell
disease (Andreotti, King, Macy, Compas, & DeBaun, 2014), and in non-surgery-related
delirium (Adamis et al., 2014). The mechanism behind this association has been explored
further in experimental mice models of induced inflammation, which show cognitive deficits
in response to immune activation (Ming, Sawicki, & Bekar, 2015), or transgenic animal
models which overexpress cytokines, including IL-6, in the brain (Heyser, Masliah, Samimi,
Campbell, & Gold, 1997). IL-6, for example, increases with aging, in animal models and in
human plasma (Ye & Johnson, 1999), and has been associated with the cognitive decline
associated with aging (Godbout & Johnson, 2004). However, mice model studies of the

effects of IL-6 on learning and memory have shown that the effects of this cytokine are
complex and dependent on age, with both very low levels and excessive levels impairing
cognition (Braida et al., 2004; Heyser et al., 1997). These findings are reflective of the
requirement that inflammatory signalling be tightly controlled; baseline levels of signalling
are required for normal function, but dysregulated inflammation has pathological outcomes.
The signalling pathways initiating, controlling and fine-tuning inflammation are complex.
However certain key players have been identified which sit at nodes or intersections of
these pathways and have particularly strong associations with the cognitive dysfunction
associated with surgery. The high-mobility group box-1 chromatin protein (HMGB1) has a
pivotal role in inflammatory pathways. The post-surgical environment of elevated cytokines
and oxidative stress drives both the release and activation of HMGB1 in humans (Manganelli
et al., 2010;) and in mice (N. Terrando et al., 2010; Niccolò Terrando et al., 2010). HMGB1
then drives further inflammation, in a feed-forward mechanism which promotes further
activation of inflammatory signalling pathways and the production of damaging oxidative
molecules by inflammatory cells as demonstrated in both animal models (Lee et al., 2014);
and in humans (Tang et al., 2011). HGMB1 can also promote long-term inflammation via
promotion of immune cell proliferation and maturation (X.-M. Zhu et al., 2009).
The pivotal role of this cytokine as a driver of systemic inflammation is highlighted by clinical
evidence that levels of HMGB1 after surgery are predictive of the degree of post- surgery
inflammation and morbidity over the short and long term (Kornblit et al., 2008; Suda et al.,
2006; Takahata et al., 2011). Clinical and animal studies have demonstrated that elevations
of HGMB1 post-surgery are associated with poor performance on cognitive tasks in both
mice (R.-L. Li et al., 2013); and in humans (LIN, WANG, CHEN, HU, & OUYANG, 2014).

Critically, levels of this inflammatory molecule are mechanistically linked with the
development of POCD. In a landmark experiment, a single peripheral administration of
HMGB1 induced cognitive deficits in a mice model (Vacas, Degos, Tracey, & Maze, 2014).
Furthermore, administration of an antibody neutralising HMGB1 prevented the cognitive
decline associated with surgery and reduced the circulating inflammatory cytokine burden
(Vacas et al.). These findings emphasise the central role of this factor in regulating post-
surgical inflammatory responses and consequential cognitive deficits. Notably, in other
animal studies, elevated expression of HMGB1 was observed not only in the periphery, but
in the hippocampus, an area of the brain associated with memory functions (Li et al., Lin et
al.) Both surgery and anaesthesia induce elevations in HMGB1 expression in the
hippocampus in conjunction with the development of cognitive deficits (He et al., 2012).
This raises the important question of the mechanisms by which alterations in peripheral
inflammatory signals can impact on CNS function and therefore cognition.
2.2 CNS inflammation
The central nervous system was classically thought to be impervious to peripheral
inflammatory factors, due to the existence of the blood brain barrier (BBB) and paucity of
lymphatic drainage, although the recent discovery of a brain lymphatic system has
challenged this assumption (Iliff, Goldman, & Nedergaard, 2015; Louveau et al., 2015). The
BBB does tightly regulate the transit of inflammatory factors, cells and other substances into
the CNS, and also monitors the peripheral environment. However, peripheral inflammatory
states can compromise the integrity of the BBB, allowing for increased entry of
inflammatory factors. Surgery and anaesthesia both induce blood-brain barrier dysfunction

which may be driven by peripheral inflammatory factors such as HMGB1 but may also
encourage further CNS expression of inflammatory cytokines (He et al., 2012).
Considerable evidence from preclinical models demonstrates that elevated inflammatory
cytokines in the periphery are a well-documented contributor to neuroinflammation via
their capacity to disrupt blood brain barrier integrity (Cibelli et al., 2010; Terrando 2010a,
2010b, Poon, Ho, Chiu, Wong, & Chang, 2015). The activation and dysfunctional activity of
endothelial cells in the BBB in response to peripheral inflammatory stimuli is now
considered to be the initial event in the development of neuroinflammation (X. Zheng et al.,
2014). Pro-inflammatory cytokines can transverse the BBB directly using specific receptors
and transporters on the surface of BBB endothelial cells (Pan et al., 2011). These
inflammatory mediators can also gain access to the CNS via the circumventricular regions
where the BBB is either absent or discontinuous. Markers of BBB dysfunction are elevated
post-surgery, and are associated with both peripheral and central inflammation in animals
(He et al., 2012); and in humans (Bromander et al., 2012).
Increased levels of inflammatory markers in the CSF following surgery, including IL-6, TNFα
and HMGB1, have been repeatedly observed in both cardiac and non-cardiac surgery
(MacLullich et al., 2011; Reinsfelt et al., 2012; Tang et al., 2011; Woiciechowsky et al., 1997).
Importantly, such elevations have been directly associated with cognitive dysfunction in
humans (Barrientos, Frank, Watkins, & Maier, 2012;) and mouse models Cibelli et al., 2010;;
K. Ji, Akgul, Wollmuth, & Tsirka, 2013; K. Ji, Miyauchi, & Tsirka, 2013), suggestive of a link
between peripheral and central inflammation driving neurocognitive dysfunction. In the
CNS, inflammation is mediated by the action of glial cells, to which we turn.

2.3 Glial activation
Microglia are the resident immune cells of the CNS and have a lineage similar to peripheral
macrophages. Microglia have the capacity to modulate rearrangement of surface molecules
mediating cell-cell and cell-matrix interactions, as well as releasing multiple factors and
compounds with proinflammatory, immunoregulatory and oxidative effects (Kettenmann,
Hanisch, Noda, & Verkhratsky, 2011). Microglia express specialised receptors for
inflammatory signals such as bacterial endotoxin or endogenous ligands such as HGMB1, in
particular the toll-like receptor 4 (TLR-4) (I.-D. Kim & Lee, 2013; J.-B. Kim et al., 2006). The
elevation of peripheral inflammatory factors induced by surgery prompts microglial
morphology changes and upregulation of TLR-4 (F. Wang, 2014). Activated microglia
themselves produce cytokines, resulting in de novo production of a range of inflammatory
factors in areas of the CNS, in particular but not restricted to the hippocampus. These
factors include TNFα, IL-1, IL-6, oxidative species and other signalling molecules (Norden &
Godbout, 2013).
Astrocytes are numerically the dominant CNS glial cell. The astrocytic protein S100β (S100
calcium binding protein β) is highly abundant in the brain and serves key roles in multiple
homeostatic and damage/infection associated processes, through both autocrine and
paracrine signalling (Donato et al., 2013). Although this protein is expressed by some
selected cells in the periphery, peripheral circulating levels of S100β are a key potential
biomarker of CNS stress (Michetti et al., 2012; Sun & Feng, 2013).

At low levels, S100β acts as a neurotrophic or supportive factor (Arcuri, Bianchi, Brozzi, &
Donato, 2004). However, elevations of this protein can drive neurotoxic pathways, via a
number of mechanisms. S100β may induce direct neuronal damage (Fano’ et al., 1993; Sorci
et al., 2010), or activate both microglia and astrocytes (Petrova, Hu, & Van Eldik, 2000;
Bianchi et al., 2007; Hu et al., 1997) and induce microglial oxidative species production
(Adami, Bianchi, Pula, & Donato, 2004). When viewed as a whole there is considerable in
vitro evidence that high levels of S100B have a causative role in the development and
maintenance of neuroinflammation (Bianchi, Adami, Giambanco, & Donato, 2006; Bianchi,
Kastrisianaki, Giambanco, & Donato, 2011) operating through similar receptors to HMGB1
(Han, Kim, & Mook-Jung, 2011; R.-L. Li et al., 2013; Ryckman, Vandal, Rouleau, Talbot, &
Tessier, 2003).
Peripheral inflammation, microglial activation, and microglial cytokine production are
temporally and spatially correlated with the development of cognitive dysfunction in animal
models (Wang et al., 2012; and Wang, 2014). This finding has been corroborated in several
animal models of surgery-induced cognitive changes (Hovens et al., 2014, 2015).
Interestingly these cognitive deficits, hippocampal microgliosis and cytokine expression
associated with peripheral surgery could be ameliorated by administration of the non-
selective inflammatory inhibitor ibuprofen, as suggested by mice models (Xu et al., 2014).
Cognitive deficits after surgery could also be ameliorated by blockade of TNFα, a key player
in inflammatory cascades (Terrando et al., 2010a). This was associated with suppressed
microgliosis in the hippocampus and reduced peripheral and central inflammation in mice.
Similarly, experimentally-induced peripheral inflammation induced hippocampal microglial

activation was correlated with HMGB1 production and cognitive dysfunction, and this could
be prevented by treatment with inhibitors of IL-1 signalling (Terrando, 2010b).
Peripheral surgery is known to induce elevations of both CSF and serum S100β, and these
have been correlated with neuropathological processes in humans (Reinsfelt et al., 2012).
Multiple clinical studies have documented an association between serum S100β and
impaired cognitive function after various surgery types (Bayram et al., 2013; Wang, 2014)
and studies using narrower definitions of POCD have replicated this finding (LI et al., 2012;
Linstedt et al., 2002). Preclinical studies show that S100β, HGMB1 expression and astrocyte
morphological changes occur in concert with cognitive dysfunction after experimental
surgical procedures (Li et al., 2013). A recent meta-analysis examined the association
between S100β levels in the periphery and the development of POCD and confirmed that
elevated levels of S100β post-operatively were strongly associated with POCD in humans
(Peng, Xu, & Ouyang, 2013). These data further reinforce both the hypothesis that POCD
involves disordered CNS inflammatory signalling but also that peripheral levels of factors
such as S100β can be used as potential biomarkers of cognitive dysfunction associated with
inflammatory mechanisms.
2.4 Oxidative stress in the CNS
Production of reactive oxygen species is intrinsic to a variety of processes occurring during
surgery (e.g. tissue trauma and wound healing) in addition to being a consequence of the
inflammatory reaction peri- and post-surgery (Fu et al., 2014). Elevated levels of reactive
oxygen species and markers of oxidative damage, along with depleted antioxidants have

repeatedly been reported post-surgery in animal (Ko, Isoda, & Mobbs, 2015; Kotzampassi et
al., 2009); and human studies as summarised in the review byTsai et al., (2010).
Peripheral oxidative stress may induce or exacerbate neuroinflammation via dysregulation
of BBB integrity (Abdul-Muneer, Chandra, & Haorah, 2014). Damage to the BBB may also
induce release of cytokines and oxidative species into the brain. The activation of the
endothelium may also provoke microcirculatory dysfunction ultimately leading to
compromised cerebral perfusion (Taccone et al., 2010). However, inflammation in the CNS is
a major driver of the local production of oxidative species, primarily through microglial
activation. Activated microglia release reactive oxygen species and nitric oxide along with
pro-inflammatory cytokines, together providing a toxic milieu in which neuronal function is
compromised (Heneka, Kummer, & Latz, 2014). Activated microglia and neurones may
become entwined in a degenerative positive feedback loop, in which release of HMGB1
from activated microglia and damaged neurones promotes release of oxidative species from
microglia, further precipitating injury (H.-M. Gao et al., 2011). Redox homeostasis may also
modulate microglial function in an autocrine manner, potentiating feed-forward activation
of microglia in an environment of oxidative stress (Rojo et al., 2014).
The neuroinflammatory effect of surgery is emphasised by the observation that surgical
stress raises the levels of brain nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase, a key player in oxidative stress regulation, and that this was correlated with
behavioural changes in mice (Zhang et al., 2015). Levels of oxidative species were also
positively correlated with the severity of cognitive impairment in patients with major
depressive disorder (Talarowska et al., 2011, 2012). Experimental models of POCD show

elevated markers of oxidative damage to lipids and proteins in the hippocampus (An et al.,
2012). Critically, the level of the key oxidative species nitric oxide following surgery is
predictive of the development of cognitive dysfunction in humans(Harmon et al., 2005;
Iohom et al., 2004).
2.5 Impact of inflammation and oxidative stress on neuronal integrity & signalling
Although multiple brain regions are involved in cognitive processes, the role of the
hippocampus in many of the processes underpinning learning and memory formation is
particularly well established (Epp, Chow, & Galea, 2013; K. Z. Tanaka et al., 2014).
This region of the brain also arguably contains the largest number of cytokine receptors
(Gemma, Fister, Hudson, & Bickford, 2005; Parnet et al., 1994). In particular, the
hippocampus contains the highest density of receptors for IL-1, and whilst physiological
levels of this cytokine are essential for optimal memory and learning processes, excessive
levels have been associated with diminished cognitive function in animal models (J. Chen et
al., 2008; Rachal Pugh, Fleshner, Watkins, Maier, & Rudy, 2001). The hippocampus appears
especially vulnerable to the detrimental effects of systemically elevated inflammatory
mediators such as HGMB1 due to the high density of the TNF-α receptor and numerous
other receptors on the surface of endothelial cells in this region of the brain (Rothwell,
Luheshi, & Toulmond, 1996). The mechanism underpinning impaired learning and
memory resulting from excessive levels of IL-1 and other inflammatory mediators in the
hippocampus involves detrimental effects on long term potentiation and neurogenesis in
this region of the brain, as has been demonstrated in various animal models (A. J.

Cunningham, Murray, O’Neill, Lynch, & O’Connor, 1996; Kelly et al., 2001; Vereker et al.,
2001).
Glutamate signalling is particularly important for the process of long term potentiation
thought to underpin aspects of memory formation. Experimentally-induced peripheral
inflammation fundamentally changes hippocampal neuronal activity, long-term potentiation
and synaptic plasticity via modulation of glutamate receptors in rats (Riazi et al., 2015).
Expression of the GluR2 subtype of glutamate receptor was decreased, leading to enhanced
AMPA and NMDA mediated signalling. Mice genetically susceptible to inflammatory
challenge through deficiency of a negative regulator of cytokine signalling show deficits in
multiple cognitive domains and have impaired hippocampal long-term potentiation through
pathways involving Il-1β, TNFα and HGMB1 (Costello et al., 2011). HMGB1 plays a critical
role in modulating glutamatergic neuronal activity underlying cognitive function. HMGB1
potentiates glutamate signalling through the NMDA receptor, and exacerbates glutamate-
induced toxicity associated with degenerative processes (Balosso, Liu, Bianchi, & Vezzani,
2014; Pedrazzi et al., 2012).
Suppression of microglial activity abolished the effect of peripheral inflammation on
hippocampal function, highlighting the key role of microglial-derived factors on the
modulation of glutamate signalling and neuronal function. These findings were echoed in a
similar study which demonstrated that induction of peripheral inflammation promotes Il-1β
production in the hippocampus and results in parallel decreases in glutamate release and
long-term potentiation in mice (Di Filippo et al., 2013). Further evidence for the key role of
glial inflammatory factors in the maintenance and modulation of hippocampal circuitry
comes from a mice model study focussing on TNF-α (Stellwagen & Malenka, 2006). The level

of this glial-derived pro-inflammatory cytokine was found to modulate the level of the
AMPA form of glutamate receptor and thus fine-tunes the sensitivity of neurones to
glutamate signalling. Inhibitory neurotransmission in the hippocampus is also compromised
by neuroinflammation. Acute application of TNFα induces a persistent decrease of gamma-
aminobutyric acid (GABA) receptors and a pervasive dysregulation of this important
component of synaptic plasticity regulation (Pribiag & Stellwagen, 2013).
Astrocytes, and to some extent microglia, also have the capacity to modulate availability of
the key neurotransmitter glutamate. This facilitates the balance required between
glutamate availability for signalling processes and prevention of the excessive levels
associated with excitotoxicity. The expression of specific glutamate transporters on the
astrocyte surface are regulated by cytokine stimulation, with the pro-inflammatory cytokine
TNFα upregulating glutamate transporters on cultured astrocytes (Dumont, Goursaud,
Desmet, & Hermans, 2014). Infiltration of activated T cells into the CNS provokes glutamate
release from microglia via a different subtype of glutamate transporter (Evonuk et al., 2015).
Together this suggests that altered glutamate availability, in addition to glutamate receptor
changes, may contribute to the changes in neuronal function and neuroplasticity observed
in response to inflammation.
Microglia and astrocytes also actively regulate synaptic function via modulation of synaptic
morphology and synaptogenesis ( Ji, Akgul, et al., 2013; K. Ji, Miyauchi, et al., 2013). Key to
this is the release of neurotrophic factors such as brain-derived neurotrophic factor (BDNF).
BDNF is now well established as a key player in multiple aspects of neural plasticity, learning
and memory in various animal models (Heldt, Stanek, Chhatwal, & Ressler, 2007; Lu,
Nagappan, & Lu, 2014). Inflammation and cytokine expression levels modulate the

production of BDNF (Derecki et al., 2010; Yirmiya & Goshen, 2011). Stimulation of the
immune response via administration of bacterial lipopolysaccharide induces hippocampal
cytokine production, depletion of BDNF and learning and memory deficits (S. Tanaka et al.,
2006). Intrahippocampal administration of Il-1β was shown to block the upregulation of
BDNF required for learning (Barrientos et al., 2004). Importantly, inflammatory processes
associated with surgery also result in decrements in BDNF. In an animal model of surgery,
rats showed cognitive deficits which were spatially and temporally correlated with
decreased BDNF, increased inflammatory cytokines in the periphery and brain, and
increased microglial activity (Hovens et al., 2014).
A key facet of microglial activity is their capacity to induce production and release of
reactive oxygen and nitrogen species, which are essential for the immune response to
infection but in the context of prolonged activation, have deleterious effects on brain
cytoarchitecture and neuronal function. Despite its high dependence on oxidative
metabolism, the brain has relatively low levels of antioxidants and is vulnerable to oxidative
stress. Microglia express 90% of brain glutathione, the main antioxidant species, which
highlights both the centrality of these cells to oxidative processes in the CNS and the relative
deficit of antioxidants in neurones (Rojo et al., 2014). In fact, circulating levels of glutathione
have been proposed to be a useful predictive biomarker of cognitive decline in patients with
neurodegenerative disease (Revel et al., 2015).
The role of inflammation-driven oxidative stress in neurodegenerative disease, and the
centrality of this oxidative stress to pathophysiology has been the subject of much
speculation. (Di Filippo, Chiasserini, Tozzi, Picconi, & Calabresi, 2010; Fischer & Maier, 2015).
For example, mice models have demonstrated that levels of the inflammatory cytokine TNF-

α, which approximate those in the post-stroke brain, induce striking loss of neuronal
integrity and function which was driven by dysfunction of mitochondria, the major source of
oxidant species (Doll, Rellick, Barr, Ren, & Simpkins, 2015). However, more subtle
dysregulation of inflammatory drive may also modulate the oxidative milieu of the CNS, and
in turn alter neuronal function without inducing cell death. Elevation of the pro-
inflammatory cytokine Il-1β in the CNS induces elevations of reactive oxygen species which
are coupled to disruption of long-term potentiation, an element of neuroplasticity which is
intrinsic to learning, memory and other aspects of cognition (Vereker et al., 2001). Oxidative
stress may also be considered as a significant contributor Oxidative stress is now seen as a
key contributor to the cognitive decline associated with aging, and supplementation with
anti-oxidants might ameliorate this process (Haxaire et al., 2012; Robillard, Gordon, Choi,
Christie, & MacVicar, 2011).
3. Potential contributions of anaesthetic agents to POCD
In the surgical setting, the question of whether anaesthetic agents are contributors to
cognitive dysfunction and underlying pathological processes is of particular importance.
These agents penetrate the CNS and have direct activity on neuronal signalling and activity.
It is therefore a question of some interest as to whether the changes in inflammatory and
oxidative stress parameters associated with cognitive dysfunction can be attributed to
surgical procedures and their systemic consequences as outlined above, anaesthetic use or,
perhaps most likely, a combination of the two.

Anaesthetics used in surgery are a heterogeneous group of agents with differing
pharmacological properties and mechanisms of action. In addition, studies of the effects of
anaesthesia in the clinical setting are impeded by the confounding effects of the surgery
itself. However, emerging evidence from pre-clinical studies suggests that anaesthetic use
is, in isolation, a risk for cognitive dysfunction. Studies in aged mice suggest that isoflurane
anaesthesia alone induced cognitive dysfunction, which was associated with microglial
activation and CNS inflammation (F. Wang, 2014). These results are echoed by studies
examining exposure to another volatile anaesthetic agent, sevoflurane, in which working
memory impairments and alterations in proteins associated with synaptic plasticity and
neuronal signalling were observed in rats (Ling, Ma, Yu, Zhang, & Liang, 2015). A recent
study comparing epidural anaesthesia and general anaesthesia in elderly patients
undergoing hip replacement demonstrated a higher risk of POCD in patients receiving
general anaesthesia, which was associated with elevations of circulating amyloidogenic
proteins (Shi et al., 2015). Similarly, poorer cognitive outcomes were observed following
general anaesthesia as compared to epidural anaesthesia in an earlier study of hip and knee
surgery (Pal et al., 2011). Anaesthesia depth may also impact upon cognitive outcomes
(Radtke et al., 2013; Short et al., 2015), with research suggesting lower bispectral index
scores are associated with greater incidence of post-operative delirium, but not cognitive
dysfunction in elderly surgical patients (Radtke et al).
Both clinical and pre-clinical evidence suggests that the elevations in inflammatory and
oxidative stress parameters observed following surgery may in part be attributed to the
effects of anaesthetic agents. When administered to aged animals, isoflurane induces
significant upregulation of a number of pro-inflammatory cytokines and decrements in

spatial memory skills (Li et al., 2013; Li et al., 2013). Conversely, very young mice were
shown to be more susceptible to inflammation, microglial activation and cognitive
dysfunction induced by general anaesthesia than adult (not aged) animals (Shen et al.,
2013). Use of the anti-inflammatory agent parecoxib mitigated some of the cognitive deficit
induced by general anaesthesia.
There is contrary evidence regarding the aetiological role of general anaesthesia, with
preclinical studies showing changes in S100B, HGMB1 expression and astrocyte morphology
in concert with cognitive dysfunction after experimental surgical procedures, but not in an
isoflurane anaesthesia control group (Li et al., 2013). The discrepancy between these studies
may relate to the pathways being investigated, or methodological differences in isoflurane
administration (i.e. duration of anaesthesia).
Evidence that the type of general anaesthesia impacts on outcomes post-surgery is
potentially suggestive of an aetiological role, though the nature and extent of this impact is
far from clearElderly patients undergoing major surgery were found to experience a higher
incidence of POCD following inhalational anaesthesia with sevoflurane than those who
received intravenous propofol (Qiao et al., 2015). Importantly, this was associated with
increased circulating levels of S100β and the proinflammatory cytokines TNFα and IL-6,
which could be ameliorated by adjunctive treatment with the anti-inflammatory
methylprednisolone. An aetiological role for anaesthesia in POCD was also evidenced in a
study where patients (N=921) were randomly assigned to receive either bispectral index
guided anaesthesia, associated with reduced anaesthetic exposure, or routine care. Guided
anaesthesia was associated with fewer patients with delirium (15.6% vs. 24.1%, P=0.01) and

a lower rate of POCD at 3 months (10.2% vs. 14.7%, p=0.025) (Chan, Cheng, Lee, & Gin,
2013).
Evidence from rat models also indicates that exposure to anaesthetics may also impair
mitochondrial function and potentiate oxidative damage to neurones (Sanchez et al., 2011).
Anaesthetic agents, particularly volatile anaesthetic agents targeting inhibitory GABA
receptors, directly modulate neuronal signalling. Differences in GABA receptor affinity may
underpin some of the variation between anaesthetic agents. Isoflurane, for example,
depresses long-term potentiation and shifts the ability of neuronal synapses to respond to
stimulation, which may contribute to cognitive impairment (Simon, Hapfelmeier, Kochs,
Zieglgänsberger, & Rammes, 2001). Prolonged elevation of GABA receptor activity induced
by general anaesthesia is associated with sustained impairments of cognitive function in
mouse models (Zurek et al., 2014). Importantly, blockade of the oxidative damage induced
by general anaesthetic agents by EUK-134 (a synthetic oxidative species scavenger) or
pramipexole appears to prevent the development of cognitive impairment in the rat brain
(Boscolo et al., 2012). Further, systemic inflammation can also modulate GABA receptor
function and contribute to cognitive deficits, as observed in mouse models (Wang et al.,
2012). This suggests a mechanism by which both surgery and anaesthesia-induced
inflammation may intersect with anaesthetic modulation of synaptic plasticity, a confluence
of factors contributing to cognitive dysfunction. In addition, findings that surgical insults
alone can induce significant inflammation and cognitive dysfunction in mice (Xu et al., 2014)
highlight the likelihood that surgery and anaesthesia interact in a complex and synergistic
manner to influence postoperative cognitive function.

4 Pre-existing risk factors for POCD
POCD is far from a universal consequence of surgery, while neuroinflammation following
even minor surgery appears to be a ubiquitous event. Hence while neuroinflammation is
likely an essential element underpinning the development of POCD it is clearly not the sole
driver. Other factors appear to be essential in the transition from ‘expected’ events post-
surgery and enhanced neuropathology seen in patients with POCD. Pre-existing conditions
or demographics may also act to decrease cognitive reserve; such as the presence of
physical illness, frailty, lower education levels, history of alcohol or opiate use, and the
presence of anticholinergic medication to risk post-operative cognitive change (Silbert et al.,
2007; 2015; Wang et al., 2014b) (B. Silbert et al., 2015; B. S. Silbert, Scott, Evered, Lewis, &
Maruff, 2007; F. Wang, 2014). Nadelson et al. argue that the preoperative cognitive
trajectory, the success of the surgery, and events in the perioperative period including
ongoing pain have been argued to be the most important determinant of POCD (2014) and
also make the point that cognitive decline will be observed in surgical patients if cognitive
function is measured pre- and post-surgery if the patient is already on a trajectory of
cognitive decline.
One confounding factor that may be a significant contributor to the development of POCD is
the presence of an abnormally potent and or prolonged neuroinflammatory response in a
patient with pre-existing inflammatory pathology. For example, post-stroke patients have a
significantly increased risk of developing POCD even without extensive neurological damage,
due to the underlying inflammation pre-existing as part of the stroke event (Monk et al.,
2008). Similarly, pre-existing metabolic syndrome is a recently confirmed risk factor in the
development of POCD in both cardiac and non-cardiac patients (Hudetz et al., 2010; Hudetz,

Patterson, Amole, Riley, & Pagel, 2011; Hudetz, Patterson, Iqbal, Gandhi, & Pagel, 2011a,
2011b) which is of interest considering the role of systemic inflammation and
neuroinflammation in the development and pathological consequences of the illness (Cai &
Liu, 2012; Purkayastha & Cai, 2013). Diabetes is also associated with an elevated
inflammatory burden. In a study of patients with type-2 diabetes undergoing carotid
endarterectomy, elevated pre-operative levels of C-reactive protein and monocytes were
predictive of a higher risk of cognitive dysfunction post-surgery (E. J. Heyer, Mergeche,
Bruce, & Connolly, 2013). These pathways have been further explored in animal models of
metabolic syndrome, in which mice selectively bred for poor metabolic function were more
susceptible to post-operative cognitive dysfunction (Su et al., 2012). This was associated
with an elevated inflammatory milieu as measured by several different parameters, which
appeared to be suggestive of a diminished capacity for resolving inflammation.
Advancing age is another well documented risk factor which is in itself noteworthy as levels
of circulating inflammatory markers generally increase with age. Neuroinflammatory
responses to peripheral stimuli also change with age, and this may be important for
cognition and memory (Barrientos et al., 2012; Dilger & Johnson, 2008). There is now
evidence that microglia become highly reactive or ‘primed’ with age, in a similar manner to
that observed in mild cognitive impairment or Alzheimer's disease ( Cunningham, 2012;
Norden & Godbout, 2013; Perry & Teeling, 2013). This primed state sets the scene for an
exaggerated neuroinflammatory response following activation, with increased intensity and
duration of microglial activation and cytokine production in the brain (Corona, Fenn, &
Godbout, 2011; Godbout, 2005; Ritzel et al., 2015; Wynne, Henry, & Godbout, 2009). The
link between these elevations in neuroinflammation and cognitive dysfunction has been
illustrated in several experiments in which either peripheral experimentally induced

inflammation or surgical procedures precipitate much more florid microgliosis and cytokine
expression, along with more pronounced cognitive changes, in old versus young mice (J.
Chen et al., 2008; Xu et al., 2014). Importantly, these effects were restricted to aged mice
receiving surgery under anaesthesia, and not to those receiving anaesthesia alone (Li et al.,
2013).
It is also of interest that there is a body of evidence suggesting that surgery accelerates the
development of Alzheimer’s disease (AD) or worsens its severity in some patients (Bohnen,
Warner, Kokmen, & Kurland, 1994; Fong et al., 2009; T. A. Lee, Wolozin, Weiss, & Bednar,
2005), although the latter finding is not universally replicated (Avidan et al., 2009) and
alternate biomarkers such as the ratio of amyloid-β to tau in cerebrospinal fluid have been
proposed (Xie et al., 2013). Fluctuations of perioperative amyloid-β to tau ratios are
predictive of verbal and visual memory dysfunction in AD (Xie et al., Ji et al., 2013) but this
hypothesis cannot be applied to POCD without additional high quality research. Meta-
analysis appears to show no association between exposure to general anaesthetics and the
risk of Alzheimer’s disease in humans, although there has been a paucity of high-quality
studies (Seitz, Shah, Herrmann, Beyene, & Siddiqui, 2011). Nonetheless, the presence of
mild cognitive impairment has been observed to be a possible risk factor for the
development of post-operative cognitive dysfunction, which in some studies has been
correlated with higher levels of inflammatory factors (Kazmierski et al., 2014; Oldham et al.,
2015; Veliz-Reissmüller, Torres, van der Linden, Lindblom, & Jönhagen, 2007). Interestingly
the link between POCD and dementia and mild cognitive impairment may be under-
reported as inclusion criteria for most studies are likely to exclude pre-existing diagnoses of
neurocognitive impairment, and many cohorts could be considered healthier than a
representative population of elderly surgical patients.

The presence of the ApoE allele has also been proposed as a risk factor for the development
of POCD (Ely et al., 2007; E. J. Heyer et al., 2005; Leung et al., 2007), which may relate to the
capacity for ApoE to regulate the intensity of microglial activation (Y. Liu et al., 2015)and
pathways governing the magnitude of inflammation and its resolution (Laskowitz et al.,
2001). However, the association between ApoE genotype and postoperative cognitive
changes has not been supported by all studies (Abildstrom, Christiansen, Siersma, &
Rasmussen, 2004; B. S. Silbert, Evered, Scott, & Cowie, 2008; van Munster, Korevaar, de
Rooij, Levi, & Zwinderman, 2007; Vasunilashorn et al., 2015), which is perhaps indicative of
the complexity of genetic risk factors for both dementia and cognitive decline as a whole.
Together these findings highlight the multilayered interactions between brain inflammatory
signalling, glial activity, glutamate synaptic morphology and activity, long term potentiation
and processes involved in cognition. Even in the non-injured or inflamed state, cytokines
and neurotrophic factors have the capacity to modulate these processes, (Di Filippo et al.,
2008; Yirmiya & Goshen, 2011) and therefore in states where the inflammatory drive is
heightened, including the perioperative setting, there is increased potential for disruption of
neuronal function and therefore cognitive dysfunction.
Figure 1 - Flowchart of the neuroinflammatory hypothesis of POCD
[INSERT FIGURE 1 ABOUT HERE]
The neuroinflammatory hypothesis of POCD provides a framework for potential intervention
agents. The flowchart in figure 1 provides a descriptive mechanism for how peripheral
trauma can feed forward into a cascade resulting in cognitive dysfunction, and each step is

an opportunity to mitigate this potentiality. To date, neither preventative nor intervening
agent has been established though a number of therapies have been investigated. A suitable
effective treatment could also ameliorate the longitudinal sequelae of POCD.
Novel therapies for POCD
5.1 Parecoxib/COX-II Inhibitors
Cyclooxygenase (COX) inhibitors, such as parecoxib and celecoxib, are a subtype of non-
steroidal anti-inflammatory drugs (NSAIDs) routinely used as an intervention for
inflammatory pain, including that experienced post-surgery (Derry & Moore, 2013). NSAIDs
inhibit the production of the enzyme COX that acts as a precursor to vasodilator
prostaglandins. Selective COX-II inhibitors are a class of NSAIDs that specifically bind to the
inflammatory COX-II isoform, and by interrupting the enzymatic conversion cascade
secondary to COX-II production, ameliorate inflammatory pain (Mattia & Coluzzi, 2005). For
this reason, a recent Cochrane review of clinical trials has suggested that COX-II inhibitors
have demonstrated efficacy in the treatment and management of inflammatory arthritis
and associated conditions (Kroon et al., 2015).
The mechanism of COX inhibitors also reduces the activation of microglia and subsequent
neuroinflammation (Choi, Aid, & Bosetti, 2009), and COX inhibitors are therefore routinely
the subject of translational research into conditions associated with neuroinflammation,
albeit with mixed results. A Cochrane review and meta-analysis for the use of COX-II
inhibitors for Alzheimer’s disease found no evidence to suggest any significant positive
effect, statistically or clinically (Jaturapatporn, Isaac, McCleery, & Tabet, 2012) a finding

which has recently been replicated in a large scale RCT (ADAPT-FS research group, 2015).
Similarly, evidence for the use COX-II inhibitors as an adjunct or monotherapy for
depression is extremely heterogeneous – studies showing significant improvement are
roughly approximate in weight to studies showing no effect (Eyre, Air, Proctor, Rositano, &
Baune, 2015). Meta-analysis showed that the use of celecoxib was efficacious in reducing
the severity of positive and negative symptoms of schizophrenia, but only for first-episode
schizophrenia participants as opposed to chronic participants (W. Zheng et al., 2017).
However, beyond symptomology associated with psychiatric disorders, cognitive function
appears to be a rarely examined outcome of COX-II inhibitor use. Some preclinical evidence
suggests a cognitive protection effect in rats after traumatic brain injury, but controversy
remains regarding the superiority of selective interventions for COX-I (Cernak, O’Connor, &
Vink, 2002) or II (Girgis et al., 2013) over placebo. In sum, there appears to be little support
for the use of COX-II inhibitors to treat chronic conditions, but research into acute
inflammatory states may hold some promise.
In humans, COX-II inhibitors are commonly used to treat post-operative pain, but the effect
for post-operative cognition is rarely directed examined in research. As such, even though
the existent evidence appears quite positive for the cognitive protection effect of COX-II
inhibitors, the amount of evidence is quite small. For example, in a large (n = 1062) double-
blind randomized control trial, Langford et al., (2009) demonstrated that the use of
perioperative parecoxib and valdecoxib was associated with significantly lower rates of
opioid-related confusion and concentration difficulties after major non-cardiac surgery, but
this appeared to equalize at approximately four days post-surgery. In addition, confusion
and concentration difficulties were approximated using patient self-report rating scales for

descriptions of severity and duration rather than objective measures, which complicate
comparisons with other studies.
By comparison, Y.-Z. Zhu, Yao, Zhang, Xu, and Wang, (2016) compared post-operative
cognitive performance on 122 elderly patients undergoing total knee arthroplasty at 7 days,
and 3 months post-surgery, using a battery of neuropsychological tests across a range of
cognitive domains. Participants were randomised to receive additional parecoxib or saline
after administration of general anaesthesia, and while cognitive performance at POD7 was
significantly better in the parecoxib group compared with controls, though there was no
difference at 3 months. Crucially, this convergence in performance appears to be driven by
an improvement in performance among the control group at 3 months, rather than a
delayed decline for the parecoxib group. To date, only one new study appears to be
examining the cognitive effect of NSAIDs after surgery (NCT02689024), and appears to be
focussed mainly on delirium incidence.
5.2 Statins
Statins are used to treat high cholesterol in humans. As the product of an enzymatic
reaction cascade, cholesterol production is in part rate-limited by the production of
mevalonic acid, which is itself rate-limited by conversion of the enzyme 3-hydroxy-3-
methylglutaryl-CoA reductase (HMGCR). Statins work by inhibiting conversion of HMGCR
into mevalonic acid through competitive binding of the active site of the enzyme (Friesen &
Rodwell, 2004). It is by intervention into this melavonic pathway that statins are also
purported to moderate inflammation. NADPH reduces HMGCR into mevalonic acid as part

of cholesterol production, and is associated with the production of phagocytic ROS. Statins
inhibit the HMGCR conversion process resulting in downregulation of NADPH production,
and the subsequent production of oxidative species (Margaritis, Channon, & Antoniades,
2014).
Statins have been widely researched as potential interventions for myriad of conditions,
particularly those with cognitive sequelae. In 2012 the FDA warned of potential cognitive
dysfunction after use of statins, though more recent safety reviews have found little
evidence to support this, and conversely suggest a potential cognitive protective effect in
some conditions (Mospan, 2016; Ott et al., 2015). However, the evidence for the use of
statins for cognitive change associated with neurological conditions is promising but
ultimately controversial. For example, a recent Cochrane review reported that statins do not
appear to prevent or treat dementia (McGuinness, Craig, Bullock, & Passmore, 2016).
However, McGuiness and colleagues limited included articles to only RCTs with a sample
aged over 65 years where a statin was administered for at least 12 months, which limited
the available evidence to two (albeit large) RCTs. By contrast, an earlier systematic review
and meta-analysis examining the use of statins for both short and long term cognitive
function reported a 29% reduction in long-term dementia incidence compared with controls
(Swiger, Manalac, Blumenthal, Blaha, & Martin, 2013). However, the review by Swiger and
colleagues allowed the inclusion of less controlled studies and included considerable
heterogeneity across administration regimen, dosage, and duration, as well study design
and sample characteristics. The clinical efficacy for the use of statins to treat neurological
conditions appears to remain theoretical in the absence of more definitive evidence
(Malfitano et al., 2014).

Researching examining the use of statins to moderate acute neuroinflammatory states is
promising but appears relatively undeveloped as a field. For example, in a systematic review
of preclinical data, W. Peng et al., (2014) suggested that statins appeared to be particularly
effective in protecting memory function after closed-head TBI in rodent models, though
little cognitive data is available from clinical studies and so the translational potential has
not yet been realised (Wible & Laskowitz, 2010). Similarly, the post-operative cognitive
impact of pre and perioperative statins remains largely unexplored, with only a handful of
non-randomised trials published. The evidence that is available is inconsistent – two
retrospective analyses and one smaller non-randomised prospective study reported
conflicting findings. For example, Mathew et al., (2005) observed no apparent impact of
perioperative statins on cognitive function 6 weeks post-operation with 440 elderly
cardiopulmonary bypass patients, while a post-hoc analysis of 585 carotid endarterectomy
patients revealed that the use of perioperative statins ameliorated morbidity associated
with post-operative cognitive dysfunction to the same degree as patients who did not
experience post-operative cognitive dysfunction (Heyer, Mergeche, Wang, Gaudet, &
Connolly, 2015). However, due to the retrospective nature of these studies the impact of
confounding variables cannot be estimated. By comparison, in a smaller non-randomised
control trial Das, Nanda, Bisoi, and Wadhawan (2016) compared the cognitive protection
effect of statins after off-pump CABG. Both the statin and control group demonstrated
significant memory dysfunction at 6 days post-operation in comparison with pre-surgical
performance, but the severity and breadth of dysfunction was significantly greater for the
control group. However, the absence of longitudinal follow-ups does not allow for direct
comparison with the earlier retrospective analyses.

5.3 Pregabalin
Initially developed as an anticonvulsant, pregabalin is being used in the treatment of
neuropathic pain and fibromyalgia (Toth, 2013). The antiepileptic mechanism for pregabalin
is thought to involve binding to voltage-gated calcium channels on the presynaptic
membrane, specifically the α2δ subunit (Schulze-Bonhage, 2012). This effectively limits the
rate of proconvulsant neurotransmitter release, and subsequently restricts seizures.
Pregabalin has demonstrated efficacy in reversing induced inflammatory hyperalgesia (Patel
et al., 2001) and suppresses the edema, neuronal damage, bleeding, and inflammation
resultant from traumatic brain injury in rats (Calikoglu et al., 2015). Clinical studies have
shown efficacy in modulating pain associated with multiple sclerosis; post-herpetic
neuralgia, peripheral nerve injury, radiculopathy, spinal cord injury, neuropathy, and post-
stroke pain (Dunn, Durieux, & Nemergut, 2016, p. 201; Moore, Wiffen, Derry, & McQuay,
2009).
Modulation of voltage-gated channels interferes with the activation of cytokine receptors,
and may subsequently contribute to neurotoxicity and neuron hyper excitability (Pexton,
Moeller-Bertram, Schilling, & Wallace, 2011; Vezzani & Viviani, 2015). The α2δ subunit
voltage-gated calcium channel is prominently expressed in the hippocampus (Cole et al.,
2005). By binding to the α2δ subunit, it has been proposed that pregabalin alters the release
of neurotransmitters in the hippocampus, moderating microglia activation (Kawano et al.,
2016), and downregulating subsequent cytokine production. Kawano and colleagues
demonstrated that pre-operative pregabalin reduced hippocampal production of IL-1β and
TNF-α and was protective of cognition in a rat model, while post-operative administration
was ineffective on these outcomes. In a model of diabetic mice, 10mg/kg pregabalin

significantly reduced levels of brain COX-II, glucose-transport type 4, cytosolic prostaglandin
E synthase, and nuclear factor-κB expression compared with controls, impair but did not
improve measures of learning (Sałat et al., 2016).
In a rat model of cardiopulmonary bypass with deep hypothermic circulatory arrest (Shim,
Ma, Zhang, Podgoreanu, & Mackensen, 2014), acute pre-operative administration of
pregabalin (30mg/kg) preserved some indices of neurologic function compared with saline,
though this did not translate to significant between-groups differences on the water-maze
test of long-term spatial memory. Percentages of necrotic neurones were significantly
reduced within the cerebral cortex for the pregabalin group, though no significant effect
was detected within the hippocampus. In sum, pre-clinical evidence suggests a
neuroprotective dose-response effect for pregabalin in inflammatory models, but the
impact upon cognition is less clear.
In humans, evidence for cognitive preservation is less well established. On the contrary,
acute cognitive change is an established risk of pregabalin use (Zaccara, Gangemi, Perucca,
& Specchio, 2011). In their meta-analysis, Zaccara and colleagues identified a dose-
dependent relationship between pregabalin administration in clinical populations and acute
confusional state and disturbance of attention, with positive correlation between dose and
risk. However, despite the large number of clinical studies examining psychiatric and
cognitive symptoms associated with pregabalin administration, comparatively few studies
directly examine and measure change within specific cognitive domains.
Evaluation of the cognitive impact of pregabalin is complicated due to the heterogeneity of
dose regimen across studies, though it is possible to observe a dose-response effect for
cognition. For example, Hindmarch, Trick, and Ridout (2005) found mixed evidence of

cognitive change after administration of 150mg TID for three days in a small sample of
healthy adults. Small but significant dysfunction in attention, CNS arousal and subjective
arousal was observed, while no significant changes to reaction speed, visual processing, and
memory were detected. Comparatively, significant dysfunction to executive function and
visual processing in healthy adults was associated with a larger dose of 600mg per day for 8
weeks (Salinsky, Storzbach, & Munoz, 2010). By contrast, Myhre, Diep, and Stubhaug (2016)
found no evidence of cognitive change in healthy adults after two 150mg doses of
pregabalin, at 13 hours and 1 hour prior to testing respectively. However, the combination
of remifentanil and pregabalin adversely impacted performance on cognitive tests beyond
that of either drug in isolation, suggesting an interaction effect of pregabalin with other
medications.
Despite some promising pre-clinical data, the cognitive impairment witnessed in the clinical
setting suggests it would not be a prime candidate for targeted exploration as an agent to
protect against POCD. Given its increasing use in the perioperative setting for the treatment
of acute neuropathic pain and in the prevention of chronic post-surgical pain, it would be
useful to analyse any influence it does have on early and late cognitive function within
studies examining POCD.
5.4 Dexmedetomidine
Dexmedetomidine is a α2 receptor agonist, used as a sedative agent with analgesic
properties (Dunn et al., 2016). In comparison with other α2 receptor agonists,
dexmedetomidine is highly selective for the locus coeruleus in the brainstem, suppressing
release of noradrenaline and adrenaline resulting in sedation purported to be akin to
natural sleep (Giovannitti, Thoms, & Crawford, 2015; Nelson et al., 2003). The modulation of

spinal noradrenaline and adrenaline is purported to be responsible for the analgesic
properties of dexmedetomidine (Coursin, Coursin, & Maccioli, 2001; Funai et al., 2014;
Yaksh, 1985). In vitro evidence suggests that dexmedetomidine mediates levels of
inflammation in human whole blood (ex vivo) through the moderation of inflammatory
cytokines induced by administration of lipopolysaccharide (Kawasaki et al., 2013), while
administration of dexmedetomidine in rats was associated with increased vagal nerve
activity and inhibited cytokine production (S.-T. Li & Wu, 2015; Xiang, Hu, Li, & Li, 2014).
Pre-clinical evidence suggests that dexmedetomidine is effective in protecting against
anaesthetic-induced cognitive impairment in a dose-dependent manner, though this is not a
universal finding. In a model of neonatal rats exposed to isoflurane 0.75% for 6 hours,
higher doses of dexmedetomidine (1, 10, and 25µg/kg respectively) were associated with
greater levels of neuroprotection compared with controls, with a specific reduction in
caspase-3 induced apoptosis in the hippocampus, thalamus, and cortex (Sanders et al.,
2009). High dose dexmedetomidine (25µg/kg) also preserved learning at 40 days post
isoflurane exposure controlsrelative to isofluorane alone, and reversed neurotoxicity to pre-
isoflurane exposure baseline levels in the hippocampus and thalamus, but not in the cortex.
In a similar investigation, Qian et al., (2015) reported that the pre-operative administration
of 25 µg/kg but not 15 µg/kg of dexmedetomidine was sufficient to protect against cognitive
dysfunction induced by splenectomy accompanied by 1.5-2.0% isoflurane and 100mg/kg
pre-operative ketamine in a rat model. By comparison, both 15 and 25 µg/kg
dexmedetomidine significantly reduced Il-β and TNF-α mRNA and protein expression
relative to controls. Qian and colleagues were also able to demonstrate that
dexmedetomidine administration reduced hippocampal levels of the pro-apoptotic genes

caspase-3 and BAX to attenuate neuronal apoptosis induced by anaesthesia and surgery
trauma. Hippocampal protection of 10 µg/kg dexmedetomidine after laparotomy in rats, in
comparison to the control group has also been observed in conjunction with preserved
learning and memory function (Wan, Xu, & Bo, 2014).
However, the dose-response effect of dexmedetomidine and neurotoxicity secondary to
inflammation may not adhere to a normal distribution. Sato, Kimura, Nishikawa, Tobe, and
Masaki (2010) demonstrated that 100µg/kg of intraperitoneal dexmedetomidine alone was
insufficient to protect against neurologic performance impairment 3 days after cerebral
ischemia in rats, despite a statistically significant protective effect upon neuronal survival in
the hippocampus compared with controls. However, the combination of dexmedetomidine
and induced hypothermia after ischemia (body temperature cooled to a mean of 35°C) not
only preserved hippocampal neuron survival, but also preserved neurological function
scores 3 days after ischemia. Dexmedetomidine alone was also ineffective for reducing
caudate nucleus apoptosis, and only when combined with hypothermic treatment was
caudate nucleus survival preserved.
Meta-analyses by B. Li, Wang, Wu, and Gao, (2015) and Man, Guo, Cao, and Mi, (2015) show
that dexmedetomidine was superior to controls and comparative anaesthesia groups for
reducing the risk of post-operative delirium in ICU patients, across a broad range of research
methodologies and dose regimens. Additionally, the majority of included studies only
included assessments of global cognition such as the Mini-Mental State Exam or the ICU-
Confusion Assessment Method, potentially obscuring cognitive change in specific domains.
For example, clinical evidence has shown that intra-operative administration of
dexmedetomidine has shown promise in significantly reducing acute episodic delirium after

cholecystectomy (Y. Li, He, Chen, & Qu, 2015) and carotid endarterectomy (Ge et al., 2016),
with approximately comparable outcomes despite dexmedetomidine dose disparity; 1mg/kg
for ten minutes followed by 0.4mg/kg/hour for the duration of surgery in Li and colleagues,
and 0.3 µg/kg for ten minutes before anaesthesia followed by a continuous 0.3 µg/kg/hour
until 30 minutes before surgery conclusion in Ge and colleagues. Both studies demonstrated
marked reduction in inflammatory biomarkers; IL-1β, IL-6 and CRP (Li et al.,) and in S100B
and the concentration of malondialdehyde but not neuron-specific enolase (Ge et al.).
Interestingly, in both studies the dexmedetomidine group demonstrated significantly
reduced rates of cognitive impairment at around 6 to 24 hours after surgery compared with
the control groups, in which cognition tended to recover and approximate the
dexmedetomidine groups at approximately days 3 to 4. In sum, the available evidence
suggests that dexmedetomidine is a potentially effective protective agent for cognition in
the early post-operative period, though the longitudinal impact of this protection is not yet
widely examined.
5.5 Lidocaine
Lidocaine works by targeting specific voltage-gated sodium channels associated with
neuropathic and inflammatory pain (Lauretti, 2008; Oliveira, Issy, & Sakata, 2010). Lidocaine
allosterically couples with the channel to stabilise it in an inactive state (Amir et al., 2006;
Sheets & Hanck, 2003), effectively halting the transmission of action potentials from the
administration site.
Due to capacity of lidocaine to suppress pain, it has been proposed that this agent may
likewise reduce inflammatory responses. The majority of available research supports this
hypothesis, with in vivo and in vitro evidence demonstrating a significant reduction in

biological correlates of inflammation such as IL-6, & IL-8 in rabbits; TNF-α and IL-1β in mice
and rats, and levels of IL-8 and CRP in humans after surgery (Caracas, Maciel, Martins, de
Souza, & Maia, 2009; van der Wal et al., 2015). Reduction in biological correlates of
inflammation in preclinical models has also translated to cognitive protection, including the
attenuation of memory impairment after intraoperative lidocaine administration (Tan, Cao,
Zhang, & Zuo, 2014) increased neuronal survival and cognitive protection after transient
global ischaemia (Popp et al., 2011); and the attenuation of memory and learning sequelae
2-4 weeks after isoflurane exposure (D. Lin et al., 2012); all in rat models, and all with
comparable lidocaine administration (1.5-2 mg/kg during the perioperative period).
Clinical evidence for post-operative cognitive protection due to lidocaine is mixed (Bilotta et
al., 2013). The majority of studies examine elderly cardiac patients, and typically use 1-1.5
mg/kg loading lidocaine doses immediately prior to or at the commencement of surgery,
followed by maintenance until surgical conclusion (Bilotta et al.). Lidocaine administration in
this fashion appears to provide neuroprotection early in the post-operative period (Mitchell
et al., 2009; D. Wang et al., 2002), but does not appear to be associated with longer-term
outcomes (Mitchell et al.; Mathew et al., 2009). For example, cardiac artery bypass surgical
patients were administered 1.5 mg/kg lidocaine immediately after surgical incision, and
maintained at 4mg/min for the duration of the procedure and post-operative cognitive
outcomes were compared with a control group that was given saline. Both groups
experienced significant levels of cognitive dysfunction at 9 days after surgery with significant
decreases to executive function, processing speed, short-term memory, and visuospatial
motor function compared with pre-surgical performance; while working memory and verbal
associative learning were preserved in the lidocaine group (D. Wang et al.).

Lidocaine for neuroprotection in non-cardiac patients is less extensively examined, and may
be similarly controversial. In an examination of urologic and orthopaedic patients, Heidari,
Rahavi, and Hashemi, (2013) found no difference in post-operative cognition as measured
by the MMSE in the first 24 hours between a 1.5 mg/kg lidocaine bolus-and-maintenance
treated group compared with saline controls; while K. Chen, Wei, Zheng, Zhou, and Li,
(2015) found that intravenous 1 mg/kg bolus followed by 1.5 mg/kg maintenance lidocaine
was neuroprotective in elderly spinal surgery patients. At 3 days after surgery, the lidocaine
group had significantly lower levels of S100B, malonaldehyde, and NSE compared with
controls, while the levels of TNFα were unchanged in either group. Post-operative cognition
at day 3 was showed a small but significant decline in the control group compared with
baseline function, whereas cognition in the lidocaine group was preserved. More recently,
Y. Peng et al., (2016) demonstrated that perioperative lidocaine did not confer greater
cognitive protection from neurological compromise in patients following supratentorial
tumour removal at any stage up to 6 months after surgery, compared with saline controls,
though brain oxygen consumption and metabolism was significantly lower throughout
surgery in the lidocaine group and this is a neurologically compromised group.
5.6 Ketamine
Ketamine is a common anaesthetic agent with hypnotic, analgesic, and amnesiac properties,
shown to be an NMDA receptor antagonist (M. Gao, Rejaei, & Liu, 2016). At sub-anaesthetic
doses, ketamine can be used to manage chronic neuropathic pain (Zgaia et al., 2015).
Ketamine has been shown to moderate inflammatory macrophage activation and
production of cytokines including IL-1β, IL-6 and TNF-α in both preclinical and clinical models
(De Kock, Loix, & Lavand’homme, 2013; F.-L. Liu, Chen, & Chen, 2012). As a glutamate

antagonist, ketamine has also been purported to potentially ameliorate depressive
symptoms associated with excessive glutamate levels, as observed in a number of clinical
trials (DeWilde, Levitch, Murrough, Mathew, & Iosifescu, 2015). Subsequent upregulation of
BDNF and mammalian target of rapamycin (mTOR) in the prefrontal cortex after ketamine
administration may promote synaptogenesis in preclinical models, along with cognitive
protective effects (Y. Lee et al., 2016). X. Zhu et al., (2015) demonstrated that administration
of 100mg/kg ketamine reversed upregulation of IL-β, TNF-α and amyloid- β after
electroshock therapy in a rat model, and attenuated associated memory dysfunction.
Reversing the upregulation of amyloids suggests that ketamine may show therapeutic
promise for management of neurodegenerative disorders. A study by Murman et al., (1997),
was able to demonstrate in a small pilot that patients with Huntington’s disease did not
appear to be more susceptible to cognitive change due to ketamine infusion compared with
controls, but this area is not well explored.
Few human studies have directly examined perioperative ketamine administration for
protection of post-operative cognition. Mortero et al., (2001) demonstrated that a
combination of propofol and ketamine (mean dose: 3.7 µg/kg) significantly improved post-
operative cognition in a non-cardiac sample in comparison to propofol alone. Hudetz et al.,
(2009) and Nagels et al., (2004) both examined elderly cardiac surgery patients, but with
differing ketamine regimens and inconsistent cognitive effects. Nagel and colleagues
administered a 2.5mg/kg bolus prior to surgical commencement and maintained this
infusion, whereas participants in Hudetz and colleagues were administered a single
0.5mg/kg bolus at induction. Hudetz and colleagues were able to demonstrate a significant
protective cognitive effect at one-week post-surgery, while Nagels and colleagues found no

effect at either one or ten weeks with the exception of improved performance on a single
outcome for the ketamine group.
5.7 Minocycline
Minocycline is a tetracycline antibiotic typically used in the treatment of acne, and has
shown anti-inflammatory and microglial inhibitory properties (Dean, Data-Franco,
Giorlando, & Berk, 2012; Garner et al., 2012). Minocycline is highly fat soluble and is able to
easily cross the blood-brain barrier (Garrido-Mesa, Zarzuelo, & Gálvez, 2013). Substantial
evidence from animal models demonstrates the potential of minocycline as an adjunct
therapy in managing neurodegenerative disease (Garrido-Messa et al.). In vitro evidence
suggests that the therapeutic mechanism of minocycline relates to its anti-inflammatory and
microglial inhibitory effects (Karachitos, Solis Garcia del Pozo, W.J. de Groot, Kmita, &
Jordan, 2012; H.-S. Kim & Suh, 2009). Specifically, it has been proposed that minocycline to
reduce the excitoxicity resultant from increased production of glutamate, mediating the
subsequent production of mitochondrial ROS and associated neurodegeneration (Karachitos
et al.). The potential for pro-cognitive effects of minocycline is further evidenced by the
capacity of this drug to regulate long-term potentiation and glutamatergic function via
modulation of microglial inflammatory cytokine production (S.-Y. Li et al., 2013; Riazi et al.,
2015).
Clinical evidence for minocycline as a pro-cognitive agent is promising but mixed, with few
placebo-controlled trials to date. Grieco et al., (2014) demonstrated a significant cognitive
improvement in children with Angelman syndrome through open-label administration of
minocycline, with medium-to-large effects upon communication and language
comprehension, at doses of 3mg/kg BID for 16 weeks; positive effects of comparable size

were observed in an open-label trial of minocycline for Fragile X syndrome (Paribello et al.,
2010). Open-label adjuvant administration of 100mg of minocycline each day for 2 years
appeared to significantly delay the progression of cognitive and motor decline in patients
with Huntington’s disease (Bonelli, et al., 2004). Evidence from placebo-controlled trials is
less encouraging; Nakasujja et al., (2012) and Sacktor et al., (2011) both found that the
administration of 100mg of minocycline orally every 12 hours for 24 weeks did not
attenuate cognitive dysfunction associated with HIV in humans when compared with
placebo, and later examination of the biomarkers of oxidative stress revealed limited
positive change in minocycline patients in comparison with placebos (Sacktor et al., 2014).
Interestingly, minocycline may actually promote CNS apoptosis in the brain of adolescents
and children via exacerbation of synaptic pruning (Inta, Lang, Borgwardt, Meyer-Lindenberg,
& Gass, 2016; Na, Jung, & Kim, 2014); suggesting that the effects of minocycline in the
developing brain may differ from those observed in the adult.
Given the putative neuroinflammatory hypothesis of POCD and similarity with other
conditions associated with neuroinflammation, it is possible that minocycline may have
potential for the prevention and treatment of POCD. Pre-clinical evidence suggests that
minocycline is effective in reducing the severity of post-operative cognitive dysfunction,
purportedly via anti-inflammatory mechanisms. For example, H.-L. Wang, Liu, Xue, Liao, and
Fang, (2016) examined minocycline for reducing post-operative cognitive dysfunction in
aged mice, with mice separated into control, minocycline, isoflurane, minocycline +
isoflurane, surgery, or minocycline + surgery. All minocycline was administered at 45 mg/kg
12 hours before surgery or isoflurane exposure, with isoflurane at 1.4% concentration in
50% oxygen for 2 hours. Mice who received isoflurane or surgery without minocycline
demonstrated significantly increased levels of IL-β, TNF-α, and TNF-γ as well as significantly

impaired processing speed and learning compared with controls. Pre-treatment with
minocycline attenuated these differences substantially. The findings of Wang and
colleagues support earlier findings documenting the capacity of minocycline to alleviate
surgery and anaesthesia-induced cognitive deficits via anti-inflammatory mechanisms in
rodent models (Jin et al., 2013; Kong et al., 2013; S.-Y. Li et al., 2013; Tian, Guo, Wu, Ma, &
Zhao, 2015). Similarly, in transgenic models of Alzheimer’s disease (Biscaro, Lindvall, Tesco,
Ekdahl, & Nitsch, 2012) and animal models of amyloid angiopathy-related cognitive
dysfunction (Fan et al., 2007), minocycline demonstrated significant pro-cognitive effects
which were correlated with anti-inflammatory rather than anti-amyloid effects. Minocycline
has also been shown to alleviate age-related cognitive deficits via modulation of microglial
activation in aged and adult mice (Kohman, Bhattacharya, Kilby, Bucko, & Rhodes, 2013).
The protective effects of minocycline appear to be dose-dependent in mice; Z. Li et al.,
(2016) found significant post-operative spinal microglia and macrophage inhibition with
0.05mg/kg minocycline for 14 days, but not within the prefrontal cortex.
5.8 N-acetylcysteine
N-acetylcysteine (NAC) is a widely available supplement, and is FDA approved for a number
of indications, including paracetamol overdose. Additionally, NAC is used to assist in the
management of bronchitis and COPD. NAC is a bioavailable precursor for glutathione, and
acts to reduce systemic markers of inflammation and suppress mitochondrial dysfunction.
NAC thus appears to target many of the cellular processes implicated in cognitive
dysfunction. Substantive evidence from multiple pre-clinical pathological models indicates
that NAC exerts protective effects via anti-inflammatory activity. In vitro evidence has

shown that NAC has the capacity to downregulate pro-inflammatory cytokine production
and downstream signalling pathways, including critical pro-inflammatory cytokines such as
IL-6 and HGMB-1 (Gabryel, Bielecka, Bernacki, Łabuzek, & Herma, 2011) in multiple tissue
types (Y.-H. Lee et al., 2014b; Usatyuk et al., 2003; C. Wang et al., 2015). NAC also
suppresses the transcription and activity of TLR-4 and similar key receptors in the
inflammatory system (Hou et al., 2012). Interestingly, evidence from clinical studies suggests
that NAC also increases the production of anti-inflammatory cytokines, notably IL-10, IL-4
and IL-1 (Santiago et al., 2008). Strong preclinical evidence from rat models also
demonstrates that NAC reduces the reactivity of microglia (Amar Karalija, Novikova,
Kingham, Wiberg, & Novikov, 2012), their level of activation (Berman et al., 2010) and the
levels of cytokines and reactive oxygen species released following the activation of these
glial cells (B. Wang, Navath, Romero, Kannan, & Kannan, 2009). This in turn reduces
damage to neuronal cells due to inflammatory processes (A. Karalija, Novikova, Kingham,
Wiberg, & Novikov, 2014).
A series of studies have reported improvements in cognitive function in animals with
induced traumatic brain injury following NAC supplementation (Eakin et al., 2014; Günther
et al., 2015). These studies indicate that suppression of inflammation and microglial
activation may be key to the therapeutic response to NAC (G. Chen, Shi, Hu, & Hang, 2008;
Nazıroğlu, Şenol, Ghazizadeh, & Yürüker, 2014a; Şenol, Nazıroğlu, & Yürüker, 2014). NAC
acting as a glutathione precursor can reduce the evoked oxidative stress and reverse the
behavioural deficits in mice resultant from glutathione depletion (Choy, Dean, Berk, Bush, &
van den Buuse, 2010; Dean et al., 2011), and mice engineered to exhibit mitochondrial
dysfunction and elevated reactive oxygen species show deficits of learning and memory on

complex tests which can be reversed by NAC treatment (Otte et al., 2011). Mitochondrial
dysfunction and oxidative stress is also a feature of the neurodegenerative Huntington’s
disease. NAC is able to ameliorate the cognitive deficits observed in mice expressing
elevated levels of the amyloidogenic proteins implicated in Alzheimer’s disease (Hsiao, Kuo,
Chen, & Gean, 2012; Parachikova, Green, Hendrix, & LaFerla, 2010), and Huntingtons’s
disease (Sandhir, Sood, Mehrotra, & Kamboj, 2012) which appears to be associated with
modulation of oxidative stress (Huang et al., 2010; Tchantchou, Graves, Rogers, Ortiz, &
Shea, 2005). The improvement in cognitive function with NAC treatment following brain
injury following resolution of oxidative stress has also been observed in preclinical models
(G. Chen et al., 2008; Nazıroğlu, Şenol, Ghazizadeh, & Yürüker, 2014b; Şenol et al., 2014;
Xiong, Peterson, & Lee, 1999). Promisingly, support for this mechanism and subsequent
cognitive protection has also been demonstrated in preclinical rat models of post-operative
cognitive change. (Dhanda, Kaur, & Sandhir, 2013; Prakash, Kalra, & Kumar, 2015).
There is accumulating clinical evidence for the potential efficacy of NAC in various
psychiatric and neurological conditions (Berk, Malhi, Gray, & Dean, 2013) and a recent
systematic review suggested that supplementation with NAC as either an adjunct or
monotherapy was associated with significantly pro-cognitive effects for a variety of
conditions, including psychiatric disorders, Alzheimer’s disease, traumatic brain injury, and
healthy populations (Skvarc et al., 2017). Importantly for translation to acute induction of
cognitive dysfunction, a recent study demonstrated efficacy of NAC in the setting of mild
traumatic brain injury (Hoffer, Balaban, Slade, Tsao, & Hoffer, 2013). Individuals exposed to
blast injury in the course of active military service received NAC (4 grammes daily) for seven
days following the event, and a series of symptoms including headaches, memory loss, sleep

disturbance and neurocognitive dysfunction were assessed. Those receiving NAC showed
improved performance in multiple cognitive domains relative to the placebo group, and also
showed milder ancillary symptoms of brain injury. Although limited and preliminary, the
available clinical studies provide intriguing evidence for the pro-cognitive effects of NAC.
Perhaps more importantly, these studies highlight the potential efficacy of NAC in settings
where inflammation and oxidative stress play a role in the pathological process. As far as
could be ascertained, only one trial is currently examining the efficacy of NAC for POCD,
though no data are available yet (Skvarc et al., 2016).
5.9 Preoperative cognitive exercise
Cognitive reserve is an established protective factor for POCD (Silbert et al., 2007; F. Wang,
2014) and increased levels of cognitive reserve are strongly protective for incidence of
dementia; including higher educational attainment, increased occupational complexity,
premorbid IQ, and preference for mentally stimulating leisure activities (Valenzuela &
Sachdev, 2006). Additionally, the possibility of enhancing this reserve in humans through
cognitive exercise (“brain-training”) has been demonstrated, albeit with low quality data
(Valenzuela & Sachdev, 2009).
Evidence from preclinical models suggests that the provision of a cognitively stimulating
environment actively promotes neurogenesis. Fares et al., (2013) and Hannan, (2014)
reported significantly larger proportions of hippocampal surface area and cortical thickness
in rats housed in enriched environments compared to conventionally housed animals.
Strikingly, enrichment of the preoperative environment has demonstrated significant
neuroprotection in rat models of POCD, with significant reduction in TNF-α and IL1-β after

surgery in aged rats (Kawano et al., 2015). In cognitively healthy humans, physical but not
cognitive exercise improved global cognition and was associated with increased grey matter
volume, while cognitive but not physical exercise was associated with reduced memory loss
(Suo et al., 2016). Two clinical trials are currently planned to examine the efficacy of pre-
operative cognitive exercise for reducing cognitive dysfunction in cardiac patients
(NCT02053207) and delirium in non-cardiac patients (NCT02230605), but no data was
available at the time of writing.
6.0 Conclusions
There is speculative yet promising evidence to suggest that immuno-inflammatory and
redox processes contribute to the disruptions in synaptic plasticity and glutamate signalling
which underpins cognitive dysfunction in a number of settings, including POCD. POCD may
have long-term consequences for quality of life following surgery and may have a significant
impact on the experience of the patient, their family and the healthcare burden in the
community. Emerging evidence supports the potential efficacy of neuroprotective agents in
ameliorating POCD, though clinical research remains relatively embryonic and can be
considered mixed at best without considerably more investigation. The majority of potential
therapies showed great pre-clinical promise for the mitigation of POCD, but translation into
clinical efficacy has proven to be problematic so far for a number of reasons. For example,
evidence for the efficacy of lidocaine or ketamine for POCD in humans is scant and
conflicting, with the few papers available rarely in agreement. Research into the use of
dexmedetomidine or COX-II inhibitors is extremely encouraging but requires larger and
more longitudinal randomised control trials. Conversely, perioperative use of statins or

pregabalin may be associated with increased severity of POCD, though the reliance upon
retrospective studies does not allow for potential confounds to be adequately controlled.
Further, despite good evidence for the preclinical efficacy of minocycline, NAC, or
preoperative cognitive exercise for mitigation of POCD, clinical studies remain in the
embryonic stage. To date, most research has focused upon exploration of analgesic
interventions, though anti-inflammatory interventions are a sizeable minority.
Given the lack of conclusive findings, the prevalence and impact of POCD, exploration into
potential therapies should be encouraged to the point of priority. Given the inherent
vulnerability of surgical patients, researchers and clinicians should be especially vigilant of
potential risks and complications resultant from such interventions. In particular,
dexmedetomidine, COX-II inhibitors, minocycline, and NAC appear to show the greatest
promise for potential translation via research and should be thoroughly investigated
through randomised control trials. Presently, a large-scale trial specifically exploring NAC for
POCD is currently underway (ANZCTR12614000411640). Trials such as this allow the
evaluation of suitable therapies, and once more therapies (both pharmacological and
behavioural) have been similarly evaluated, the clinical, health, and economic impact of a
multi-pronged evidence-based intervention could then be evaluated for overall efficacy.
7.0 Competing interests and role of funding
DRS is supported by the Sydney Parker Smith bequest and Centre for Research Cooperation
in Mental Health scholarships. MB is supported by a NHMRC Senior Principal Research
Fellowship 1059660. OMD has received grant support from the Brain and Behavior
Foundation, Marion and EH Flack Trust, Simons Autism Foundation, Australian Rotary
Health, Stanley Medical Research Institute, Deakin University, Brazilian Society Mobility

Program, Lilly, NHMRC, Australasian Society for Bipolar and Depressive Disorders and
Servier. She has also received in kind support from BioMedica Nutracuticals, NutritionCare
and Bioceuticals. All other authors are supported by their affiliated institutions.
The authors are currently conducting several intervention studies examining the efficacy of
NAC and Minocycline.
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Figure 1 - Flowchart of POCD
Cognitive dysfunction
Compromised neuronal function (glutamate signalling, plasticity)
CNS cytokine and ROS production
Activation of microglia and astrocytes
Peripheral cytokines traverse blood-brain barrier
Increased permeability of the blood-brain barrier
Activation of peripheral inflammatory repsonse
Trauma to peripheral tissue +/- exposure to anaesthetic agents
Positive
feedback
loop