Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 20, 2026.

Biomarkers of postoperative delirium and cognitive dysfunction

Ganna Androsova, Roland Krause, Georg Winterer and 1 more

Frontiers in Aging Neuroscience · 2015 · Review

doi:10.3389/fnagi.2015.00112

Abstract

Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

More than 40% of surgical procedures in the US are performed on patients aged 65 and over Control Prevention Centers for Disease. Elderly patients frequently experience postoperative cognitive impairment, characterized by progressive cognitive and sensory decline. An acute phase of cognitive impairment is postoperative delirium (POD; according to DSM-5: 293.0 “Delirium Due to Another Medical Condition”; Rudolph et al., ). Deliria are further classified by duration and level of activity such as hyperactive, hypoactive or mixed. Patients with POD frequently develop a chronic phase of cognitive impairment, i.e., postoperative cognitive dysfunction (POCD; according to DSM-5: 294.10/11 “Major Neurocognitive Disorder Due to Another Medical Condition Without/With Behavioral Disturbance” or 331.83 “Mild Neurocognitive Disorder Due to Another Medical Condition”; Rudolph et al., ). POCD is developed in 32% of patients with short delirium duration (1–2 days) and in 55% of patients with longer delirium (Rudolph et al., ). The incidence of POD/POCD varies depending on the study and type of surgery; as illustrated on Figure 1, POD incidence ranges from 13.2% to 41.7% and POCD incidence ranges from 8.9% to 46.1%. The prevalence of POD and POCD is associated with higher mortality, increased incidence of postoperative complications, longer duration of hospital stay, greater utilization of social financial assistance and earlier retirement (Greene et al.,; Robinson et al.,; Steinmetz et al.,; Ansaloni et al.,; Liu et al., ). Patients older than 65 are predisposed to POD and POCD if they have hypoalbuminemia, abnormal preoperative serum sodium, potassium, glucose or blood sugar levels as well as psychopathological symptoms, alcohol abuse or co-morbidities (Moller et al.,; Abildstrom et al.,; Newman et al.,; Chang et al.,; Monk et al.,; Deiner and Silverstein,; Ansaloni et al.,; Kazmierski et al., ). The cognitive status of elderly patients including depression, dementia or cognitive impairment is a significant risk factor for development of POD (Elie et al.,; Leung et al.,; Minden et al.,; Inouye,; McAvay et al.,; Greene et al.,; Kosar et al., ). For instance, dementia is a significant risk factor that increases delirium occurrence risk by fivefold (Elie et al., ); vice versa, delirium itself may lead to dementia and long-term cognitive deterioration (Jackson et al., ).

Postoperative delirium is defined in DSM-5 by several criteria including clouding of consciousness with reduced awareness of environment and difficulty in sustaining and/or shifting attention. In addition, POD is characterized by changes in cognition that affect memory, language and orientation in time/space (American Psychiatric Association, ). The impairment of memory, perceptual-motor abilities, language and attention are transit characteristics between POD and POCD. Memory impairment significantly affects cognitive decline and leads to impaired social and professional functioning in POCD patients. Memory deterioration lasting more than 1 month signifies the entry into the chronic phase of the cognitive impairment (American Psychiatric Association, ). POCD following delirium might increase the rate of cognitive deterioration in Alzheimer’s disease (Gross et al., ). Specific characteristics of POCD include decline in speed of processing the information and disturbance in executive functioning but the patient typically remains oriented to person, time and space (Tsai et al., ). The decline in POCD is mostly recognized by comparison to the patient’s pre-operative capabilities (Deiner and Silverstein, ). Delirium is usually measured by standardized clinical tests such as the Confusion Assessment Method (Inouye et al., ).

To improve diagnosis and treatment of POD/POCD, research aimed to identify prognostic and diagnostic biological markers. Biomarkers can determine severity and phase of the cognitive impairment, stratify patients who are likely to respond to specific treatment and monitor the efficiency of the treatment. Genetic markers (Papadopoulou et al., ), RNA (Sørensen and Ørntoft, ) and microRNA (Scherzer et al., ) levels, proteins (Wang et al., ), and post-translational changes such as glycosylation (Norton et al.,; Drake et al., ) and phosphorylation (Deguchi et al., ), have been demonstrated as prognostic biomarkers in a variety of diseases including disorders of the central nervous system (CNS) and these biochemical entities should be considered as possible markers for POD and POCD.

The most prominent hypothesis for the molecular mechanisms of POD and POCD is a central cholinergic deficiency caused by deregulation of cholinergic anti-inflammatory pathways leading to increased inflammation (Inouye, ). Despite detection of decreased acetylcholine levels, several studies reported contradictory findings regarding levels of serum anticholinergic activity (SAA; see Section Biological Markers of Postoperative Delirium). Another suggestion is that delirium is caused by a combination of dopamine excess and acetylcholine deficiency (Trzepacz, ). Low tryptophan levels can be associated with delirium via decreased synthesis of brain serotonin or alteration of melatonin production, which has been challenged (see Section Biological Markers of Postoperative Delirium). The association between POD/POCD and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1beta, interleukin-6 and interleukin-8, neuronal injury marker and C-reactive protein was shown by several studies and questioned by others (see Sections Biological Markers of Postoperative Delirium and Common Biomarkers of Postoperative Delirium and Cognitive Dysfunction for Details). Some POD/POCD patients have elevation in serum cortisol levels that may be explained by genetic variation of the glucocorticoid receptor gene (Perroud et al., ). The isoforms of apolipoprotein E can provoke cholinergic deficiency and acetylcholinesterase unblocking (Soininen et al., ), although some results are contradicting. The amyloid beta peptide associated with Alzheimer’s disease was also observed in the serum of POCD patients. These and other findings are discussed in details in Sections Biological Markers of Postoperative Delirium, Common Biomarkers of Postoperative Delirium and Cognitive Dysfunction and Biological Markers of Postoperative Cognitive Dysfunction.

Here we review the known genetic risk factors and physiological and immunological changes that have been associated with POD and POCD. Deiner and Silverstein reviewed the postoperative delirium and cognitive dysfunction in 2009. More recent reviews discussed biomarkers and genetic variance for delirium alone (Khan et al.,; Stoicea et al., ). This article comprises a literature review on both POD and POCD biomarkers with a focus on recent findings. The current knowledge about the contributing biomarkers to postoperative delirium and cognitive dysfunction is summarized in Figure 2. POD and POCD have a wide range of contributing mechanisms and some biomarkers are overlapping. A more detailed description of the known and potentially novel biomarkers is provided below.

Biological Markers of Postoperative Delirium

The leading hypothesis suggests that delirium can be caused by a central cholinergic deficiency (Inouye, ) and is based on treatment with drugs which impair cholinergic function (Tune et al., ). The impact on muscarinic anticholinergic burden can be measured by SAA (Plaschke et al., ). Increase of SAA levels is correlated with greater number of delirium symptoms, whereas SAA decrease is correlated with delirium resolution (Mach et al.,; Flacker et al.,; Mussi et al., ). Several studies questioned the association between SAA and delirium, considering that a temporal profile of SAA can be influenced by pre-existing cognitive impairment, infection or illness (Flacker and Lipsitz,; Plaschke et al.,; van Munster et al., ). The impact of drugs on the cholinergic system was addressed in detail by Fox et al. and Praticò et al..

Acetylcholine plays an important role in memory, associative learning and selective attention (Hasselmo,; Everitt and Robbins, ). Impairment of its receptors, such as nicotinic and muscarinic acetylcholine receptors, might lead to cholinergic deficiency and delirium development (Hshieh et al., ). Postsynaptic M1 muscarinic receptors are predominantly expressed in hippocampus, cerebral cortex and striatum (Hersch et al.,; Levey, ) and play a role in cognitive functioning, memory and learning (Anagnostaras et al.,; Volpicelli and Levey,; Fisher, ). Inhibition of the M1 muscarinic receptor was hypothesized to cause POD and POCD (Praticò et al., ). Inhibition of postsynaptic nicotinic receptors by isoflurane and nitrous oxide results in learning and memory impairment after surgery (Culley et al.,; Kong et al., ). Vice versa, agonists of the nicotinic receptors can improve cognitive function (Wagner et al., ): activation of the nicotinic acetylcholine receptor alpha 7 prevents the cognitive decline after surgery by inhibition of NF-kappaB (nuclear factor kappa B) activation and suppression of macrophage migration into the hippocampus (Terrando et al., ). This phenomenon shows the bidirectional communication between the nervous and the immune system (Ader et al., ). Therefore, acetylcholine and its receptors are likely contributors to the onset of POD and POCD.

The cholinergic anti-inflammatory pathway, mediated by acetylcholine, is associated with neurocognitive decline (Ramlawi et al., ). It suppresses NF-kappaB activation and inhibits the release of inflammatory cytokines (e.g., tumor necrosis factor, interleukin (IL)-1β, IL-6, and IL-18) but not IL-10, an anti-inflammatory cytokine (Borovikova et al.,; van Gool et al., ). Septic and aseptic inflammation can trigger acute cognitive deficits in patients with cholinergic system depletion (Field et al., ). Acetylcholinesterase and butyrylcholinesterase inactivate acetylcholine through hydrolysis, possibly enhancing inflammation. Decreased cholinesterase activity in delirious patients was correlated with elevated levels of C-reactive protein and IL-6 (Cerejeira et al., ). C-reactive protein (CRP) is a marker of nonspecific acute-phase response in inflammation, infection and tissue damage (Pepys and Hirschfield, ), correlated with cognitive decline (Tilvis et al., ). The association between high CRP levels and delirium was shown by several studies (Beloosesky et al.,; Macdonald et al.,; Burkhart et al.,; Pol et al.,; Ritchie et al.,; Zhang et al., ), and questioned by others (Lemstra et al.,; Girard et al., ).

An inflammatory response to postoperative stress may contribute to delirium via disruption of the blood-brain barrier (Rudolph et al., ). The increased risk is correlated with elevated monocyte chemotactic protein 1, procalcitonin, human leukocyte antigen-DR, CD68, IL-1β, IL-6, IL-8, IL-18 and anti-inflammatory IL-1 receptor antagonist (van Munster et al.,,; van den Boogaard et al.,; Cape et al., ). Elevated levels of the pro-inflammatory cytokines IL-2 and tumor necrosis factor-α (TNF-α) were detected in the POD patients who had undergone coronary artery bypass graft surgery (Kazmierski et al.,,). Inhibition of inflammatory IL-12/IL-23-mediated pathways may reduce Alzheimer’s disease pathology and reverse cognitive deficits in aged mice (Vom Berg et al., ). van Munster et al. observed high levels of IL-8 and cortisol before a delirium onset and high levels of IL-6 and S100 calcium-binding protein B (S100B) in the course of delirium but functional genetic variations in interleukin-6 gene (IL6), interleukin-6 receptor gene (IL6R) and interleukin-8 gene (IL8) were not associated with delirium (van Munster et al., ). Likewise, the association between delirium and higher IL-1, IL-6 and TNF-α plasma levels was not confirmed (Adamis et al.,, ). The lower plasma concentrations of the coagulation marker protein C together with elevated plasma concentrations of soluble tumor necrosis factor receptor-1 were associated with increased risk for delirium (Girard et al., ).

S100B is an indicator of the direct neuronal injury, e.g., by cerebrovascular accidents and traumatic brain injury (Berger et al., ). Several studies consistently demonstrated highly elevated levels of S100B in patients with delirium (Pfister et al.,; van Munster et al.,,,; van den Boogaard et al., ). Grandi et al. found no difference in levels of S100B in delirious and control patients. The same study indicated that neuron-specific enolase and brain-derived neurotrophic factor (BDNF) could be potential biomarkers for delirium in intensive care unit patients (Grandi et al., ). BDNF plays role in synaptic plasticity, neuronal survival, differentiation and growth (Acheson et al.,; Huang and Reichardt, ). Similarly to BDNF, insulin growth factor-1 (IGF-1) promotes neuronal proliferation, development, survival and enhanced synaptic transmission in CNS (Frost et al.,; Shcheglovitov et al.,; Huat et al., ). Tumor necrosis factor-α (TNF-α) can be involved in neurodegeneration through inhibition of IGF-1 (Frost et al.,; Bassil et al., ). Low baseline levels of IGF-1 were associated with an increased risk of delirium incidence (Wilson et al.,; Adamis et al.,, ). Due to the neuroprotective function, low levels of IGF-1 may have a significant effect on delirium severity (Adamis et al., ). Understanding the complex connection between the cholinergic system and increased pro-inflammatory response as well as neurodegeneration is likely to shed light on the molecular and cellular causes of delirium.

Another popular hypothesis suggests that delirium can be caused by dopamine excess and acetylcholine deficiency relative and/or absolute to each other (Trzepacz, ). Cytokines can disrupt the neurotransmitter system balance, leading to reduced acetylcholine release (Willard et al., ) and increased dopamine and norepinephrine release (Stefano et al., ). Delirium, related to anticholinergic mechanisms, was successfully treated with the dopamine receptor antagonists (Alagiakrishnan and Wiens, ). One of such receptors is dopamine receptor D2 (DRD2); its dysfunction leads to hallucinations, impairment of motor and frontal lobe functions (Volkow et al.,; Makoff et al., ). The gene encoding for D2 subtype of dopamine receptor (DRD2) was associated with schizophrenia and movement disorders (Kukreti et al.,; Koning et al., ). Seven single nucleotide polymorphisms (SNPs) in the SLC6A3 (solute carrier family 6, member 3) gene and three genetic polymorphisms in the DRD2 gene are associated with delirium (van Munster et al., ). The SLC6A3 gene is coding for the dopamine transporter, hence variation of this gene can lead to a lower concentration of cerebral basal dopamine, diminishing the risk of delirium (van Munster et al., ). One of the detected genetic polymorphisms in SLC6A3 was associated with pediatric bipolar disorder (Mick et al., ); although no connection was found between bipolar disorder in adults and postoperative delirium.

Apolipoprotein E (ApoE) regulates the cholesterol metabolism, participates in repairing and maintaining of neuronal membranes and myelin during development and after injury (Ignatius et al., ). It is responsible for cholinergic neuron destruction by increased synthesis and defective clearance of amyloid beta (Kowall et al., ). Different isoforms of APOE gene can provoke cholinergic deficiency and acetylcholinesterase unblocking (Soininen et al., ). The carriers of APOE ε4 allele have greater risk of delirium development (Adamis et al.,; Leung et al.,; van Munster et al., ) and are more predisposed to cellular damage within the brain (Olivecrona and Koskinen, ). The APOE ε4 allele was found to be correlated with longer duration of delirium in mechanically ventilated critically ill patients (Ely et al., ). There might be a connection between neurodegeneration due to pro-inflammatory response and enhanced APOE activity that causes cholinergic deficiency in POD patients. Even so, some studies question the association of APOE ε4 with delirium (Adamis et al.,; Bryson et al.,; Abelha et al., ).

Elevated serum cortisol levels were correlated with POD risk and degree, being dependent on hypothalamic-pituitary-adrenal axis hyperactivity at preexisting cognitive and functional impairment (van Munster et al.,; Bisschop et al.,; Cerejeira et al.,; Colkesen et al.,; Kazmierski et al., ). A possible epigenetic explanation of cortisol sensitivity is the methylation of the glucocorticoid receptor gene NR3C1 (nuclear receptor family 3, group C, member 1; Perroud et al., ). The increased diurnal cortisol and higher sensitivity to glucocorticoids were associated with homozygous NR3C1 haplotype 4 (Manenschijn et al., ). The carriers of this haplotype had a 92% decreased risk of developing POD independently of age, cognitive and functional state (Manenschijn et al., ). This study concluded that development of delirium and its pathogenesis is correlated with glucocorticoid signaling. High levels of glucocorticoids affect working memory and thereby explain the cognitive deficits and inattention (Lupien et al., ). Mild cognitive impairment was further associated with increased cortisol levels and POD risk (Kazmierski et al., ).

The neurometabolic pathway facilitates communication between brain and metabolic organs and consequently influences various neurodegenerative disorders, normal and pathophysiological aging (Siddiqui et al., ). Alteration in the neurometabolic status of the hippocampus can potentially impair growth and survival of neuronal cells, which is a common neuropathology of Alzheimer’s disease (Wenk,; Cong et al., ). Metabolic syndrome (e.g., hyperglycemia, diabetes) together with inflammation can contribute to cognitive decline (Yaffe et al., ). Prevention of metabolic syndrome by preoperative conventional glucose control might reduce the incidence of POD/POCD (Yaffe et al.,; Finfer et al., ).

The changes of amino acid concentrations in serum and urine have been associated with POD pathogenesis. An increased risk of delirium development was associated with decreased plasma tryptophan and the ratio of tryptophan as well as the increased or decreased ratio of tyrosine to large neutral amino acids (van der Mast et al.,; Robinson et al.,; Pandharipande et al., ). It was hypothesized that high levels of tyrosine lead to dopamine and norepinephrine excess that are involved in delirium pathogenesis (Pandharipande et al., ).

The low tryptophan levels might be associated with delirium via decreased synthesis of brain serotonin (van der Mast et al.,; Robinson et al.,; Pandharipande et al., ). de Jonghe et al. questioned the association between lower levels of tryptophan and delirium. Following the inflammatory response, tryptophan catabolisation via the kynurenine pathway is increased (Adams Wilson et al., ). Elevated plasma kynurenine and kynurenine/tryptophan ratio were correlated with fewer days without acute brain dysfunction in form of delirium or coma (Adams Wilson et al., ). Another suggested connection of tryptophan with delirium is alteration of melatonin production via serotonin synthesis (Pandharipande et al., ). Melatonin participates in regulation of circadian rhythms and quality and duration of sleep (Brzezinski, ). POD patients frequently have disrupted sleep-wake cycle, decreased delta melatonin concentrations (Yoshitaka et al., ) and abnormal circadian postoperative patterns of melatonin secretion (Shigeta et al., ).

Sunwoo et al. observed a higher frequency of normal and phosphorylated α-synuclein-positive pathologies in 16 delirious patients that underwent gastrostomy for stomach cancer. Sunwoo and colleagues concluded that POD clinical characteristics are analogous to the core features of α- as dementia with Lewy bodies, Parkinson disease dementia; patients experience altered sleep-wake cycles, visual hallucinations, disorganized thinking and attention impairment (Sunwoo et al., ). α-synuclein may be involved in the neurotransmitter release controlling through the SNARE complex (Kang et al.,; Tanzi et al., ). The delirious state is strongly influenced by the balance between cholinergic and dopaminergic systems, pro-inflammatory signaling, apolipoprotein E isoform, glucocorticoid signaling and the neurometabolic state. Many additional contributors at genetic, proteomic, metabolic and immune levels are to be expected.

Common Biomarkers of Postoperative Delirium and Cognitive Dysfunction

Postoperative delirium correlates with early postoperative cognitive dysfunction (at 7 days; Rudolph et al.,; Hudetz et al., ) and delirious patients have 14 times greater chance of POCD development (Hudetz et al., ). In this chapter, we will discuss the common biomarkers found in both cognitive impairments, which are summarized in Figure 2.

Among the above-discussed genetic markers, the APOE ε4 allele was associated with greater risk to develop postoperative delirium (Adamis et al.,; Leung et al.,; van Munster et al., ) and cognitive dysfunction at 7 days postoperatively (Cao et al., ). The association with POCD was however not detected by other studies of APOE ε4 variation at 1 week, 1–3 months and 1 year postoperatively (Abildstrom et al.,; Rentowl and Hanning,; McDonagh et al.,; Bryson et al.,; Cao et al., ).

The elevated cortisol levels were detected in both POD (van den Boogaard et al.,; Cerejeira et al., ) and POCD patients (Zhang et al., ). The magnitude of cortisol elevation correlated with levels of anti-inflammatory cytokine IL-10 and pro-inflammatory cytokine IL-6. Similarly to POD, POCD is associated with elevation of other pro-inflammatory markers including IL-1β, IL-8 and TNF-α (Rothenburger et al.,; Hudetz et al.,; Li et al.,; Bi et al., ). TNF-α stimulates IL-1β production in the brain and causes postoperative cognitive decline via peripheral cytokine cascade (Terrando et al., ). Reducing IL-1 release by peripheral TNF-α blockade might prevent POD, POCD and neuroinflammation (Terrando et al., ). Nonspecific acute-phase response in inflammation is present during POD and POCD. POCD patients have elevated levels of CRP following coronary artery bypass grafting (Hudetz et al., ), liver transplantation (Li et al., ) and lumbar discectomy (Zhang et al., ). Contradictory to previous findings, plasma levels of inflammatory marker matrix metalloproteinase-9 were decreased in POD patients and elevated in POCD patients (Girard et al.,; Zhang et al., ).

Elevated levels of S100B were associated with POD (Pfister et al.,; van Munster et al.,,,; van den Boogaard et al., ). Likewise, POCD patients have increased serum levels of S100B, which is an indicator of neuronal injury (Rasmussen et al.,; Li et al.,; Lili et al., ). S100B-induced neuroinflammation mediates the RAGE (receptor for advanced glycation end product) signaling in microglia (Bianchi et al., ). The RAGE signaling pathway may up-regulate pro-inflammatory cytokines via NF-kappaB signaling, indicating its possible role in surgery-induced cognitive decline pathogenesis (Li et al., ). Yet McDonagh et al. did not find an association between POCD and S100B or CRP.

BDNF showed correlation with POD occurrence in patients (Grandi et al., ) and POCD occurrence in aged mice (Tian et al., ). It was associated with other neuropsychiatric disorders such as schizophrenia, depression, bipolar disorder and has been suggested as early marker of brain injury (Chiaretti et al.,; Muglia et al.,; Teixeira et al., ).

Copeptin is correlated with severity of the illness and is presumed to be a prognostic measure of outcome prediction in acute illness (Katan and Christ-Crain, ). Postoperative plasma copeptin level can be an independent predictor of POD and POCD after coronary artery bypass graft surgery (Dixson et al., ). This study observed higher levels of postoperative copeptin in POD and POCD patients compared to controls.

A significant fluctuation of urinary 6-sulfatoxymelatonin (6-SMT), a major metabolite of melatonin, was detected in POCD patients compared to controls (Wu et al., ). Clinical subtypes of POD are differently related to the urinary levels of 6-sulfatoxymelatonin: hypoactive patients have higher 6-SMT, whenever hyperactive patients have lower 6-SMT (Balan et al., ). However, the association between melatonin and delirium has been challenged by independent studies after failure to confirm these findings (de Jonghe et al., ).

As mentioned above, postoperative delirium and cognitive dysfunction may have common contributing factors and biomarkers such as apolipoprotein E isoforms, cortisol signaling, pro-inflammatory cytokines, neurodegenerative marker S100B, copeptin and 6-sulfatoxymelatonin levels.

Biological Markers of Postoperative Cognitive Dysfunction

Patients with postoperative cognitive dysfunction display biomarkers distinct from delirious patients, which might be related not only to pathology but also postoperative time. The majority of the detected POCD biomarkers are related to inflammation. A recent study reported a positive association between the pro-inflammatory protein S100A8 and POCD development (Lu et al., ) and imbalance between T helper 17 cells, a pro-inflammatory subset of CD4+T cells, and regulatory T cells, an anti-inflammatory subset of CD4+T cells, was observed in POCD patients (Tian et al., ).

Postoperative cognitive dysfunction can be predicted by lower preoperative endotoxin immunity following cardiac surgery (Mathew et al., ). Lower preoperative levels of immunoglobulin M (anti-endotoxin core antibody) are associated with the greater incidence and severity of POCD (Mathew et al., ). A similar study by Rothenburger et al. suggested an association between lower levels of immunoglobulin M and elevated levels of endotoxin together with IL-8 (Rothenburger et al., ).

5′ adenosine monophosphate-activated protein kinase (AMPK) protects CNS by inhibition of inflammatory responses through various mechanisms, including NF-kappaB pathway (Sag et al.,; Salminen et al., ). This pathways includes NF-kappaB activation by chemokines, cytokines or adhesion molecules and activation of inflammatory cytokines IL-1 and TNF-α (Renard et al.,; Chandel et al., ). A significant elevation of NF-kappaB, IL-1β and AMPK was shown to result in Toll-like receptor 4 signaling on microglia in the hypothalamus of a POCD rat model (Wang et al.,; Bi et al., ). Interleukin-1β and NF-kappaB levels gradually decreased over postoperative days (Wang et al.,; Bi et al., ). Interleukin-1β can be a viable target to interrupt the POCD pathogenesis, as IL-1β-mediated inflammation was triggered by peripheral surgery-induced innate immune response (Cibelli et al., ). Another study demonstrated experimentally that inhibition of IL-1 receptors prevents development of POCD and neuroinflammation (Barrientos et al., ).

Le et al. suggested that hippocampus impairment leads to POCD development after they observed a significant reduction of neuronal dendritic spines and neuroinflammation signified by activated microglia, elevation of TNF-α and interleukin-1β in the hippocampi of aged rats. Amyloid beta 1–42 oligomers can impair cognitive and metabolic processes in the hippocampus (Pearson-Leary and McNay, ). The elevated levels of amyloid beta 1–42 were associated with a cognitive impairment caused by its interference with insulin signaling in the hippocampus (Pearson-Leary and McNay, ). The amyloid hypothesis suggests that amyloid beta peptide is deposited in the brain of Alzheimer’s dementia patients and can form the senile plaques that perturb various signaling mechanisms (Cras et al., ). Old mice that developed short-term POCD upon abdominal surgery had Alzheimer’s dementia-like changes: gliosis in brain, enhanced transcriptional and translational activity of the β-amyloid precursor protein, enhanced production of amyloid beta peptide, and hyper-phosphorylation of tau in the hippocampus (Wan et al., ). POCD patients after liver transplantation had significantly elevated levels of serum amyloid beta peptide, suggesting similar mechanisms as in Alzheimer’s disease (Li et al., ).

Urinary biomarkers could be promising diagnostic and prognostic indicators of postoperative cognitive dysfunction. A high ratio of trypsin inhibitor/creatinine was suggested to be an independent risk factor of POCD in lumbar discectomy patients (Zhang et al., ). Urinary excretion levels of 8-isoprostane/creatinine were elevated as well in POCD patients at 7 days postoperatively compared to control patients (Cheng et al., ).

The major POCD biomarkers include inflammation-related molecules, imbalance between pro- and anti-inflammatory signaling and metabolic levels in urine.

Potential Biomarkers of Postoperative Delirium and Cognitive Dysfunction

At present, there is no standard biomarker for diagnosis and prognosis of postoperative cognitive impairments. Some findings on biomarker association with POD/POCD are contradictory. Thus, generation of genomic, proteomic and metabolomics data as well as implementation of imaging techniques such as MRI are required. In this section, we review the potential biomarkers possibly involved in occurrence and/or progression of postoperative delirium and cognitive dysfunction.

S100A8 (myeloid-related protein-8, calgranulin A), S100A9 (myeloid-related protein-14, calgranulin B), S100A12 (EN-RAGE, calgranulin C) are reliable markers of inflammation (Foell et al., ) and potential markers of plaque instability (Abbas et al., ). Inhibition of S100A9 significantly improved learning and memory, and reduced neuropathology of Alzheimer’s disease (Chang et al., ). Thus, it is promising to investigate potential connection between the calgranulins and POD/POCD.

As mentioned above, inflammation is associated with both POD and POCD. The pro-inflammatory cytokine IL-18 was not studied yet in the context of POD/POCD. Alzheimer’s patients have increased levels of IL-18 in different regions of the brain (Ojala et al., ). Being co-localized with tau-protein and amyloid beta plaques, IL-18 mediates the hyperphosphorylation of tau (Ojala et al.,; Sutinen et al., ). IL-18 can influence the integrity of neurons and increase neuroinflammation in the brain (Bossù et al.,; Sutinen et al., ), thus contributing to cognitive decline in Alzheimer’s disease (Bossù et al., ). IL-18 receptor complex (IL-18Rα/β) expression is perturbed in preclinical state of mild cognitive impairment and Alzheimer’s disease (Salani et al., ). Specifically, IL-18Rα might play role in autoimmune brain damage (e.g., encephalomyelitis) via production of IL-17-producing T helper cells (Gutcher et al., ). A splice variant of IL-18Rβ encodes a putative truncated soluble protein that might be a regulator of IL-18 functioning (Andre et al., ).

SIGIRR (also called TIR8) is a potential inhibitor of pro-inflammatory IL-18, IL-1 and Toll-like receptor signaling (Thomassen et al.,; Wald et al.,; Mantovani et al., ). The anti-inflammatory effect of SIGIRR might be extended to the brain, as it inhibits inflammation in cooperation with IL-1F5 (a potential anti-inflammatory cytokine; Costelloe et al., ). TIGIRR receptor might be an accessory chain for mature IL-37a (Boraschi et al., ). IL-37a isoform is exclusively located in the brain and might be a potential anti-inflammatory cytokine (Boraschi et al., ). Another isoforms of IL-37 can bind to IL-18Rα and IL-18-binding protein, enhancing IL-18 inhibition (Boraschi et al., ).

IL1RAPL (IL-1 receptor accessory protein-like) gene was identified as a X-linked mental retardation locus (Carrié et al., ). IL1RAPL gene encodes a protein homologous to the IL-1/Toll receptor family. Patients with cognitive impairment had a nonsense mutation and deletions in IL1RAPL gene (Carrié et al., ). IL1RAPL gene might have a potential role in memory and learning functioning due to its over-expression in brain structures responsible for memory development such as hippocampus, dentate gyrus and entorhinal cortex (Carrié et al., ).

Several studies have reported a possible disruption of the blood-brain barrier integrity during POD (Pfister et al.,; Rudolph et al., ). Blood-brain barrier disruption is associated with cognitive, behavioral and mood disturbances (Shalev et al., ). Zonulin is a protein that modulates the intercellular tight junction integrity and increases blood-brain barrier permeability (Fasano et al., ). Zonulin is involved in movement of macromolecules, fluid and leukocytes between intestinal lumen and bloodstream (Lu et al.,; Fasano, ). Since zonulin can increase intestinal and bovine brain microvessel endothelial cells permeability, the elevated circulating levels of zonulin can indicate blood-brain barrier pathologies (Karyekar et al.,; Fasano, ). Zonulin has been already associated with several diseases: celiac disease (Fasano et al.,; Fasano, ), schizophrenia (Wan et al., ), Devic’s disease (Bai et al., ), multiple sclerosis (Takeoka et al., ) and Guillain-Barré syndrome (Jin et al.,; Yang et al., ).

Cholinergic-nicotinic genes can be implicated in POD/POCD pathology. Genetic variation within exon 5 of the α4 subunit of nicotinic acetylcholine receptor (CHRNA4) gene can modulate the attention network function (Winterer et al., ) and was implicated in nicotine dependence (Feng et al.,; Li et al., ). Several rare CHRNA4 SNPs were negatively associated with nicotine dependence indicating its protective effect (Wessel et al.,; Xie et al., ). Nicotine can improve attention, memory and efficiently treat cognitive impairments (Rezvani and Levin, ). Patients with genetic variation of CHRNA4 might abuse nicotine as self-medication of attention deficits in autosomal dominant nocturnal frontal lobe epilepsy (Hirose et al.,; Cho et al., ), schizophrenia (Winterer et al.,; Winterer, ) and attention deficit/hyperactivity disorder (Lambert and Hartsough, ). In addition, variants on the CHRNA5-CHRNA3-CHRNA4 gene cluster, implicated in nicotine dependence, are associated with cognitive performance (Winterer et al., ).

System Biology Approaches for Biomarker Discovery

To identify, prevent or treat postoperative delirium and cognitive dysfunction we need to connect the incidental findings into an encompassing model and relate the pathomechanisms underlying POD/POCD with clinical outcomes. The biomarkers discussed so far are conceptually linked by the known molecular interactions and pathways and illustrated in Figure 3. Many findings are contradictory between cohorts and studies, which further complicates the investigation of underlying mechanisms. The toolbox of integrated systems biology can help to model the complex dependencies and conceptualize the unknown pathomechanisms contributing to POD/POCD origin and progression. Due to the sparse knowledge on cognitive impairments, we are limited in the choice of methodologies. Predictions of novel targets for study cannot utilize the simulations as appropriately large training and test data needs yet to be collected.

Knowledge maps formed by an integration of large-scale experimental data and text-mining results enable specialists to collaborate on highly detailed information. The dissection of the knowledge map into functionally/pathway enriched modules can reduce the overall complexity and indicate the sub-network(s) deregulated in POD/POCD. Networks built on the list of the seed genes/proteins reviewed in this article may indicate enriched pathways that are related directly or indirectly to POD/POCD. We can proceed with prediction of the upstream regulators, hubs and bottlenecks of the given pathways and sub-networks. Such regulators are potentially interesting as targets since they could modulate the network state and dampen imbalance and deregulation. Network approach enables us to study dynamical changes of the system such as responsiveness, adaptation and stability. For example, network analysis of the metabolic positron emission tomography scans from Parkinson’s disease patients identified two distinct disease-related patterns (Eckert et al., ). One of the patterns is related to motor manifestations of Parkinson’s disease, the other pattern is correlated with the patients’ performance on memory and executive functioning tests. In case of POD/POCD, networks can initially be based on the literature mining results where large-scale human experimental data is not accessible. Networks based on experimental data and supported by literature evidence may give stronger results and reflect the network dynamics.

Systems biology methods, applied to Parkinson’s disease, made a significant contribution for integration of known pathomechanisms. Parkinson’s disease is a multi-factorial condition with complex interplay between genetic and environmental factors (Calne et al., ). A recently published Parkinson’s disease map is able to capture the known contributing mechanisms, integrate the underlying pathways and visualize large experimental data on top of the solid, literature derived and reviewed network (Fujita et al., ). The principle of the Parkinson’s disease map could be well applied to investigate other complex diseases including POD and POCD.

Magnetic resonance imaging revealed the vulnerable regions in brain of POD patients (Root et al., ) as well as white-matter hyperintensities (Hatano et al., ) and brain atrophy (Gunther et al., ). Integration of imaging results with information at different levels (i.e., DNA, RNA, proteins, etc.) gives a rise to mathematical/computational modeling of POD and POCD states. Iterative prediction and cross-validation steps improve such models and system behavior and response to perturbations can be predicted. For instance, neuroimaging integration with genetic and demographic information by a Support Vector Machine algorithm successfully differentiated Alzheimer disease and mild cognitive impairment from controls (Kohannim et al., ). The integrated systems biology approaches in the context of POD/POCD lead a step forward to personalized medicine and effective clinical trials.

Conclusion

Postoperative delirium and cognitive dysfunction has been elucidated on the molecular basis and many biomarkers have been identified. Hypotheses to explain the major features of the disease onset and pathology were formulated but at this point, we understand little how much the markers and mechanisms explain the pathology. In particular, we know little about possible molecular influences on POD/POCD sub-types such as slow and fast progression or hypo- and hyperactive delirium. Common molecular mechanisms with other syndromes, in particular schizophrenia, promise further insights but have not been investigated on a sufficient scale. As neuropsychiatric syndromes present themselves in the most complex manner, we require global standardization efforts and patient cohorts for comparative investigations.

We have reviewed the knowledge about molecular mechanisms underlying POD and POCD and described many biomarkers associated with these postoperative complications, and it is clear that postoperative delirium and cognitive dysfunction are multifactorial conditions. Among the identified pathomechanisms, some biomarkers were common, such as elevation of TNF-α, interleukin-1β, interleukin-6, interleukin-8, interleukin-10, CRP, S100B, matrix metalloproteinase-9, BDNF, copeptin and cortisol levels as well as presence of ApoE ε4 allele. The application of integrated systems biology approaches may elucidate the unknown pathomechanisms contributing to POD/POCD origin and progression. Combining experimental measurements, imaging techniques and mathematical/computational modeling can give a potential to reconstruct the underlying network of molecular interactions and predict reliable biomarkers of postoperative delirium and cognitive dysfunction.

PubMed Search Strategy

We reviewed the pertinent literature retrieved by a search in the PubMed database (on November 20, 2014) using the following query: “(biomarker OR marker) AND [(postoperative delirium) OR delirium OR (postoperative cognitive dysfunction) OR POCD] AND (hasabstract[text] AND Humans[Mesh]) NOT (Alzheimer OR Parkinson)”. The search yielded 254 publications. The ones cited in the review are those that, in the author’s view, make a substantial contribution to the knowledge about existing and potential biomarkers of POD/POCD.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 221

  1. 1.

    Abbas A. Aukrust P. Dahl T. B. Bjerkeli V. Sagen E. B. L. Michelsen A.. (2012 ). High levels of S100A12 are associated with recent plaque symptomatology in patients with carotid atherosclerosis. Stroke 43, 1347–1353.

    Not in our library10.1161/strokeaha.111.642256

  2. 2.

    Abelha F. J. Fernandes V. Botelho M. Santos P. Santos A. Machado J. C.. (2012 ). Apolipoprotein E e4 allele does not increase the risk of early postoperative delirium after major surgery. J. Anesth. 26, 412–421.

    Not in our library10.1007/s00540-012-1326-5

  3. 3.

    Abildstrom H. Christiansen M. Siersma V. D. Rasmussen L. S. (2004 ). Apolipoprotein E genotype and cognitive dysfunction after noncardiac surgery. Anesthesiology 101, 855–861.

    Not in our library10.1097/00000542-200410000-00009

  4. 4.

    Abildstrom H. Rasmussen L. S. Rentowl P. Hanning C. D. Rasmussen H. Kristensen P. A.. (2000 ). Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly. ISPOCD group. International study of post-operative cognitive dysfunction. Acta Anaesthesiol. Scand. 44, 1246–1251.

    Not in our library10.1034/j.1399-6576.2000.441010.x

  5. 5.

    Acheson A. Conover J. C. Fandl J. P. DeChiara T. M. Russell M. Thadani A.. (1995 ). A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374, 450–453.

    Not in our library10.1038/374450a0

  6. 6.

    Adamis D. Lunn M. Martin F. C. Treloar A. Gregson N. Hamilton G.. (2009 ). Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients. Age Ageing 38, 326–332.

    Not in our library10.1093/ageing/afp014

  7. 7.

    Adamis D. Treloar A. Martin F. C. Gregson N. Hamilton G. Macdonald A. J. D. (2007 ). APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients. Int. J. Geriatr. Psychiatry 22, 688–694.

    Not in our library10.1002/gps.1732

  8. 8.

    Adams Wilson J. R. Morandi A. Girard T. D. Thompson J. L. Boomershine C. S. Shintani A. K.. (2012 ). The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*. Crit. Care Med. 40, 835–841.

    Not in our library10.1097/ccm.0b013e318236f62d

  9. 9.

    Ader R. Cohen N. Felten D. (1995 ). Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet 345, 99–103.

    Not in our library10.1016/s0140-6736(95)90066-7

  10. 10.

    Alagiakrishnan K. Wiens C. A. (2004 ). An approach to drug induced delirium in the elderly. Postgrad. Med. J. 80, 388–393.

    Not in our library10.1136/pgmj.2003.017236

  11. 11.

    American Psychiatric Association (2013 ). Diagnostic and Statistical Manual of Mental Disorders. 5th Edn. Arlington, VA: American Psychiatric Publishing, Inc.

    Not in our library

  12. 12.

    Anagnostaras S. G. Murphy G. G. Hamilton S. E. Mitchell S. L. Rahnama N. P. Nathanson N. M.. (2003 ). Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat. Neurosci. 6, 51–58.

    Not in our library10.1038/nn992

  13. 13.

    Andre R. Wheeler R. D. Collins P. D. Luheshi G. N. Pickering-Brown S. Kimber I.. (2003 ). Identification of a truncated IL-18Rβ mRNA: a putative regulator of IL-18 expressed in rat brain. J. Neuroimmunol. 145, 40–45.

    Not in our library10.1016/j.jneuroim.2003.09.005

  14. 14.

    Ansaloni L. Catena F. Chattat R. Fortuna D. Franceschi C. Mascitti P.. (2010 ). Risk factors and incidence of postoperative delirium in elderly patients after elective and emergency surgery. Br. J. Surg. 97, 273–280.

    Not in our library10.1002/bjs.6843

  15. 15.

    Bai S. Liu S. Guo X. Qin Z. Wang B. Li X.. (2009 ). Proteome analysis of biomarkers in the cerebrospinal fluid of neuromyelitis optica patients. Mol. Vis. 15, 1638–1648.

    Not in our library

  16. 16.

    Balan S. Leibovitz A. Zila S. O. Ruth M. Chana W. Yassica B.. (2003 ). The relation between the clinical subtypes of delirium and the urinary level of 6-SMT. J. Neuropsychiatry Clin. Neurosci. 15, 363–366.

    Not in our library10.1176/appi.neuropsych.15.3.363

  17. 17.

    Barrientos R. M. Hein A. M. Frank M. G. Watkins L. R. Maier S. F. (2012 ). Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J. Neurosci. 32, 14641–14648.

    Not in our library10.1523/jneurosci.2173-12.2012

  18. 18.

    Bassil F. Fernagut P. O. Bezard E. Meissner W. G. (2014 ). Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog. Neurobiol. 118, 1–18.

    Not in our library10.1016/j.pneurobio.2014.02.005

  19. 19.

    Beloosesky Y. Grinblat J. Pirotsky A. Weiss A. Hendel D. (2004 ). Different C-reactive protein kinetics in post-operative hip-fractured geriatric patients with and without complications. Gerontology 50, 216–222.

    Not in our library10.1159/000078350

  20. 20.

    Berger R. P. Adelson P. D. Pierce M. C. Dulani T. Cassidy L. D. Kochanek P. M. (2005 ). Serum neuron-specific enolase, S100B and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children. J. Neurosurg. 103, 61–68.

    Not in our library10.3171/ped.2005.103.1.0061

  21. 21.

    Bi Y. Liu S. Yu X. Wang M. Wang Y. (2014 ). Adaptive and regulatory mechanisms in aged rats with postoperative cognitive dysfunction. Neural Regen. Res. 9, 534–539.

    Not in our library10.4103/1673-5374.130084

  22. 22.

    Bianchi R. Adami C. Giambanco I. Donato R. (2007 ). S100B binding to RAGE in microglia stimulates COX-2 expression. J. Leukoc. Biol. 81, 108–118.

    Not in our library10.1189/jlb.0306198

  23. 23.

    Bisschop P. H. de Rooij S. E. Zwinderman A. H. van Oosten H. E. van Munster B. C. (2011 ). Cortisol, insulin and glucose and the risk of delirium in older adults with hip fracture. J. Am. Geriatr. Soc. 59, 1692–1696.

    Not in our library10.1111/j.1532-5415.2011.03575.x

  24. 24.

    Boraschi D. Lucchesi D. Hainzl S. Leitner M. Maier E. Mangelberger D.. (2011 ). IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur. Cytokine Netw. 22, 127–147.

    Not in our library10.1684/ecn.2011.0288

  25. 25.

    Borovikova L. V. Ivanova S. Zhang M. Yang H. Botchkina G. I. Watkins L. R.. (2000 ). Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462.

    Not in our library10.1038/35013070

  26. 26.

    Bossù P. Ciaramella A. Salani F. Bizzoni F. Varsi E. Di Iulio F.. (2008 ). Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain Behav. Immun. 22, 487–492.

    Not in our library10.1016/j.bbi.2007.10.001

  27. 27.

    Bossù P. Ciaramella A. Salani F. Vanni D. Palladino I. Caltagirone C.. (2010 ). Interleukin-18, from neuroinflammation to Alzheimer’s disease. Curr. Pharm. Des. 16, 4213–4224.

    Not in our library10.2174/138161210794519147

  28. 28.

    Bryson G. L. Wyand A. Wozny D. Rees L. Taljaard M. Nathan H. (2011 ). Une étude de cohorte prospective évaluant les associations entre le delirium, le dysfonctionnement cognitif postopératoire et le génotype de l’apolipoprotéine E après une chirurgie ouverte de l’aorte. Can. J. Anesth. Can. D’anesthésie 58, 246–255.

    Not in our library10.1007/s12630-010-9446-6

  29. 29.

    Brzezinski A. (1997 ). Melatonin in humans. N. Engl. J. Med. 336, 186–195.

    Not in our library10.1056/nejm199701163360306

  30. 30.

    Burkhart C. S. Dell-Kuster S. Gamberini M. Moeckli A. Grapow M. Filipovic M.. (2010 ). Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 24, 555–559.

    Not in our library10.1053/j.jvca.2010.01.003

  31. 31.

    Calne D. B. Mcgeer E. Eisen A. Spencer P. (1986 ). Alzheimer’s disease, Parkinson’s disease and motoneurone disease: abiotropic interaction between agening and environment? Lancet 328, 1067–1070.

    Not in our library10.1016/s0140-6736(86)90469-1

  32. 32.

    Cao L. Wang K. Gu T. Du B. Song J. (2014 ). Association between APOE epsilon 4 allele and postoperative cognitive dysfunction: a meta-analysis. Int. J. Neurosci. 124, 478–485.

    Not in our library10.3109/00207454.2013.860601

  33. 33.
    Cerebrospinal fluid markers of neuroinflammation in delirium: A role for interleukin-1β in delirium after hip fracture · 2014
    No notice
  34. 34.

    Carrié A. Jun L. Bienvenu T. Vinet M. C. McDonell N. Couvert P.. (1999 ). A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat. Genet. 23, 25–31.

    Not in our library10.1038/12623

  35. 35.

    Cerejeira J. Batista P. Nogueira V. Vaz-Serra A. Mukaetova-Ladinska E. B. (2013 ). The stress response to surgery and postoperative delirium: evidence of hypothalamic-pituitary-adrenal axis hyperresponsiveness and decreased suppression of the GH/IGF-1 Axis. J. Geriatr. Psychiatry Neurol. 26, 185–194.

    Not in our library10.1177/0891988713495449

  36. 36.

    Cerejeira J. M. S. Nogueira V. Luís P. Vaz-Serra A. Mukaetova-Ladinska E. B. (2012 ). The cholinergic system and inflammation: common pathways in delirium pathophysiology. J. Am. Geriatr. Soc. 60, 669–675.

    Not in our library10.1111/j.1532-5415.2011.03883.x

  37. 37.

    Chandel N. S. Trzyna W. C. McClintock D. S. Schumacker P. T. (2000 ). Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J. Immunol. 165, 1013–1021.

    Not in our library10.4049/jimmunol.165.2.1013

  38. 38.

    Chang K. A. Kim H. J. Suh Y. H. (2012 ). The role of S100a9 in the pathogenesis of Alzheimer’s disease: the therapeutic effects of S100a9 knockdown or knockout. Neurodegener. Dis. 10, 27–29.

    Not in our library10.1159/000333781

  39. 39.

    Chang Y.-L. Tsai Y.-F. Lin P.-J. Chen M.-C. Liu C.-Y. (2008 ). Prevalence and risk factors for postoperative delirium in a cardiovascular intensive care unit. Am. J. Crit. Care 17, 567–575.

    Not in our library

  40. 40.

    Cheng Q. Wang J. Wu A. Zhang R. Li L. Yue Y. (2013 ). Can urinary excretion rate of 8-isoprostrane and malonaldehyde predict postoperative cognitive dysfunction in aging? Neurol. Sci. 34, 1665–1669.

    Not in our library10.1007/s10072-013-1314-z

  41. 41.

    Chiaretti A. Piastra M. Polidori G. Di Rocco C. Caresta E. Antonelli A.. (2003 ). Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injury. Intensive Care Med. 29, 1329–1338.

    Not in our library10.1007/s00134-003-1852-6

  42. 42.

    Cho Y.-W. Motamedi G. K. Laufenberg I. Sohn S.-I. Lim J.-G. Lee H.. (2003 ). A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. Arch. Neurol. 60, 1625–1632.

    Not in our library10.1001/archneur.60.11.1625

  43. 43.

    Cibelli M. Fidalgo A. R. Terrando N. Ma D. Monaco C. Feldmann M.. (2010 ). Role of interleukin-1beta in postoperative cognitive dysfunction. Ann. Neurol. 68, 360–368.

    Not in our library10.1002/ana.22082

  44. 44.

    Colkesen Y. Giray S. Ozenli Y. Sezgin N. Coskun I. (2013 ). Relation of serum cortisol to delirium occurring after acute coronary syndromes. Am. J. Emerg. Med. 31, 161–165.

    Not in our library10.1016/j.ajem.2012.07.001

  45. 45.

    Cong W. N. Wang R. Cai H. Daimon C. M. Scheibye-Knudsen M. Bohr V. A.. (2013 ). Long-term artificial sweetener Acesulfame Potassium treatment alters neurometabolic functions in C57BL/6J mice. PLoS One 8:e70257.

    Not in our library10.1371/journal.pone.0070257

  46. 46.

    Control Prevention Centers for Disease (2010 ). National hospital discharge survey: procedures by selected patient characteristics. Number and percentage with and without procedures. CDC/NCHS Natl. Hosp. Disch. Surv. Available online at: http://www.cdc.gov/nchs/data/nhds/4procedures/2010pro_numberpercentage.pdf

    Not in our library

  47. 47.

    Costelloe C. Watson M. Murphy A. McQuillan K. Loscher C. Armstrong M. E.. (2008 ). IL-1F5 mediates anti-inflammatory activity in the brain through induction of IL-4 following interaction with SIGIRR/TIR8. J. Neurochem. 105, 1960–1969.

    Not in our library10.1111/j.1471-4159.2008.05304.x

  48. 48.

    Cras P. Kawai M. Lowery D. Gonzalez-DeWhitt P. Greenberg B. Perry G. (1991 ). Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc. Natl. Acad. Sci. U S A 88, 7552–7556.

    Not in our library10.1073/pnas.88.17.7552

  49. 49.

    Culley D. J. Baxter M. Yukhananov R. Crosby G. (2003 ). The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth. Analg. 96, 1004–1009.

    Not in our library10.1213/01.ane.0000052712.67573.12

  50. 50.

    Deguchi A. Soh J.-W. Li H. Pamukcu R. Thompson W. J. Weinstein I. B. (2002 ). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation provides a biomarker for the action of exisulind and related agents that activate protein kinase G. Mol. Cancer Ther. 1, 803–809.

    Not in our library

  51. 51.

    Deiner S. Silverstein J. H. (2009 ). Postoperative delirium and cognitive dysfunction. Br. J. Anaesth. 103(Suppl.), i41–i46.

    Not in our library10.1093/bja/aep291

  52. 52.

    de Jonghe A. van Munster B. C. Fekkes D. van Oosten H. E. de Rooij S. E. (2012 ). The tryptophan depletion theory in delirium: not confirmed in elderly hip fracture patients. Psychosomatics 53, 236–243.

    Not in our library10.1016/j.psym.2011.09.009

  53. 53.

    de Jonghe A. van Munster B. C. Goslings J. C. Kloen P. van Rees C. Wolvius R.. (2014 ). Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ 186, E547–E556.

    Not in our library10.1503/cmaj.140495

  54. 54.

    Dixson L. Walter H. Schneider M. Erk S. Schäfer A. Haddad L.. (2014 ). Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain. Proc. Natl. Acad. Sci. U S A 111, 9657–9662.

    Not in our library10.1073/pnas.1404082111

  55. 55.

    Drake P. M. Cho W. Li B. Prakobphol A. Johansen E. Anderson N. L.. (2010 ). Sweetening the pot: adding glycosylation to the biomarker discovery equation. Clin. Chem. 56, 223–236.

    Not in our library10.1373/clinchem.2009.136333

  56. 56.

    Eckert T. Tang C. Eidelberg D. (2007 ). Assessment of the progression of Parkinson’s disease: a metabolic network approach. Lancet Neurol. 6, 926–932.

    Not in our library10.1016/s1474-4422(07)70245-4

  57. 57.

    Elie M. Cole M. G. Primeau F. J. Bellavance F. (1998 ). Delirium risk factors in elderly hospitalized patients. J. Gen. Intern. Med. 13, 204–212.

    Not in our library10.1046/j.1525-1497.1998.00047.x

  58. 58.

    Ely E. W. Girard T. D. Shintani A. K. Jackson J. C. Gordon S. M. Thomason J. W. W.. (2007 ). Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit. Care Med. 35, 112–117.

    Not in our library10.1097/01.ccm.0000251925.18961.ca

  59. 59.

    Everitt B. J. Robbins T. W. (1997 ). Central cholinergic systems and cognition. Annu. Rev. Psychol. 48, 649–684.

    Not in our library10.1146/annurev.psych.48.1.649

  60. 60.

    Fasano A. (2011 ). Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity and cancer. Physiol. Rev. 91, 151–175.

    Not in our library10.1152/physrev.00003.2008

  61. 61.

    Fasano A. Not T. Wang W. Uzzau S. Berti I. Tommasini A.. (2000 ). Zonulin, a newly discovered modulator of intestinal permeability and its expression in coeliac disease. Lancet 355, 1518–1519.

    Not in our library10.1016/s0140-6736(00)02169-3

  62. 62.

    Feng Y. Niu T. Xing H. Xu X. Chen C. Peng S.. (2004 ). A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. Am. J. Hum. Genet. 75, 112–121.

    Not in our library10.1086/422194

  63. 63.

    Field R. H. Gossen A. Cunningham C. (2012 ). Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium. J. Neurosci. 32, 6288–6294.

    Not in our library10.1523/jneurosci.4673-11.2012

  64. 64.

    Finfer S. Chittock D. R. Su S. Y.-S. Blair D. Foster D. Dhingra V.. (2009 ). Intensive versus conventional glucose control in critically ill patients. N. Engl. J. Med. 360, 1283–1297.

    Not in our library10.1056/nejmoa0810625

  65. 65.

    Fisher A. (2008 ). Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease. Neurotherapeutics 5, 433–442.

    Not in our library10.1016/j.nurt.2008.05.002

  66. 66.

    Flacker J. M. Cummings V. Mach J. R. Bettin K. Kiely D. K. Wei J. (1998 ). The association of serum anticholinergic activity with delirium in elderly medical patients. Am. J. Geriatr. Psychiatry 6, 31–41.

    Not in our library10.1097/00019442-199800610-00005

  67. 67.

    Flacker J. M. Lipsitz L. A. (1999 ). Serum anticholinergic activity changes with acute illness in elderly medical patients. J. Gerontol. A Biol. Sci. Med. Sci. 54, M12–M16.

    Not in our library10.1093/gerona/54.1.m12

  68. 68.

    Foell D. Frosch M. Sorg C. Roth J. (2004 ). Phagocyte-specific calcium-binding S100 proteins as clinical laboratory markers of inflammation. Clin. Chim. Acta 344, 37–51.

    Not in our library10.1016/j.cccn.2004.02.023

  69. 69.

    Fox C. Smith T. Maidment I. Chan W.-Y. Bua N. Myint P. K.. (2014 ). Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. Age Ageing 43, 604–615.

    Not in our library10.1093/ageing/afu096

  70. 70.

    Frost R. A. Nystrom G. J. Lang C. H. (2003 ). Tumor necrosis factor-alpha decreases insulin-like growth factor-I messenger ribonucleic acid expression in C2C12 myoblasts via a Jun N-terminal kinase pathway. Endocrinology 144, 1770–1779.

    Not in our library10.1210/en.2002-220808

  71. 71.

    Fujita K. A. Ostaszewski M. Matsuoka Y. Ghosh S. Glaab E. Trefois C.. (2014 ). Integrating pathways of parkinson’s disease in a molecular interaction map. Mol. Neurobiol. 49, 88–102.

    Not in our library10.1007/s12035-013-8489-4

  72. 72.

    Girard T. D. Ware L. B. Bernard G. R. Pandharipande P. P. Thompson J. L. Shintani A. K.. (2012 ). Associations of markers of inflammation and coagulation with delirium during critical illness. Intensive Care Med. 38, 1965–1973.

    Not in our library10.1007/s00134-012-2678-x

  73. 73.

    Grandi C. Tomasi C. D. Fernandes K. Stertz L. Kapczinski F. Quevedo J.. (2011 ). Brain-derived neurotrophic factor and neuron-specific enolase, but not S100β, levels are associated to the occurrence of delirium in intensive care unit patients. J. Crit. Care 26, 133–137.

    Not in our library10.1016/j.jcrc.2010.10.006

  74. 74.

    Greene N. H. Attix D. K. Weldon B. C. Smith P. J. McDonagh D. L. Monk T. G. (2009 ). Measures of executive function and depression identify patients at risk for postoperative delirium. Anesthesiology 110, 788–795.

    Not in our library10.1097/aln.0b013e31819b5ba6

  75. 75.

    Gross A. L. Jones R. N. Habtemariam D. A. Fong T. G. Tommet D. Quach L.. (2012 ). Delirium and long-term cognitive trajectory among persons with dementia. Arch. Intern. Med. 172, 1324–1331.

    Not in our library10.1001/archinternmed.2012.3414

  76. 76.

    Gunther M. L. Morandi A. Krauskopf E. Pandharipande P. Girard T. D. Jackson J. C.. (2012 ). The association between brain volumes, delirium duration and cognitive outcomes in intensive care unit survivors. Crit. Care Med. 40, 2022–2032.

    Not in our library10.1097/ccm.0b013e318250acc0

  77. 77.

    Gutcher I. Urich E. Wolter K. Prinz M. Becher B. (2006 ). Interleukin 18-independent engagement of interleukin 18 receptor-alpha is required for autoimmune inflammation. Nat. Immunol. 7, 946–953.

    Not in our library10.1038/ni1377

  78. 78.

    Hasselmo M. E. (1995 ). Neuromodulation and cortical function: modeling the physiological basis of behavior. Behav. Brain Res. 67, 1–27.

    Not in our library10.1016/0166-4328(94)00113-t

  79. 79.

    Hatano Y. Narumoto J. Shibata K. Matsuoka T. Taniguchi S. Hata Y.. (2013 ). White-matter hyperintensities predict delirium after cardiac surgery. Am. J. Geriatr. Psychiatry 21, 938–945.

    Not in our library10.1016/j.jagp.2013.01.061

  80. 80.

    Hersch S. M. Gutekunst C. A. Rees H. D. Heilman C. J. Levey A. I. (1994 ). Distribution of m1–m4 muscarinic receptor proteins in the rat striatum: light and electron microscopic immunocytochemistry using subtype-specific antibodies. J. Neurosci. 14, 3351–3363.

    Not in our library10.1523/jneurosci.14-05-03351.1994

  81. 81.

    Hirose S. Iwata H. Akiyoshi H. Kobayashi K. Ito M. Wada K.. (1999 ). A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology 53, 1749–1753.

    Not in our library10.1212/wnl.53.8.1749

  82. 82.

    Hshieh T. T. Fong T. G. Marcantonio E. R. Inouye S. K. (2008 ). Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J. Gerontol. A Biol. Sci. Med. Sci. 63, 764–772.

    Not in our library10.1093/gerona/63.7.764

  83. 83.

    Huang E. J. Reichardt L. F. (2001 ). Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736.

    Not in our library10.1146/annurev.neuro.24.1.677

  84. 84.

    Huat T. J. Khan A. A. Pati S. Mustafa Z. Abdullah J. M. Jaafar H. (2014 ). IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells. BMC Neurosci. 15:91.

    Not in our library10.1186/1471-2202-15-91

  85. 85.

    Hudetz J. A. Gandhi S. D. Iqbal Z. Patterson K. M. Pagel P. S. (2011 ). Elevated postoperative inflammatory biomarkers are associated with short- and medium-term cognitive dysfunction after coronary artery surgery. J. Anesth. 25, 1–9.

    Not in our library10.1007/s00540-010-1042-y

  86. 86.

    Hudetz J. A. Patterson K. M. Byrne A. J. Pagel P. S. Warltier D. C. (2009 ). Postoperative delirium is associated with postoperative cognitive dysfunction at one week after cardiac surgery with cardiopulmonary bypass. Psychol. Rep. 105, 921–932.

    Not in our library10.2466/pr0.105.3.921-932

  87. 87.

    Ignatius M. J. Gebicke-Härter P. J. Skene J. H. Schilling J. W. Weisgraber K. H. Mahley R. W.. (1986 ). Expression of apolipoprotein E during nerve degeneration and regeneration. Proc. Natl. Acad. Sci. U S A 83, 1125–1129.

    Not in our library10.1073/pnas.83.4.1125

  88. 88.

    Inouye S. K. (2006 ). Delirium in older persons. N. Engl. J. Med. 354, 1157–1165.

    Not in our library10.1056/nejmra052321

  89. 89.

    Inouye S. K. van Dyck C. H. Alessi C. A. Balkin S. Siegal A. P. Horwitz R. I. (1990 ). Clarifying confusion: the confusion assessment method: a new method for detection of delirium. Ann. Intern. Med. 113, 941–948.

    Not in our library10.7326/0003-4819-113-12-941

  90. 90.

    Jackson J. C. Gordon S. M. Hart R. P. Hopkins R. O. Ely E. W. (2004 ). The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychol. Rev. 14, 87–98.

    Not in our library10.1023/b:nerv.0000028080.39602.17

  91. 91.

    Jin T. Hu L. S. Chang M. Wu J. Winblad B. Zhu J. (2007 ). Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients. Eur. J. Neurol. 14, 563–568.

    Not in our library10.1111/j.1468-1331.2007.01761.x

  92. 92.

    Kang J. Lemaire H. G. Unterbeck A. Salbaum J. M. Masters C. L. Grzeschik K. H.. (1987 ). The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736.

    Not in our library10.1038/325733a0

  93. 93.

    Karyekar C. S. Fasano A. Raje S. Lu R. Dowling T. C. Eddington N. D. (2003 ). Zonula occludens toxin increases the permeability of molecular weight markers and chemotherapeutic agents across the bovine brain microvessel endothelial cells. J. Pharm. Sci. 92, 414–423.

    Not in our library10.1002/jps.10310

  94. 94.

    Katan M. Christ-Crain M. (2010 ). The stress hormone copeptin: a new prognostic biomarker in acute illness. Swiss Med. Wkly. 140:w13101.

    Not in our library10.4414/smw.2010.13101

  95. 95.

    Kazmierski J. Banys A. Latek J. Bourke J. Jaszewski R. (2013 ). Cortisol levels and neuropsychiatric diagnosis as markers of postoperative delirium: a prospective cohort study. Crit. Care 17:R38.

    Not in our library10.1186/cc12548

  96. 96.

    Kazmierski J. Banys A. Latek J. Bourke J. Jaszewski R. (2014a ). Raised IL-2 and TNF-α concentrations are associated with postoperative delirium in patients undergoing coronary-artery bypass graft surgery. Int. Psychogeriatr. 26, 845–855.

    Not in our library10.1017/s1041610213002378

  97. 97.

    Kazmierski J. Banys A. Latek J. Bourke J. Jaszewski R. Sobow T.. (2014b ). Mild cognitive impairment with associated inflammatory and cortisol alterations as independent risk factor for postoperative delirium. Dement. Geriatr. Cogn. Disord. 38, 65–78.

    Not in our library10.1159/000357454

  98. 98.

    Khan B. A. Zawahiri M. Campbell N. L. Boustani M. A. (2011 ). Biomarkers for delirium–a review. J. Am. Geriatr. Soc. 59(Suppl. 2), S256–S261.

    Not in our library10.1111/j.1532-5415.2011.03702.x

  99. 99.

    Kohannim O. Hua X. Hibar D. P. Lee S. Chou Y.-Y. Y. Toga A. W.. (2010 ). Boosting power for clinical trials using classifiers based on multiple biomarkers. Neurobiol. Aging 31, 1429–1442.

    Not in our library10.1016/j.neurobiolaging.2010.04.022

  100. 100.

    Kong F.-J. Ma L.-L. Zhang H.-H. Zhou J.-Q. (2015 ). Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane-induced cognitive impairment in aged rats. J. Surg. Res. 194, 255–261.

    Not in our library10.1016/j.jss.2014.09.043

  101. 101.

    Koning J. P. Vehof J. Burger H. Wilffert B. Al Hadithy A. Alizadeh B.. (2012 ). Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients. Psychopharmacology (Berl) 219, 727–736.

    Not in our library10.1007/s00213-011-2394-1

  102. 102.

    Kosar C. M. Tabloski P. A. Travison T. G. Jones R. N. Schmitt E. M. Puelle M. R. (2014 ). Effect of preoperative pain and depressive symptoms on the risk of postoperative delirium: a prospective cohort study. Lancet Psychiatry 1, 431–436.

    Not in our library10.1016/s2215-0366(14)00006-6

  103. 103.

    Kowall N. W. Beal M. F. Busciglio J. Duffy L. K. Yankner B. A. (1991 ). An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. Proc. Natl. Acad. Sci. U S A 88, 7247–7251.

    Not in our library10.1073/pnas.88.16.7247

  104. 104.

    Kukreti R. Tripathi S. Bhatnagar P. Gupta S. Chauhan C. Kubendran S.. (2006 ). Association of DRD2 gene variant with schizophrenia. Neurosci. Lett. 392, 68–71.

    Not in our library10.1016/j.neulet.2005.08.059

  105. 105.

    Lambert N. M. Hartsough C. S. (1998 ). Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants. J. Learn. Disabil. 31, 533–544.

    Not in our library10.1177/002221949803100603

  106. 106.

    Le Y. Liu S. Peng M. Tan C. Liao Q. Duan K.. (2014 ). Aging differentially affects the loss of neuronal dendritic spine, neuroinflammation and memory impairment at rats after surgery. PLoS One 9:e106837.

    Not in our library10.1371/journal.pone.0106837

  107. 107.

    Lemstra A. W. Kalisvaart K. J. Vreeswijk R. van Gool W. A. Eikelenboom P. (2008 ). Pre-operative inflammatory markers and the risk of postoperative delirium in elderly patients. Int. J. Geriatr. Psychiatry 23, 943–948.

    Not in our library10.1002/gps.2015

  108. 108.

    Leung J. M. Sands L. P. Mullen E. A. Wang Y. Vaurio L. (2005 ). Are preoperative depressive symptoms associated with postoperative delirium in geriatric surgical patients? J. Gerontol. A Biol. Sci. Med. Sci. 60, 1563–1568.

    Not in our library10.1093/gerona/60.12.1563

  109. 109.

    Leung J. M. Sands L. P. Wang Y. Poon A. Kwok P. Kane J. P.. (2007 ). Apolipoprotein E e4 allele increases the risk of early postoperative delirium in older patients undergoing noncardiac surgery. Anesthesiology 107, 406–411.

    Not in our library10.1097/01.anes.0000278905.07899.df

  110. 110.

    Levey A. I. (1996 ). Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc. Natl. Acad. Sci. U S A 93, 13541–13546.

    Not in our library10.1073/pnas.93.24.13541

  111. 111.

    Li M. D. Beuten J. Ma J. Z. Payne T. J. Lou X.-Y. Garcia V.. (2005 ). Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum. Mol. Genet. 14, 1211–1219.

    Not in our library10.1093/hmg/ddi132

  112. 112.

    Li X. Wen D.-X. Zhao Y.-H. Hang Y.-N. Mandell M. S. (2013b ). Increase of beta-amyloid and C-reactive protein in liver transplant recipients with postoperative cognitive dysfunction. Hepatobiliary Pancreat. Dis. Int. 12, 370–376.

    Not in our library10.1016/s1499-3872(13)60058-2

  113. 113.

    Li Y. C. Xi C. H. An Y. F. Dong W. H. Zhou M. (2012 ). Perioperative inflammatory response and protein S-100β concentrations–relationship with post-operative cognitive dysfunction in elderly patients. Acta Anaesthesiol. Scand. 56, 595–600.

    Not in our library10.1111/j.1399-6576.2011.02616.x

  114. 114.

    Li R. L. Zhang Z. Z. Peng M. Wu Y. Zhang J. J. Wang C. Y.. (2013a ). Postoperative impairment of cognitive function in old mice: a possible role for neuroinflammation mediated by HMGB1, S100B and RAGE. J. Surg. Res. 185, 815–824.

    Not in our library10.1016/j.jss.2013.06.043

  115. 115.

    Lili X. Zhiyong H. Jianjun S. (2013 ). A preliminary study of the effects of ulinastatin on early postoperative cognition function in patients undergoing abdominal surgery. Neurosci. Lett. 541, 15–19.

    Not in our library10.1016/j.neulet.2013.02.008

  116. 116.

    Liu P. Li Y. Wang X. Zou X. Zhang D. Wang D.. (2013 ). High serum interleukin-6 level is associated with increased risk of delirium in elderly patients after noncardiac surgery: a prospective cohort study. Chin. Med. J. (Engl) 126, 3621–3627.

    Not in our library10.3760/cma.j.issn.0366-6999.20130211

  117. 117.

    Lu R. Wang W. Uzzau S. Vigorito R. Zielke H. R. Fasano A. (2000 ). Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain. J. Neurochem. 74, 320–326.

    Not in our library10.1046/j.1471-4159.2000.0740320.x

  118. 118.

    Lu S.-M. Yu C.-J. Liu Y.-H. Dong H.-Q. Zhang X. Zhang S.-S.. (2015 ). S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway. Brain Behav. Immun. 44, 221–234.

    Not in our library10.1016/j.bbi.2014.10.011

  119. 119.

    Lupien S. J. Gillin C. J. Hauger R. L. (1999 ). Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav. Neurosci. 113, 420–430.

    Not in our library10.1037/0735-7044.113.3.420

  120. 120.

    Macdonald A. Adamis D. Treloar A. Martin F. (2007 ). C-reactive protein levels predict the incidence of delirium and recovery from it. Age Ageing 36, 222–225.

    Not in our library10.1093/ageing/afl121

  121. 121.

    Mach J. R. Dysken M. W. Kuskowski M. Richelson E. Holden L. Jilk K. M. (1995 ). Serum anticholinergic activity in hospitalized older persons with delirium: a preliminary study. J. Am. Geriatr. Soc. 43, 491–495.

    Not in our library10.1111/j.1532-5415.1995.tb06094.x

  122. 122.

    Makoff A. J. Graham J. M. Arranz M. J. Forsyth J. Li T. Aitchison K. J.. (2000 ). Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson’s disease. Pharmacogenetics 10, 43–48.

    Not in our library10.1097/00008571-200002000-00006

  123. 123.

    Manenschijn L. van Rossum E. F. C. Jetten A. M. de Rooij S. E. van Munster B. C. (2011 ). Glucocorticoid receptor haplotype is associated with a decreased risk of delirium in the elderly. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 316–321.

    Not in our library10.1002/ajmg.b.31165

  124. 124.

    Mantovani A. Locati M. Polentarutti N. Vecchi A. Garlanda C. (2004 ). Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR. J. Leukoc. Biol. 75, 738–742.

    Not in our library10.1189/jlb.1003473

  125. 125.

    Mathew J. P. Grocott H. P. Phillips-Bute B. Stafford-Smith M. Laskowitz D. T. Rossignol D.. (2003 ). Lower endotoxin immunity predicts increased cognitive dysfunction in elderly patients after cardiac surgery. Stroke 34, 508–513.

    Not in our library10.1161/01.str.0000053844.09493.58

  126. 126.

    McAvay G. J. Van Ness P. H. Bogardus S. T. Zhang Y. Leslie D. L. Leo-Summers L. S.. (2007 ). Depressive symptoms and the risk of incident delirium in older hospitalized adults. J. Am. Geriatr. Soc. 55, 684–691.

    Not in our library10.1111/j.1532-5415.2007.01150.x

  127. 127.

    McDonagh D. L. Mathew J. P. White W. D. Phillips-Bute B. Laskowitz D. T. Podgoreanu M. V.. (2010 ). Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype and biomarkers of brain injury. Anesthesiology 112, 852–859.

    Not in our library10.1097/aln.0b013e3181d31fd7

  128. 128.

    Mick E. Kim J. W. Biederman J. Wozniak J. Wilens T. Spencer T.. (2008 ). Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3). Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1182–1185.

    Not in our library10.1002/ajmg.b.30745

  129. 129.

    Minden S. L. Carbone L. A. Barsky A. Borus J. F. Fife A. Fricchione G. L.. (2005 ). Predictors and outcomes of delirium. Gen. Hosp. Psychiatry 27, 209–214.

    Not in our library10.1016/j.genhosppsych.2004.12.004

  130. 130.

    Moller J. T. Cluitmans P. Rasmussen L. S. Houx P. Rasmussen H. Canet J.. (1998 ). Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 351, 857–861.

    Not in our library10.1016/s0140-6736(97)07382-0

  131. 131.

    Monk T. G. Weldon B. C. Garvan C. W. Dede D. E. van der Aa M. T. Heilman K. M.. (2008 ). Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 108, 18–30.

    Not in our library10.1097/01.anes.0000296071.19434.1e

  132. 132.

    Muglia P. Vicente A. M. Verga M. King N. Macciardi F. Kennedy J. L. (2003 ). Association between the BDNF gene and schizophrenia. Mol. Psychiatry 8, 146–147.

    Not in our library10.1038/sj.mp.4001221

  133. 133.

    Mussi C. Ferrari R. Ascari S. Salvioli G. (1999 ). Importance of serum anticholinergic activity in the assessment of elderly patients with delirium. J. Geriatr. Psychiatry Neurol. 12, 82–86.

    Not in our library10.1177/089198879901200208

  134. 134.

    Newman M. F. Kirchner J. L. Phillips-Bute B. Gaver V. Grocott H. Jones R. H.. (2001 ). Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N. Engl. J. Med. 344, 395–402.

    Not in our library10.1056/nejm200102083440601

  135. 135.

    Norton P. A. Comunale M. A. Krakover J. Rodemich L. Pirog N. D’Amelio A.. (2008 ). N-linked glycosylation of the liver cancer biomarker GP73. J. Cell. Biochem. 104, 136–149.

    Not in our library10.1002/jcb.21610

  136. 136.

    Ojala J. Alafuzoff I. Herukka S. K. van Groen T. Tanila H. Pirttilä T. (2009 ). Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol. Aging 30, 198–209.

    Not in our library10.1016/j.neurobiolaging.2007.06.006

  137. 137.

    Olivecrona Z. Koskinen L. O. D. (2012 ). The release of S-100B and NSE in severe traumatic head injury is associated with APOE ε4. Acta Neurochir. (Wien) 154, 675–680.

    Not in our library10.1007/s00701-012-1292-6

  138. 138.

    Pandharipande P. P. Morandi A. Adams J. R. Girard T. D. Thompson J. L. Shintani A. K.. (2009 ). Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med. 35, 1886–1892.

    Not in our library10.1007/s00134-009-1573-6

  139. 139.

    Papadopoulou E. Davilas E. Sotiriou V. Georgakopoulos E. Georgakopoulou S. Koliopanos A.. (2006 ). Cell-free DNA and RNA in plasma as a new molecular marker for prostate and breast cancer. Ann. N Y Acad. Sci. 1075, 235–243.

    Not in our library10.1196/annals.1368.032

  140. 140.

    Pearson-Leary J. McNay E. C. (2012 ). Intrahippocampal administration of amyloid-β(1–42) oligomers acutely impairs spatial working memory, insulin signaling and hippocampal metabolism. J. Alzheimers Dis. 30, 413–422.

    Not in our library10.3233/jad-2012-112192

  141. 141.

    Pepys M. B. Hirschfield G. M. (2003 ). C-reactive protein: a critical update. J. Clin. Invest. 111, 1805–1812.

    Not in our library10.1172/jci18921

  142. 142.

    Perroud N. Paoloni-Giacobino A. Prada P. Olié E. Salzmann A. Nicastro R.. (2011 ). Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl. Psychiatry 1:e59.

    Not in our library10.1038/tp.2011.60

  143. 143.
    Cerebral perfusion in sepsis-associated delirium · 2008
    No notice
  144. 144.

    Plaschke K. Hill H. Engelhardt R. Thomas C. Von Haken R. Scholz M.. (2007a ). EEG changes and serum anticholinergic activity measured in patients with delirium in the intensive care unit. Anaesthesia 62, 1217–1223.

    Not in our library10.1111/j.1365-2044.2007.05255.x

  145. 145.

    Plaschke K. Thomas C. Engelhardt R. Teschendorf P. Hestermann U. Weigand M. A.. (2007b ). Significant correlation between plasma and CSF anticholinergic activity in presurgical patients. Neurosci. Lett. 417, 16–20.

    Not in our library10.1016/j.neulet.2007.02.015

  146. 146.

    Pol R. A. van Leeuwen B. L. Izaks G. J. Reijnen M. M. P. J. Visser L. Tielliu I. F. J.. (2014 ). C-reactive protein predicts postoperative delirium following vascular surgery. Ann. Vasc. Surg. 28, 1923–1930.

    Not in our library10.1016/j.avsg.2014.07.004

  147. 147.

    Praticò C. Quattrone D. Lucanto T. Amato A. Penna O. Roscitano C.. (2005 ). Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium. Med. Hypotheses 65, 972–982.

    Not in our library10.1016/j.mehy.2005.05.037

  148. 148.

    Ramlawi B. Rudolph J. L. Mieno S. Feng J. Boodhwani M. Khabbaz K.. (2006 ). C-Reactive protein and inflammatory response associated to neurocognitive decline following cardiac surgery. Surgery 140, 221–226.

    Not in our library10.1016/j.surg.2006.03.007

  149. 149.

    Rasmussen L. S. Christiansen M. Rasmussen H. Kristensen P. A. Moller J. T. (2000 ). Do blood concentrations of neurone specific enolase and S-100 beta protein reflect cognitive dysfunction after abdominal surgery? ISPOCD group. Br. J. Anaesth. 84, 242–244.

    Not in our library10.1093/oxfordjournals.bja.a013410

  150. 150.

    Renard P. Zachary M. D. Bougelet C. Mirault M. E. Haegeman G. Remacle J.. (1997 ). Effects of antioxidant enzyme modulations on interleukin-1-induced nuclear factor kappa B activation. Biochem. Pharmacol. 53, 149–160.

    Not in our library10.1016/s0006-2952(96)00645-4

  151. 151.

    Rentowl P. Hanning C. D. (2004 ). Odour identification as a marker for postoperative cognitive dysfunction: a pilot study. Anaesthesia 59, 337–343.

    Not in our library10.1111/j.1365-2044.2004.03678.x

  152. 152.

    Rezvani A. H. Levin E. D. (2001 ). Cognitive effects of nicotine. Biol. Psychiatry 49, 258–267.

    Not in our library10.1016/s0006-3223(00)01094-5

  153. 153.

    Ritchie C. W. Newman T. H. Leurent B. Sampson E. L. (2014 ). The association between C-reactive protein and delirium in 710 acute elderly hospital admissions. Int. Psychogeriatr. 26, 717–724.

    Not in our library10.1017/s1041610213002433

  154. 154.

    Robinson T. N. Raeburn C. D. Angles E. M. Moss M. (2008 ). Low tryptophan levels are associated with postoperative delirium in the elderly. Am. J. Surg. 196, 670–674.

    Not in our library10.1016/j.amjsurg.2008.07.007

  155. 155.

    Robinson T. N. Raeburn C. D. Tran Z. V. Angles E. M. Brenner L. A. Moss M. (2009 ). Postoperative delirium in the elderly: risk factors and outcomes. Ann. Surg. 249, 173–178.

    Not in our library10.1097/sla.0b013e31818e4776

  156. 156.

    Root J. C. Pryor K. O. Downey R. Alici Y. Davis M. L. Holodny A.. (2013 ). Association of pre-operative brain pathology with post-operative delirium in a cohort of non-small cell lung cancer patients undergoing surgical resection. Psychooncology 22, 2087–2094.

    Not in our library10.1002/pon.3262

  157. 157.

    Rothenburger M. Soeparwata R. Deng M. C. Berendes E. Schmid C. Tjan T. D. T.. (2001 ). The impact of anti-endotoxin core antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery. J. Am. Coll. Cardiol. 38, 124–130.

    Not in our library10.1016/s0735-1097(01)01323-7

  158. 158.

    Rudolph J. L. Marcantonio E. R. Culley D. J. Silverstein J. H. Rasmussen L. S. Crosby G. J.. (2008a ). Delirium is associated with early postoperative cognitive dysfunction. Anaesthesia 63, 941–947.

    Not in our library10.1111/j.1365-2044.2008.05523.x

  159. 159.

    Rudolph J. L. Ramlawi B. Kuchel G. A. McElhaney J. E. Xie D. Sellke F. W.. (2008b ). Chemokines are associated with delirium after cardiac surgery. J. Gerontol. A Biol. Sci. Med. Sci. 63, 184–189.

    Not in our library10.1093/gerona/63.2.184

  160. 160.

    Sag D. Carling D. Stout R. D. Suttles J. (2008 ). Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633–8641.

    Not in our library10.4049/jimmunol.181.12.8633

  161. 161.

    Salani F. Ciaramella A. Bizzoni F. Assogna F. Caltagirone C. Spalletta G.. (2013 ). Increased expression of Interleukin-18 receptor in blood cells of subjects with mild cognitive impairment and Alzheimer’s disease. Cytokine 61, 360–363.

    Not in our library10.1016/j.cyto.2012.11.001

  162. 162.

    Salminen A. Hyttinen J. M. T. Kaarniranta K. (2011 ). AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J. Mol. Med. (Berl.) 89, 667–676.

    Not in our library10.1007/s00109-011-0748-0

  163. 163.

    Scherzer C. R. Eklund A. C. Morse L. J. Liao Z. Locascio J. J. Fefer D.. (2007 ). Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc. Natl. Acad. Sci. U S A 104, 955–960.

    Not in our library10.1073/pnas.0610204104

  164. 164.

    Shalev H. Serlin Y. Friedman A. (2009 ). Breaching the blood-brain barrier as a gate to psychiatric disorder. Cardiovasc. Psychiatry Neurol. 2009:278531.

    Not in our library10.1155/2009/278531

  165. 165.

    Shcheglovitov A. Shcheglovitova O. Yazawa M. Portmann T. Shu R. Sebastiano V.. (2013 ). SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503, 267–271.

    Not in our library10.1038/nature12618

  166. 166.

    Shigeta H. Yasui A. Nimura Y. Machida N. Kageyama M. Miura M.. (2001 ). Postoperative delirium and melatonin levels in elderly patients. Am. J. Surg. 182, 449–454.

    Not in our library10.1016/s0002-9610(01)00761-9

  167. 167.

    Siddiqui S. Fang M. Ni B. Lu D. Martin B. Maudsley S. (2012 ). Central role of the EGF receptor in neurometabolic aging. Int. J. Endocrinol. 2012:739428.

    Not in our library10.1155/2012/739428

  168. 168.

    Soininen H. Lehtovirta M. Helisalmi S. Linnaranta K. Heinonen O. Riekkinen P. (1995 ). Increased acetylcholinesterase activity in the CSF of Alzheimer patients carrying apolipoprotein epsilon4 allele. Neuroreport 6, 2518–2520.

    Not in our library10.1097/00001756-199512150-00017

  169. 169.

    Sørensen K. D. Ørntoft T. F. (2010 ). Discovery of prostate cancer biomarkers by microarray gene expression profiling. Expert Rev. Mol. Diagn. 10, 49–64.

    Not in our library10.1586/erm.09.74

  170. 170.

    Stefano G. B. Bilfinger T. V. Fricchione G. L. (1994 ). The immune-neuro-link and the macrophage: postcardiotomy delirium, HIV-associated dementia and psychiatry. Prog. Neurobiol. 42, 475–488.

    Not in our library10.1016/0301-0082(94)90048-5

  171. 171.

    Steinmetz J. Christensen K. B. Lund T. Lohse N. Rasmussen L. S. ISPOCD Group (2009 ). Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110, 548–555.

    Not in our library10.1097/aln.0b013e318195b569

  172. 172.

    Stoicea N. McVicker S. Quinones A. Agbenyefia P. Bergese S. D. (2014 ). Delirium-biomarkers and genetic variance. Front. Pharmacol. 5:75.

    Not in our library10.3389/fphar.2014.00075

  173. 173.

    Sunwoo M. K. Hong J. Y. Choi J. Park H. J. Kim S. H. Lee P. H. (2013 ). β-Synuclein pathology is related to postoperative delirium in patients undergoing gastrectomy. Neurology 80, 810–813.

    Not in our library10.1212/wnl.0b013e3182840782

  174. 174.
    Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells · 2012
    No notice
  175. 175.

    Takeoka T. Shinohara Y. Furumi K. Mori K. (1983 ). Impairment of blood-cerebrospinal fluid barrier in multiple sclerosis. J. Neurochem. 41, 1102–1108.

    Not in our library10.1111/j.1471-4159.1983.tb09058.x

  176. 176.

    Tanzi R. E. Gusella J. F. Watkins P. C. Bruns G. A. St George-Hyslop P. Van Keuren M. L.. (1987 ). Amyloid beta protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus. Science 235, 880–884.

    Not in our library10.1126/science.2949367

  177. 177.

    Teixeira A. L. Barbosa I. G. Diniz B. S. Kummer A. (2010 ). Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark. Med. 4, 871–887.

    Not in our library10.2217/bmm.10.111

  178. 178.

    Terrando N. Eriksson L. I. Kyu Ryu J. Yang T. Monaco C. Feldmann M.. (2011 ). Resolving postoperative neuroinflammation and cognitive decline. Ann. Neurol. 70, 986–995.

    Not in our library10.1002/ana.22664

  179. 179.

    Terrando N. Monaco C. Ma D. Foxwell B. M. J. Feldmann M. Maze M. (2010 ). Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc. Natl. Acad. Sci. U S A 107, 20518–20522.

    Not in our library10.1073/pnas.1014557107

  180. 180.

    Thomassen E. Renshaw B. R. Sims J. E. (1999 ). Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11, 389–399.

    Not in our library10.1006/cyto.1998.0452

  181. 181.

    Tian A. Ma H. Cao X. Zhang R. Wang X. Wu B. (2015 ). Vitamin D improves cognitive function and modulates Th17/T reg cell balance after hepatectomy in mice. Inflammation 38, 500–509.

    Not in our library10.1007/s10753-014-9956-4

  182. 182.

    Tilvis R. S. Kähönen-Väre M. H. Jolkkonen J. Valvanne J. Pitkala K. H. Strandberg T. E. (2004 ). Predictors of cognitive decline and mortality of aged people over a 10-year period. J. Gerontol. A Biol. Sci. Med. Sci. 59, 268–274.

    Not in our library10.1093/gerona/59.3.m268

  183. 183.

    Trzepacz P. T. (2000 ). Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin. Clin. Neuropsychiatry 5, 132–148.

    Not in our library

  184. 184.

    Tsai T. L. Sands L. P. Leung J. M. (2010 ). An update on postoperative cognitive dysfunction. Adv. Anesth. 28, 269–284.

    Not in our library10.1016/j.aan.2010.09.003

  185. 185.

    Tune L. E. Damlouji N. F. Holland A. Gardner T. J. Folstein M. F. Coyle J. T. (1981 ). Association of postoperative delirium with raised serum levels of anticholinergic drugs. Lancet 2, 651–653.

    Not in our library10.1016/s0140-6736(81)90994-6

  186. 186.
    Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients · 2011
    No notice
  187. 187.

    van der Mast R. C. van den Broek W. W. Fekkes D. Pepplinkhuizen L. Habbema J. D. (2000 ). Is delirium after cardiac surgery related to plasma amino acids and physical condition? J. Neuropsychiatry Clin. Neurosci. 12, 57–63.

    Not in our library10.1176/jnp.12.1.57

  188. 188.

    van Gool W. A. van de Beek D. Eikelenboom P. (2010 ). Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375, 773–775.

    Not in our library10.1016/s0140-6736(09)61158-2

  189. 189.

    van Munster B. C. Aronica E. Zwinderman A. H. Eikelenboom P. Cunningham C. de Rooij S. E. J. (2011a ). Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation Res. 14, 615–622.

    Not in our library10.1089/rej.2011.1185

  190. 190.

    van Munster B. C. Bisschop P. H. Zwinderman A. H. Korevaar J. C. Endert E. Wiersinga W. J.. (2010a ). Cortisol, interleukins and S100B in delirium in the elderly. Brain Cogn. 74, 18–23.

    Not in our library10.1016/j.bandc.2010.05.010

  191. 191.

    van Munster B. C. de Rooij S. E. J. A. Yazdanpanah M. Tienari P. J. Pitkälä K. H. Osse R. J.. (2010b ). The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B, 648–655.

    Not in our library10.1002/ajmg.b.31034

  192. 192.

    van Munster B. C. Korevaar J. C. Korse C. M. Bonfrer J. M. Zwinderman A. H. de Rooij S. E. (2010c ). Serum S100B in elderly patients with and without delirium. Int. J. Geriatr. Psychiatry 25, 234–239.

    Not in our library10.1002/gps.2326

  193. 193.

    van Munster B. C. Korevaar J. C. Zwinderman A. H. Leeflang M. M. de Rooij S. E. J. A. (2009a ). The association between delirium and the apolipoprotein E epsilon 4 allele: new study results and a meta-analysis. Am. J. Geriatr. Psychiatry 17, 856–862.

    Not in our library10.1097/jgp.0b013e3181ab8c84

  194. 194.

    van Munster B. C. Korevaar J. C. Zwinderman A. H. Levi M. Wiersinga W. J. De Rooij S. E. (2008 ). Time-course of cytokines during delirium in elderly patients with hip fractures. J. Am. Geriatr. Soc. 56, 1704–1709.

    Not in our library10.1111/j.1532-5415.2008.01851.x

  195. 195.

    van Munster B. C. Korse C. M. de Rooij S. E. Bonfrer J. M. Zwinderman A. H. Korevaar J. C. (2009b ). Markers of cerebral damage during delirium in elderly patients with hip fracture. BMC Neurol. 9:21.

    Not in our library10.1186/1471-2377-9-21

  196. 196.

    van Munster B. C. Thomas C. Kreisel S. H. Brouwer J. P. Nanninga S. Kopitz J.. (2012 ). Longitudinal assessment of serum anticholinergic activity in delirium of the elderly. J. Psychiatr. Res. 46, 1339–1345.

    Not in our library10.1016/j.jpsychires.2012.06.015

  197. 197.

    van Munster B. C. Yazdanpanah M. Tanck M. W. T. de Rooij S. E. J. A. Van De Giessen E. Sijbrands E. J. G.. (2010d ). Genetic polymorphisms in the DRD2, DRD3 and SLC6A3 gene in elderly patients with delirium. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 153, 38–45.

    Not in our library10.1002/ajmg.b.30943

  198. 198.

    van Munster B. C. Zwinderman A. H. de Rooij S. E. (2011b ). Genetic variations in the interleukin-6 and interleukin-8 genes and the interleukin-6 receptor gene in delirium. Rejuvenation Res. 14, 425–428.

    Not in our library10.1089/rej.2011.1155

  199. 199.

    Volkow N. D. Gur R. C. Wang G. J. Fowler J. S. Moberg P. J. Ding Y. S.. (1998 ). Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am. J. Psychiatry 155, 344–349.

    Not in our library10.1176/ajp.155.3.344

  200. 200.

    Volpicelli L. A. Levey A. I. (2004 ). Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog. Brain Res. 145, 59–66.

    Not in our library10.1016/s0079-6123(03)45003-6

  201. 201.

    Vom Berg J. Prokop S. Miller K. R. Obst J. Kälin R. E. Lopategui-Cabezas I.. (2012 ). Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 18, 1812–1819.

    Not in our library10.1038/nm.2965

  202. 202.

    Wagner M. Schulze-Rauschenbach S. Petrovsky N. Brinkmeyer J. von der Goltz C. Gründer G.. (2013 ). Neurocognitive impairments in non-deprived smokers–Results from a population-based multi-center study on smoking-related behavior. Addict. Biol. 18, 752–761.

    Not in our library10.1111/j.1369-1600.2011.00429.x

  203. 203.

    Wald D. Qin J. Zhao Z. Qian Y. Naramura M. Tian L.. (2003 ). SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat. Immunol. 4, 920–927.

    Not in our library10.1038/ni968

  204. 204.

    Wan C. La Y. Zhu H. Yang Y. Jiang L. Chen Y.. (2007 ). Abnormal changes of plasma acute phase proteins in schizophrenia and the relation between schizophrenia and haptoglobin (Hp) gene. Amino Acids 32, 101–108.

    Not in our library10.1007/s00726-005-0292-8

  205. 205.

    Wan Y. Xu J. Meng F. Bao Y. Ge Y. Lobo N.. (2010 ). Cognitive decline following major surgery is associated with gliosis, β-amyloid accumulation and τ phosphorylation in old mice. Crit. Care Med. 38, 2190–2198.

    Not in our library10.1097/ccm.0b013e3181f17bcb

  206. 206.

    Wang Y. He H. Li D. Zhu W. Duan K. Le Y.. (2013 ). The role of the TLR4 signaling pathway in cognitive deficits following surgery in aged rats. Mol. Med. Rep. 7, 1137–1142.

    Not in our library10.3892/mmr.2013.1322

  207. 207.

    Wang X. Yu J. Sreekumar A. Varambally S. Shen R. Giacherio D.. (2005 ). Autoantibody signatures in prostate cancer. N. Engl. J. Med. 353, 1224–1235.

    Not in our library10.1056/nejmoa051931

  208. 208.

    Wenk G. L. (2003 ). Neuropathologic changes in Alzheimer’s disease. J. Clin. Psychiatry 64, 7–10.

    Not in our library

  209. 209.

    Wessel J. McDonald S. M. Hinds D. A. Stokowski R. P. Javitz H. S. Kennemer M.. (2010 ). Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerström test for nicotine dependence. Neuropsychopharmacology 35, 2392–2402.

    Not in our library10.1038/npp.2010.120

  210. 210.

    Willard B. Hauss-Wegrzyniak B. Wenk G. L. (1999 ). Pathological and biochemical consequences of acute and chronic neuroinflammation within the basal forebrain cholinergic system of rats. Neuroscience 88, 193–200.

    Not in our library10.1016/s0306-4522(98)00216-4

  211. 211.

    Wilson K. Broadhurst C. Diver M. Jackson M. Mottram P. (2005 ). Plasma insulin growth factor-1 and incident delirium in older people. Int. J. Geriatr. Psychiatry 20, 154–159.

    Not in our library10.1002/gps.1265

  212. 212.

    Winterer G. (2010 ). Why do patients with schizophrenia smoke? Curr. Opin. Psychiatry 23, 112–119.

    Not in our library10.1097/yco.0b013e3283366643

  213. 213.

    Winterer G. Mittelstrass K. Giegling I. Lamina C. Fehr C. Brenner H.. (2010 ). Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153, 1448–1458.

    Not in our library10.1002/ajmg.b.31126

  214. 214.

    Winterer G. Musso F. Konrad A. Vucurevic G. Stoeter P. Sander T.. (2007 ). Association of attentional network function with exon 5 variations of the CHRNA4 gene. Hum. Mol. Genet. 16, 2165–2174.

    Not in our library10.1093/hmg/ddm168

  215. 215.

    Wu Y. Wang J. Wu A. Yue Y. (2014 ). Do fluctuations in endogenous melatonin levels predict the occurrence of postoperative cognitive dysfunction (POCD)? Int. J. Neurosci. 124, 787–791.

    Not in our library10.3109/00207454.2014.882919

  216. 216.

    Xie P. Kranzler H. R. Krauthammer M. Cosgrove K. P. Oslin D. Anton R. F.. (2011 ). Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biol. Psychiatry 70, 528–536.

    Not in our library10.1016/j.biopsych.2011.04.017

  217. 217.

    Yaffe K. Kanaya A. Lindquist K. Simonsick E. M. Harris T. Shorr R. I.. (2004 ). The metabolic syndrome, inflammation and risk of cognitive decline. JAMA 292, 2237–2242.

    Not in our library10.1001/jama.292.18.2237

  218. 218.

    Yang Y.-R. Liu S.-L. Qin Z.-Y. Liu F.-J. Qin Y.-J. Bai S.-M.. (2008 ). Comparative proteomics analysis of cerebrospinal fluid of patients with Guillain-Barré syndrome. Cell. Mol. Neurobiol. 28, 737–744.

    Not in our library10.1007/s10571-007-9257-7

  219. 219.

    Yoshitaka S. Egi M. Morimatsu H. Kanazawa T. Toda Y. Morita K. (2013 ). Perioperative plasma melatonin concentration in postoperative critically ill patients: its association with delirium. J. Crit. Care 28, 236–242.

    Not in our library10.1016/j.jcrc.2012.11.004

  220. 220.

    Zhang Y.-H. Guo X.-H. Zhang Q.-M. Yan G.-T. Wang T.-L. (2014a ). Serum CRP and urinary trypsin inhibitor implicate postoperative cognitive dysfunction especially in elderly patients. Int. J. Neurosci. [Epub ahead of print].

    Not in our library10.3109/00207454.2014.949341

  221. 221.

    Zhang Z. Pan L. Deng H. Ni H. Xu X. (2014b ). Prediction of delirium in critically ill patients with elevated C-reactive protein. J. Crit. Care 29, 88–92.

    Not in our library10.1016/j.jcrc.2013.09.002

Cited by papers we hold 9

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.