Hereditary vulnerabilities to post-operative cognitive dysfunction and dementia

Progress in Neuro-Psychopharmacology & Biological Psychiatry 47 (2013) 128–134

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Hereditary vulnerabilities to post-operative cognitive dysfunction and dementia☆ Kirk J. Hogan ⁎ Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, B6/319 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792, USA

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Article history: Received 5 November 2012 Received in revised form 26 February 2013 Accepted 27 February 2013 Available online 3 April 2013 Keywords: Alzheimer's disease Epigenetics Genotype Post-operative cognitive function Post-operative dementia Surgery

a b s t r a c t In view of multiple prospective investigations reporting an incidence of 10% or greater in elderly patients after cardiac and non-cardiac procedures, it is surprising that no families, twins or even individual cases have been reported with persistent post-operative cognitive dysfunction (POCD) or post-operative dementia (POD) that is otherwise unexplained. As POCD and POD research has shifted in recent years from surgical and anesthetic variables to predictors of intrinsic, patient-specific susceptibility, a number of markers based on DNA sequence variation have been investigated. Nevertheless, no heritable, genomic indices of persistent POCD or post-operative dementia lasting 3 months or longer after surgery have been identified to date. The present manuscript surveys challenges confronting the search for markers of heritable vulnerability to POCD and POD, and proposes steps forward to be taken now, including the addition of surgical and anesthetic descriptors to ongoing longitudinal dementia protocols and randomized clinical trials (RCTs) comprising serial psychometric testing, and a fresh focus on phenotypes and genotypes shared between outliers with “extreme” POCD and POD traits. © 2013 Elsevier Inc. All rights reserved.

1. Introduction No heritable, genomic predictors of persistent post-operative cognitive dysfunction (POCD) or post-operative dementia (POD) lasting 3 months or longer have been identified to date. Clearly, most patients do not exhibit cognitive decline after surgery, and some doubt the existence of either phenotype (Avidan and Evers, 2011; Avidan et al., 2009; Selnes et al., 2012). For those who recognize POCD and POD phenotypes, differential susceptibility is the best contemporary evidence pointing to possible genetic predispositions to long-lasting neuropsychological changes after surgery. In the present manuscript, efforts to detect genotypes that correlate with decrements in high-order brain performance, for example, impaired verbal, visuo-spatial, and semantic scores, worsened secondary and implicit memory, learning, problem-solving, and emotional instability after operative procedures in the absence of recognized anatomic (e.g. elevated intracranial pressure), vascular, metabolic, or drug-related changes are considered, and suggestions for advancing further toward this goal are provided. 1.1. Definitions Two overlapping post-operative cognitive syndromes may arise from distinct experimental protocols. To test whether “POCD” is caused by Abbreviations: POCD, post-operative cognitive dysfunction; POD, post-operative dementia; aMCI, amnestic minimal cognitive impairment; MH, malignant hyperthermia; RCT, randomized clinical trial; MMSE, Minnesota Mental Status Exam; CAM, Confusion Assessment Method. ☆ This manuscript was screened for plagiarism using Article Checker. ⁎ Tel.: +1 608 263 8100; fax: +1 608 263 0575. E-mail address: [email protected]. 0278-5846/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2013.02.018

surgery, baseline psychometric testing of participants who are cognitively normal is performed before a scheduled procedure, and at fixed intervals such as 1 day, 1 week, 1 month, 3 months, 1 year or longer thereafter. Control participants may be those in good health, those with shared disorders that are medically managed, or both, who are otherwise matched for age, education, gender, lack of pre-operative mental deficits, and other variables of interest including surgical and anesthetic management. “POD” is used herein to refer to post-operative dementia observed in weeks to months after an operation, and does not refer to post-operative delirium that resolves within days of a surgical procedure. To test whether surgery hastens the onset and speeds the progression of POD, surgical and anesthetic variables are recorded in longitudinal investigations that model the time course of dementia in susceptible and control populations through psychometric evaluation at fixed intervals. Accordingly, neuropsychological testing in POCD protocols is in-phase with surgery, whereas neuropsychological testing in POD protocols is not in-phase with surgery. As used herein, “surgery” refers to surgery and anesthesia, and “anesthesia” refers to general and regional anesthesia unless otherwise indicated. “Genotype” refers to genomic and mitochondrial DNA sequence variations, and to heritable DNA modifications without sequence variation also known as “epigenotypes”, unless otherwise indicated. 1.2. Context Three questions addressing hereditary vulnerabilities to postoperative dementia may be articulated: 1. Do genotypes predict those at risk for POCD? 2. Do genotypes predict those at risk for POD? 3. Do genotypes resolve the relationship between POCD and POD?

K.J. Hogan / Progress in Neuro-Psychopharmacology & Biological Psychiatry 47 (2013) 128–134

While superficially simple, these questions are deceptively complex. A first issue is that both POCD and POD are syndromes, not diseases, with overlapping signs and symptoms and multifactorial etiologies that are disparate within and between the two conditions. It may therefore be more accurate to refer to the post-operative cognitive dysfunctions and dementias. In turn, the most prominent component of POD, Alzheimer's “disease”, is itself a multifactorial syndrome comprising numerous monogenic and polygenic causes, acquired contributors and associations, predisposing conditions and disorders, prodromal syndromes including amnestic minimal cognitive impairment (aMCI), partially predictive biomarkers, and diverse clinical pathways (Cruchaga et al., 2012). These considerations are crucial to weigh in the design, conduct and interpretation of investigations aimed at disclosing novel POCD and POD genotype: phenotype correlations. Mapping heterogeneous syndromes rather than well-defined traits to DNA sequence variations is fraught with deadends and misallocated resources. A second issue is that each of us will become demented if we live long enough. Extraordinarily few centenarians are able to work (e.g., as peri-operative caregivers) and to fully care for themselves because of cognitive deficits in the absence of other crippling conditions. Thus, post-operative cognitive phenotypes of interest to surgeons, anesthesiologists, patients, family members, third party payers, the personal injury bar, government, and other stakeholders are not the “risk” or incidence of dementia after surgery per se, but the age of onset, clinical spectrum, severity and rate of progression of cognitive descent. The challenge of quantifying POCD and POD phenotypes, if they are as real as numerous prospective investigations attest (Abildstrom et al., 2000; Ballard et al., 2012; Canet et al., 2003; Johnson et al., 2002; Moller et al., 1998; Monk et al., 2008; Price et al., 2008; Rasmussen et al., 2003; Steinmetz et al., 2009; Stygall et al., 2003) is warranted by consideration of the phenotype itself comprising loss of one's identity while alive, and the number of patients who may be predisposed with millions of elders undergoing elective and emergent procedures each year. Nevertheless, even so transparent a phenotype as the age of dementia onset is elusive to determine with precision from the patient, caregivers or third party historians (e.g., spouses), laboratory testing or medical records in the absence of high frequency psychometric testing, and for this reason its exact derivation is a crucial variable that is often glossed over by authors, reviewers and editors. If genotypes that reliably predict POCD and POD are identified, their clinical utility will be difficult to over-state. Discrete heritable biomarkers of POCD and POD susceptibility will refine knowledge of the incidence, etiology and relationship between the syndromes, support informed consent in clinical and research settings, denote novel preventive and therapeutic interventions, and improve counseling to probands and family members. Modern technologies able to discriminate DNA sequence variations exhibit exceptional analytical validity, low cost and breath-taking speed. However, detection of heritable vulnerabilities arising from epigenetic DNA modifications consisting of variation in DNA methylation, histone modifications, chromatin conformation, noncoding RNAs, etc. remains a technical frontier (Section 6 below). Whereas genomic variation in the cellular elements of the nervous system are for the most part shared with those observed in easily accessible circulating lymphocytes and cheek fibroblasts, the extent of sharing of epigenetic marks between tissues of different embryonic origin and fate is presently unresolved. Despite high potential levels of clinical utility and analytical validity of genomic hereditary biomarkers, their clinical validity, that is, the ability of a genotype to predict a phenotype of interest, has yet to be established for a first DNA-based predictor of persistent POCD or POD. 2. POCD phenotypes in-phase with surgery In seeking to identify novel genotype:phenotype correlations, a trait of interest must be well-defined. To preclude “chromo-phrenology” wherein ill-defined proclivities are mapped to “protuberances” of the genome,

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investigators must be able to unequivocally distinguish participants and controls with and without the POCD phenotype. Resolving a consensual phenotype as a predicate to genomic experimentation for well recognized diagnoses such as asthma, autism or schizophrenia is very much more challenging than it appears, with subtle assumptions and hidden confounders often coming to light only after replication efforts have failed. Moreover, the POCD phenotype is both a diagnosis by exclusion in which inter-current central nervous system pathophysiology, delirium, dementia and amnestic conditions are ruled out upon enrollment and serial testing of participants, and a syndrome with arbitrary boundaries characterized by wide variation in selected components of psychometric test batteries, controls, varying re-test intervals, statistical methods, and thresholds for declaring aberrancy. As noted by many (Funder et al., 2010; Hovens et al., 2012; Lewis et al., 2004; Rasmussen et al., 2001; Rudolph et al., 2010; Terrando et al., 2011), lack of a clear-cut phenotype (i.e., per DSM IV) presently constrains nongenomic investigations of POCD natural history, cause, contributors and prevention. Without firm and consensual diagnostic and procedural criteria, detection of genotypes relevant to POCD will remain a will o' the wisp. If a legitimate POCD phenotype exists (i.e., at least 10–15% of patients experience cognitive decline at 3 months or longer after non-cardiac surgery vs. 2–4% in controls in a preponderance of prospective investigations (Hovens et al., 2012)), it is astonishing that reports describing POCD or related phenotypes in sub-populations, families, twins, sibs or case reports have not been published in view of the tens of millions of patients having surgery each year. Descriptions of this nature most often precede downstream number-crunching genetic investigations using candidate gene linkage, haplotype analysis, genome wide association studies, exome and whole genome sequencing in other genomic investigations of perioperative phenotypes including malignant hyperthermia, butyrlcholinesterase deficiency, and long Q–T syndrome. In the absence of pedigree evidence for hereditary vulnerability to POCD, less convincing and efficient experimental designs must be employed. For example, POCD phenotypes in participants with and without a candidate genotype having surgery may be compared to phenotypes in participants with and without the candidate gene not having surgery matched for age, gender, education, and baseline psychometric performance. Inclusion and exclusion criteria must be pristine in order to meaningfully rule in or rule out a possible correlation between DNA sequence variation and POCD. To establish the clinical validity of candidate biomarkers, evidence of pre-existing structural, electrophysiologic, and metabolic CNS lesions (e.g. vitamin B (de Jager et al., 2012) and D (Annweiler et al., 2013) deficiency), consumption of CNS pharmaceuticals (i.e., medical and recreational drugs), the history of head trauma, and antecedent anesthesia and surgery including childhood exposure, and family history of dementia before 75, must be sought, documented, and analyzed. Baseline and serial general physical and detailed neurologic exams are essential, but are often omitted in POCD protocols. Further stratification by type of surgery comprising duration, severity, transfusion, infection, inflammation, ischemia, and complication data, and type of anesthesia comprising regional vs. general anesthesia, use of potent volatile agents, anti-inflammatory analgesics, and post-operative disposition data is most probably indicated, even though initial investigations report conflicting evidence for these factors. Because the incidence of cognitive decline in control samples from research participants that have not undergone surgery is above zero (i.e., 2–4%), large sample sizes, perhaps very large sample sizes (i.e., thousands of participants and controls), will most probably be necessary to detect and validate POCD genomic predictors, particularly in view of substantial variances around psychometric performance means. Efforts to further resolve genomic predictors of “mild”, “moderate” and “severe” (Ballard et al., 2012), or “acute”, “intermediate” and “long term” (Leung and Sands, 2009) POCD phenotypes will compound sample sizes needed to defend proposed correlations with adequate power.

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3. POCD genotypes in-phase with surgery To provide perspective for investigations that target hereditary vulnerabilities to peri-operative phenotypes, a comparison to parallel efforts in approaching the malignant hyperthermia (MH) syndrome is illustrative. Unlike the brain, skeletal muscle is relatively simple in structure with a limited repertoire of expressed dysfunctions such as weakness, cramping, hypotonia, and rhabdomyolysis. A shared pathophysiologic MH cascade of disordered calcium regulation upon exposure to triggers drugs has long been recognized, with all known causal mutations appearing directly in calcium pathway constituents. In probands, the MH-event is clear-cut and very often dramatic, with susceptibility inherited as a Mendelian autosomal dominant trait in a substantial proportion of pedigrees. In addition to the availability of DNA samples from many hundreds of families, animal models that closely resemble the human phenotype at the molecular and clinical laboratory level employing the in vitro contracture test have been exploited. Despite these many advantages for molecular genetic investigation, and over 25 years of intense effort, genetic testing of perioperative patients for MH predisposition has failed to enter clinical practice either in the operating room or for genetic counseling. One reason is that only about 60% of human MH susceptibility has been correlated to DNA sequence variations. It is now well-established that the MH syndrome is characterized by substantial allelic and locus heterogeneity (i.e., over 300 mutations in over 6 genes), with reduced penetrance (i.e., variation in the proportion of individuals with a given genotype that manifest a given phenotype), variable expressivity (i.e., divergent phenotypes arising from a shared genotype), phenocopies, and alternate Mendelian (i.e., compound heterozygosity, autosomal recessive) and non-Mendelian (i.e., epistatic (gene–gene interaction) and epigenetic mechanisms) transmission contributing to MH incidence. While the POCD syndrome shares few of the MH syndrome's virtues for molecular genetic discovery, and probably shares most or all of its vices, particular advantages stand out. Multicenter, prospective investigations with standardized methods over 30 years of both cardiac and non-cardiac patients suggest a POCD incidence that is far greater than that of MH. POCD clinical phenotypes (i.e., changes in psychometric performance) in the absence of simultaneous exposure to surgery and anesthesia are non-invasive, and are less expensive and time consuming to acquire than phenotyping by the in vitro contracture test. As well, genotype:phenotype correlations derived from the study of other dementing conditions in humans provide an abundance of candidate genes for validation in POCD settings. These advantages have attracted numerous investigators. Early reports raised hopes of an association between POCD and the presence of one or more copies of the apolipoprotein E (APOE) ε4 Alzheimer's disease-associated allele in patients after cardiac surgery (Lelis et al., 2006; Tardiff et al., 1997). However, followup investigations in cardiac (Askar et al., 2005; Bryson et al., 2011; Robson et al., 2002; Silbert et al., 2008; Steed et al., 2001) and noncardiac (Abildstrom et al., 2004; Ancelin et al., 2010; McDonagh et al., 2010) surgical patients using multi-dimensional test batteries (i.e., not solely the Minnesota Mental Status Exam (MMSE) or Confusion Assessment Method (CAM)) and 2 to 12 month test intervals, have failed to confirm APOE status as a POCD risk factor. If APOE ε4 is a contributor to neurocognitive changes, its effects appear to be evanescent, and confined to short post-operative time intervals (i.e., 1 to 50 days after surgery) in which positive associations have been described (Cai et al., 2012; Heyer et al., 2005; Lelis et al., 2006; Leung et al., 2007; Tardiff et al., 1997). While polymorphisms in genes encoding the GPIIIa constituent of the platelet integrin receptor (GPIIb/IIIa) (Mathew et al., 2001), C-reactive protein (CRP) and P-selectin (SELP) (Mathew et al., 2007) after cardiac surgery, and in genes encoding complement component 3 (C3F), complement factor H (CFH) (Gigante et al., 2011) and inducible nitric oxide synthase (NOS2A) (Yocum et al., 2009) after non-cardiac procedures (i.e., carotid endarterectomy) have been reported to alter cognitive performance within 1 month or less after surgery, others in cytochrome

P450 (CYP2D6 and CYP2C19) (Steinmetz et al., 2012) and human PERIOD3 (hPER3) (Hansen et al., 2012) do not at 1 week or longer. Because interpretation of these reports is significantly hampered by divergent test batteries, time intervals, and analytical methods, and none other than APOE have been replicated by others, it is reasonable to conclude that heritable, genomic predictors of persistent (3 months or greater) post-operative cognitive dysfunction (POCD) are unknown at present. Because there is no evidence that POCD in-phase with surgery is inherited as a Mendelian trait in multi-generation families, or populations with shared ancestral geographic origin, hypothesis-free molecular genetic studies based on shared descent (i.e., linkage of genome wide markers, haplotypes, and candidate genes to a phenotype of interest) are unlikely to be available any time soon for discovery, or for confirmation of associations disclosed by other means. Other hypothesis-free, large-scale methods of gene discovery, for example, genome wide association studies (GWAS), and whole exome and whole genome sequencing, rely on very large sample sizes with thousands of participants with and without a trait of interest, and precise phenotypic descriptors currently lacking in POCD research. Even when successful, such high-throughput endeavors typically identify numerous genomic markers each with statistically significant but small effects, and fail to identify up to 40% of the heritability of a given trait that gives rise to “missing heritability” (Zaitlen and Kraft, 2012). Nor, as noted above, are investigators able to turn to a body of case reports describing severe POCD outcomes in probands, thereby seeking features in common among outliers that may point to otherwise occult associations and hypotheses for further testing. To the contrary, patients at heightened risk are lost in comparison of sample means. Such individuals may be amenable to molecular genetic analysis (i.e., “the power of one”), and their findings may have particular relevance to others in a sample and population at large by denoting alleles at shared loci of varying severity. Because wild-type, mutant, and transgenic animal models of cognitive changes after anesthesia more nearly resemble human post-operative delirium than persistent POCD, chances that they will yield relevant human candidate genes appear remote. To the contrary, transgenic animal POCD models will most probably play an important role in confirming the causality, and resolving the pathophysiology, of candidate POCD genes first identified in humans. While there is no shortage of plausible human candidate loci based on pharmacokinetic, pharmacodynamic, and pathophysiologic variation in other settings (i.e., amyloid deposition, inflammation, calcium dysregulation, mitochondrial dysfunction (Xu et al., 2011)), the rate-limiting step in identification of POCD-related genotypes is, and will for the foreseeable future remain, identification of unambiguous POCD-related phenotypes. 4. POD phenotypes not in-phase with surgery Given its prevalence and burden, it is surprising that firm clinical evidence from prospective cohort studies or randomized clinical trials (RCTs) for or against persistent, deleterious effects of surgery and anesthesia on cognitive performance in patients with, or at risk for, all-cause dementia including changes in personality and behavior is lacking (Papon et al., 2011; Seitz et al., 2013). Even more surprising is that multiple longitudinal investigations and RCTs of Alzheimer's syndrome and other dementias (e.g., Parkinson's disease, Huntington's disease, vascular dementia, and traumatic dementia) comprising serial psychometric testing at fixed intervals are ongoing, but have thus far failed to incorporate surgical and anesthetic variables. For medico-legal, quality assurance and other administrative purposes, hard-copy and electronic medical records comprising standardized preoperative evaluations, intra-operative records, recovery room documents, and surgical and discharge summaries are thorough and accurate with few missing values. Perioperative data are easy to score, access, analyze, interpret and archive in formats compatible with other variables recorded in prospective dementia investigations. Compared to other data collected in longitudinal investigations (e.g., cerebral concussion history), surgical and anesthetic variables are

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formal, fixed in time, and common. Similarly, details of phenotypes of interest including family history of dementia and surgery, background variables such as head trauma and co-existing disease, medications, age at first cognitive sign or symptom, age of consensual dementia diagnosis, clinical spectrum, severity and rate of progression are easily extracted antecedent to inferential statistical analysis. While RCTs comprising surgery and anesthesia as independent, randomized variables one without the other are ethically and logistically precluded, the analysis of surgical and anesthetic predictors in RCTs targeting anti-dementia drugs are of great potential interest in participants, and perhaps more so in controls. Few investigators conducting longitudinal investigations of dementia are likely to be aware of surgical and anesthetic dementia concerns, just as surgeons and anesthesiologists are unlikely to be unaware of longitudinal dementia observational protocols and RCTs unless they are actively sought. Amendment of IRB-approved protocols to expand the data set in these directions is not a barrier. Unlike POCD phenotypes identified in-phase with surgery, most dementias under investigation in longitudinal trials with psychometric testing outof-phase with surgery exhibit well-described pathology at molecular, cellular, anatomic, and physiologic levels. Shared genomic predictors of susceptibility, if they exist, will serve to test whether POCD and POD protocols address related or unrelated phenotypes and final common pathophysiologic pathways.

5. POD genotypes not in-phase with surgery Whereas no heritable genomic predictors of persistent POCD have been identified, genotypes reported in correlation with predisposition to dementia are perhaps over-abundant (Cruchaga et al., 2012; Schellenberg and Montine, 2012). Hereditary vulnerability to Alzheimer's syndrome alone comprises alleles in genes encoding the amyloid precursor protein (APP), presenilins 1 and 2 (PSEN1 and PSEN2), progranulin (GRN) and microtubule associated protein tau (MAPT) giving rise to Mendelian inheritance, heightened non-Mendelian predisposition with APOE ε4 number, poly-T length polymorphisms in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog) (Li et al., 2012), and single nucleotide polymorphisms inTREM2 (triggering receptor expressed on myeloid cells 2) (Neumann and Daly, 2013), up to 12 makers identified in GWAS investigations (Table 1) (Bertram and Tanzi, 2012), over 700 candidate loci associated with inflammation, calcium, metabolic, energy, and microvascular regulation and, most recently, protective alleles (Jonsson et al., 2012). Whether any dementia-associated genotype interacts with surgical and anesthetic variables to predict an earlier post-operative onset, increased severity, or more rapid rate of progression of dementia in susceptible patients is an unanswered, but answerable, question.

Table 1 Genome Wide Association Study (GWAS) genes for late onset Alzheimer's diseasea. Gene

Protein

BIN1 CD33 CLU CR1 PICALM ATXN1 EXOC3L2 GAB2 MTHFDIL PCDH11X SORL1 TNK1

Bridging integrator 1 CD33 molecule (siglec 3) Clusterin Complement component (3b/4b) receptor 1 Phosphatidylinositol binding clatherin assembly protein Ataxin 1 Exocyst complex component 3-like 2 GRB2-associated binding protein 2 Methylenetetrahydrofolate dehydrogenase (NADP + dependent) 1-like Protocadherin 11 X-linked Sortilin related receptor Tyrosine kinase, nonreceptor, 1

a

Bertram and Tanzi, 2012.

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6. Epigenetic vulnerabilities to post-operative dementia “Epigenetics” (i.e., “above the gene”) refers to mitotically and meiotically heritable chemical and structural variations that switch gene expression off and on in the absence of DNA sequence variation comprising modifications in DNA methylation, histone substitutions, chromatin conformation, noncoding RNAs and other mechanisms (Bohacek and Mansuy, 2012; Mazzio and Soliman, 2012). Just as events and exposures in the operating room may alter DNA sequences, for example, via mutagenic radiation and compounds, and DNA sequences may alter responses to surgery and anesthesia, so may events and exposures encountered during surgery and anesthesia potentially alter the epigenome (e.g., nitrous oxide-induced hypomethylation), and be altered by epigenomic variation. Comparable to the discovery of counterpoint in music and perspective in the visual arts, resolution of epigeneotype:phenotype correlations provides a third dimension to nature vs. nurture enigmas confronted at the biochemical level since the discovery of DNA over 60 years ago (e.g., “missing heritability” in GWAS reports (Marian, 2012)). Very little that we observe, measure, manipulate or discuss in the medical or social sciences will be untouched by epigenetic experiments and emergent insights. For example, the fundamental mechanisms of learning and memory in both the nervous and immune systems have recently been traced to epigenetic sources (Kosik et al., 2012). As well, detection of epigenetic alterations holds promise to be a fruitful avenue for new and integrated approaches to the pathogenesis and treatment of the heritable and acquired dementias (Bihaqi et al., 2012; Gräff et al., 2012; He and Eggert, 2012; Irier and Jin, 2012; Marques et al., 2011; Mastroeni et al., 2011; Qureshi and Mehler, 2012), thereby fostering a cornucopia of hypotheses amenable to animal and clinical testing. Moreover, epigenetic effects arising from surgery and anesthesia may not be confined to the life span of a patient, but may reverberate in the children and grandchildren of exposed individuals as first observed by Chalon et al. (1981). 7. Steps to identify heritable vulnerabilities to post-operative cognitive dysfunction and dementia In view of rapidly expanding in vitro, animal and clinical data pointing to surgery and anesthesia as possible contributors to POCD and POD, and further in view of disproportionate risks between patients, steps may be taken now toward the identification of potential genomic and epigenomic predictors of post-operative dementia: 1. A blood sample for DNA isolation from all patients and control individuals participating in longitudinal in-phase POCD and not in-phase POD psychometric investigations should be obtained. All participants in POCD and POD investigations should be asked for permission to be re-contacted for DNA collection, whole genome amplification, and possibly white blood cell immortalization as indicated. 2. Twins and sib pairs with and without dementia after surgery, and families with multiple POCD and POD members, should be sought, investigated and reported. 3. Human studies should be prioritized to those with greatest clinical impact seeking, for example, genomic predictors in patients with: a) “severe” cognitive decrements in; b) memory and executive function (i.e., reasoning, planning, problem solving) at; c) 3 months and longer after surgery. 4. Gender differences in heritable dementias are well established with women at particular risk (Seitz et al., 2013). Similarly, heightened anesthetic requirement and a 3-fold greater incidence of perioperative awareness among women have been identified (Buchanan et al., 2011). Molecular investigations of gender differences in anesthetic responses are long overdue, and plausibly overlap gender differences in dementia predisposition and long term cognitive recovery after surgery. Such studies are particularly compelling in view of discrete and relatively small differences in male and female genomes

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(i.e., X and Y chromosomes), with a high probability that DNA variations of interest reside therein. If so, gender may be more informative as an independent variable than as a background variable to be matched in prospective POCD and POD protocols. Assembly of an inventory of prospective, longitudinal dementia databases comprising serial psychometric evaluations to which surgical and anesthetic variables may be added is a top priority. Because investigators skilled in neuropsychology are unlikely to be aware of post-operative dementia, it falls to anesthesiologists and surgeons to seek collaboration either by direct contact or indirect means e.g., review of National Institute of Health, Veteran's Administration or foundational funding registries. Databases with designs enriched for familial dementias warrant particular attention in hunting heritable biomarkers. In many instances genotyping will be underway, with only the addition of surgical and anesthetic variables needed to begin analysis of their interactions with genotypes of interest. The effects of surgery and anesthesia on the age of onset and progression in families expressing Mendelian dementias arising from known APP, PSEN1 and PSEN2 and alleles should be facile to detect in both retrospective and prospective protocols, and thereby serve to test for interactions with normal and disordered β-amyloid metabolism. Completed and ongoing RCTs for drugs aimed at halting and reversing dementia comprise serial psychometric testing. Addition of surgical and anesthetic variables to these data sets, and in particular to descriptors in untreated control patients, offers the opportunity to test for interactions in settings with strict design, monitoring, safety and compliance criteria, and may be offered as a quid pro quo to investigators interested in the highest possible match between treated and untreated samples. While performance-based psychometric assays and corollary indices of daily living will remain the cornerstones of investigations that target cognitive changes after surgery, prospective POCD and POD protocols should further contemplate the addition of serial neuroimaging (Kline et al., 2012; Shaffer et al., 2013), CSF and plasma biomarkers (Ji et al., 2012), and other objective measures to further resolve post-operative phenotypes of interest. Administrative databases have been constructed over recent decades for quality assurance, compensation, and medico-legal purposes. Using contemporary analytical methods (e.g., propensity score matching (Rosenbaum, 2010)) to interrogate administrative databases may mimic RCTs comprising independent surgical and anesthetic variables that are otherwise ethically precluded (i.e., age of dementia onset after surgical vs. medical management of a shared condition, or alternate surgical and anesthetic management for the same disorder), and thereby identify novel pathways, correlations and heritable predictors, and provide potential DNA sources. At present most, but not all, animal investigations of post-operative cognitive decline model short-term human delirium more closely than long-term dementia (Degos et al., 2013; Eckenhoff and Laudansky, 2013; Tang et al., 2013). Investigations of dementia phenotypes in aged animals, and in animals exposed to surgery and anesthesia in the remote past, are required to detect novel genes and alleles of possible relevance to human aging and dementia after surgery. Altered gene expression in the central nervous system, and epigenetic marks modified in tandem after surgery, may provide attractive candidate genotypes for subsequent human investigation. For the foreseeable future, only animal cognitive models will be available to test for trans-generational decrements in cognitive performance after surgery and anesthesia that may be traced to epigenetic marks. Genomic biomarkers of cognitive impairment after traumatic brain injury (Sharma and Laskowitz, 2012), chemotherapy (Ahles, 2012) and acute and critical care illness (Ehlenbach et al., 2010) among

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related conditions, may plausibly share predictors of cognitive loss after surgery. Closer ties between the respective research communities, who often participate in the care of the same patients, will promote the disclosure of alleles, loci, pathways and mechanisms that may underlie apparently disparate conditions. As noted, mapping diagnoses made by exclusion, heterogeneous syndromes, phenotypes with fuzzy and controversial boundaries, drifting definitions, or “research constructs” (i.e., POCD) (Jankowski et al., 2011) to DNA sequence variation is very unlikely to be productive or replicable. Strict adherence to consensual terminology is a key first step for investigators, authors, reviewers and editors. For example, stakeholders must decide whether or not MMSE or CAM changes alone in the first week after surgery legitimately define “post-operative cognitive dysfunction”, or another condition. Investigator consensus for in-phase and not in-phase postoperative dementia experimental designs, test components, test intervals, test thresholds and diagnostic criteria, and analytical methods are essential predicates before genotype:phenotype correlations may be resolved with confidence. Full disclosure of hereditary vulnerabilities to post-operative dementia at the molecular level will only be achieved after innovative technologies are introduced that measure baseline and serial psychometric performance in everyone coming to surgery (Crosby et al., 2011; Hogue et al., 2007; Long et al., 2012; Silbert et al., 2011). Although complete recovery of brain function after anesthesia is presumed by all, routine psychometric testing that is ubiquitous, rapid, low cost, accurate, easy to administer and interpret, and perhaps modeled on technologies now employed for athletic and combat-related head injury, is a critical step to improved patient safety. Comprehensive detection of hereditary vulnerabilities to postoperative dementia awaits far greater emphasis on identifying and measuring the molecular, cellular and tissue events that account for emergence from anesthesia in health and disease. Few texts or manuscripts highlight emergence from anesthesia as a subject worthy of coordinated investigation or even review. In the context of patients who may never fully emerge from anesthesia after surgery, and silicon technologies faster than the human brain, a far more profound understanding of emergence and its disorders is both mandatory and within reach. From a molecular genetic perspective, the lack of focus on individual patients in investigations reporting POCD and POD data is striking. Avoidable post-operative dementia in 1%, 0.1%, or even 0.01% of patients arising from variables under the control of surgeons and anesthesiologists is unacceptable. Genotype:phenotype correlations in outliers often provide insights of profound importance to a general population that are missed by study designs confined to correlation coefficients, odds ratios, sample means and variances. Substantial information resides in outliers and their clinical courses that may be compared and tested for differences in molecular predictors. Discovery of rare genetic variants with large effects by sequencing candidate regions and whole genomes in a small number of patients who exhibit outermost POCD and POD phenotypes (i.e., “extremetrait sequencing”) provides an alternative to gene identification using large cohorts (Cirulli and Goldstein, 2010). Accordingly, a registry of patients and samples with persistent, severe POCD and POD that is otherwise unexplained by strict criteria, could be modeled on the North American Malignant Hyperthermia Registry (NAMHR) (www.mhaus.org/mh-registry/), perhaps with sponsorship from the international Serious Adverse Events Consortium (iSAEC) (www.saeconsortium.org/). A bio-bank for brain samples from patients experiencing unequivocal POCD and POD will be requisite to a full delineation of genomic and epigenomic markers. Individuals with and without a history of surgery and anesthesia who are cognitively unimpaired nonagenarians or centenarians should also be approached to have their DNA archived and analyzed.

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8. Conclusion Research aimed at identifying heritable vulnerabilities to postoperative dementia is in full alignment with the profession's twin mandates of doing no harm and perpetual vigilance. The most crucial steps to be taken now in order to detect novel POCD and POD genotype:phenotype correlations are not genetic. Improved, consensual methods to identify post-operative phenotypes are a first priority for future progress. Success thereafter in identifying molecular markers of POCD and POD susceptibility will assure all stakeholders that surgeons and anesthesiologists are up to the task of providing better outcomes for all.

Acknowledgement A sine qua non of the present contribution is the steady inspiration in word and deed of Larry H. Hogan M.D., second to last of Ralph Water's surviving residents.

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