Pharmacological characterization of SAGE-718, a novel positive allosteric modulator of N-methyl-d-aspartate receptors.

BACKGROUND AND PURPOSE: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. EXPERIMENTAL APPROACH: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. KEY RESULTS: SAGE-718 potentiated GluN1/GluN2A-D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE-718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine-evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE-718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)-HC depletion caused by 7-dehydrocholesterol reductase inhibition. Finally, SAGE-718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. CONCLUSIONS AND IMPLICATIONS: These findings provide strong evidence that SAGE-718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.

Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and found that these mice have deficits in fear conditioning memory recall and spatial memory, as well as reduced cortical neuron dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute specifically to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features.

Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13 -/- ) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13 -/- neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13 -/- neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13 -/- neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.

Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome.

Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1-/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and ß paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased ß-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3ß, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1-/y mice. Although inhibiting either paralog prevented induction of NMDA receptor-dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis-dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1-/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.

Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity.

Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.

The Ethics of Surgery at End of Life.

The role of the anesthesiologist cannot be understated when it comes to ethical decision making, especially at end of life. To best serve patients within the limits of the law, anesthesiologists must arm themselves with an understanding of how the laws surrounding ethical decision-making impact daily practices. It is also important to know what rights and duties a patient or surrogate has in the decision-making process. With proper understanding of their responsibilities and the available tools, anesthesiologists can fulfill their roles as leaders and advocates for their patients as approaches to ethical decision-making at the end of life evolve.

Eccentric cycling emphasising a low cardiopulmonary demand increases leg strength equivalent to workload matched concentric cycling in middle age sedentary males.

OBJECTIVES: This study determined if eccentric endurance cycling, eliciting a low cardiovascular demand, could stimulate muscle strength adaptations in sedentary middle-aged males. DESIGN: Twenty-four middle-aged sedentary males were allocated to concentric (CON) or matched workload eccentric (ECC) cycling (60% peak concentric workload) according to their maximal voluntary isometric quadriceps strength. METHODS: Seventeen participants [42.7±8.3 years, BMI 28.6±5.2, peak oxygen consumption [30.5±5.8mLkg-1min-1] completed 8 weeks (2 sessions per week) of CON (n=8) or ECC (n=9) cycle training. Incline leg press (6RM), maximal voluntary isometric contraction (MVIC) torque of the quadriceps and peak oxygen consumption were measured at baseline and 8 weeks. RESULTS: Eccentric cycle training resulted in low cardiovascular demand (CON 154±2; ECC 95±3bmin-1P<0.05) and ratings of perceived exertion (CON 14.9±0.3; ECC 9.5±0.3/20 P<0.05). Peak oxygen consumption improved within the CON group (Baseline 27.4±2.1; 8 weeks: 30.0±1.7mLkg-1min-1P<0.05) and not within the ECC group (Baseline 33.2±1.5; 8 weeks 33.3±1.6mLkg-1min-1) following training. 6RM (CON 176±20; ECC 192±11kg) and MVIC (CON 199±25; ECC 199±25Nm) strength were equivalent at baseline (P>0.05). Both groups significantly increased 6RM (CON 13.0±3.0; ECC 10.7±3.2%) and MVIC (CON 12.9±4.3; ECC 18.8±3.0%) relative to their own baseline (P<0.05). Therefore, improved leg strength was equivalent between CON and ECC groups despite the varied training (P>0.05). CONCLUSIONS: In sedentary middle age males, eccentric endurance cycling with a low cardiovascular demand, increased both quadriceps isometric and 6RM strength comparable to a matched workload concentric cycling program.

Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice.

Current medications for depression typically require weeks of treatment before significant clinical improvement is observed, and are only effective in a relatively small subset of patients. Recent human clinical studies have demonstrated that ketamine, an NMDA receptor antagonist, and scopolamine, a muscarinic acetylcholine receptor antagonist, produce rapid antidepressant responses within hours of administration, and are effective in treatment-resistant patients. We hypothesize that efficacy and tolerability may be improved by combining lower doses of both drugs in the treatment of depression. We therefore conducted a preclinical study in mice to assess whether co-treatment of low doses of scopolamine and ketamine that alone are ineffective has antidepressant-like effects in the forced swim test (FST), an assay with predictive validity for antidepressant drugs. Whereas single administration of ketamine (3mg/kg intraperitoneal [i.p.]) or scopolamine (0.1mg/kg i.p.) did not reduce immobility time in the FST, co-administration of both drugs at these doses significantly reduced immobility time by 45% compared to vehicle treated controls. These results suggest that the combination of subeffective doses of ketamine and scopolamine may prove efficacious for the treatment of depression and should be evaluated in human clinical trials.

Marketing or strategy? Defining the best approach to expand the anesthesiology workforce in Israel.

There is a chronic shortage of anesthesiologists in Israel. The study by Cohen et al. suggests that a marketing campaign may be one method of addressing this shortage. This commentary argues for a more comprehensive strategy based on the US experience. This would not only involve marketing as suggested by Cohen et al. but would also involve a fundamental change in the Israel anesthesia care model, as well as providing substantial financial incentives to young physicians. We believe that a combination of these approaches will help to alleviate the shortage of anesthesia providers in Israel. Creating a new class of physician extenders, namely, anesthesiologist assistants, would also provide an employment pathway for the skilled medical technicians trained by the Israel Defense Forces, and other non-physicians with an interest in anesthesiology.

Geriatrics and the Perioperative Surgical Home.

An ever-changing health care system with a constantly increasing aging surgical population creates both opportunities for providing improved health care as well as significant challenges. Coordinated health care initiatives are needed if one is to adequately balance the need for evidence-based improved patient outcomes and the often-associated increased costs. In this article the authors postulate that a protocol-driven, multidisciplinary approach may be a pathway for implementing an effective triple aim to health care, especially in a frail geriatric population.

Costs, resource utilization, and treatment patterns for patients with metastatic melanoma in a commercially insured setting.

OBJECTIVE: To estimate real-world healthcare costs, resource utilization, and treatment patterns among metastatic melanoma (MM) patients who received a therapy recommended in current treatment guidelines during 2011 and 2012, following approval in the US of novel therapies (ipilimumab and vemurafenib). RESEARCH DESIGN AND METHODS: Administrative claims data were used in a retrospective, longitudinal, open cohort study. Adult MM patients were identified using ICD-9 codes. Therapy-based patient cohorts and index dates were defined by the first receipt of a therapy of interest: ipilimumab, vemurafenib, paclitaxel (alone and in combination), interleukin-2, dacarbazine (alone and in combination), or temozolomide. The follow-up period extended until the end of eligibility or data availability. A multivariate regression model was used to compare outcomes of the ipilimumab and vemurafenib cohorts, controlling for baseline and demographic characteristics. MAIN OUTCOME MEASURES: Direct healthcare costs (2013 US dollars) and utilization (incidence rates) were measured on a per-patient-per-month (PPPM) basis for each treatment cohort. Treatment patterns were assessed, including the frequency of patients receiving a second therapy of interest. RESULTS: The study population included 834 patients (265 ipilimumab, 234 vemurafenib, 174 paclitaxel, 104 interleukin-2, 46 dacarbazine, and 11 temozolomide). Costs ranged from $10,879 PPPM (temozolomide) to $35,472 PPPM (ipilimumab). Adjusted total costs were $18,337 PPPM higher for the ipilimumab vs. the vemurafenib cohort (p < 0.001), primarily due to higher outpatient costs. Multivariate analysis did not find significant differences in resource utilization between ipilimumab and vemurafenib, except that ipilimumab patients had fewer outpatient visits (excluding treatment visits). Ipilimumab and vemurafenib patients received a second therapy of interest (12% and 11%, respectively) less frequently than interleukin-2 and dacarbazine patients. CONCLUSIONS: The cost and resource utilization burden of MM is high and varies substantially across treatment cohorts. The two novel therapies, ipilimumab and vemurafenib, have quickly been adopted and are the most frequently used therapies. The results observed during the approximately 6 month follow-up period may not be representative of the full clinical experience of patients with MM.

Gender-specific differences in the central nervous system's response to anesthesia.

Males and females are physiologically distinct in their responses to various anesthetic agents. The brain and central nervous system (CNS), the main target of anesthesia, are sexually dimorphic from birth and continue to differentiate throughout life. Accordingly, gender has a substantial impact on the influence of various anesthetic agents in the brain and CNS. Given the vast differences in the male and female CNS, it is surprising to find that females are often excluded from basic and clinical research studies of anesthesia. In animal research, males are typically studied to avoid the complication of breeding, pregnancy, and hormonal changes in females. In clinical studies, females are also excluded for the variations that occur in the reproductive cycle. Being that approximately half of the surgical population is female, the exclusion of females in anesthesia-related research studies leaves a huge knowledge gap in the literature. In this review, we examine the reported sex-specific differences in the central nervous system's response to anesthesia. Furthermore, we suggest that anesthesia researchers perform experiments on both sexes to further evaluate such differences. We believe a key goal of research studying the interaction of the brain and anesthesia should include the search for knowledge of sex-specific mechanisms that will improve anesthetic care and management in both sexes.

Small molecule inhibitors of zinc-dependent histone deacetylases.

Lysine acetylation is an ancient, evolutionarily conserved, reversible post-translational modification. A multitude of diverse cellular functions are regulated by this dynamic modification, including energy and metabolism, protein folding, transcription, and translation. Gene expression can be manipulated through changes in histone acetylation status, and this process is controlled by the function of 2 opposing enzymes: histone acetyl transferases and histone deacetylases (HDACs). The zinc-dependent HDACs are a family of hydrolases that remove acetyl groups from lysines, and their function can be modulated by the action of small molecule ligands. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small molecule chemotypes. Structural biology has aided the development of potent, and in some cases highly isoform-selective, inhibitors that have demonstrated utility in a number of neurological disease models. Continued development and characterization of highly optimized small molecule inhibitors of HDAC enzymes will help refine our understanding of their function and, optimistically, lead to novel therapeutic treatment alternatives for a host of neurological disorders.

Therapeutic potential of isoform selective HDAC inhibitors for the treatment of schizophrenia.

Increasing evidence supports a role for epigenetic involvement in some of the neurobiological alterations observed in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Additional data support the notion that small molecule inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms associated with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the associated biological effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.

A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests.

Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary--albeit often ineffective--treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.

Trauma in the elderly: considerations for anesthetic management.

The volume of geriatric trauma patients is expected to increase significantly in coming years. Recognition of severe injuries may be delayed because they are less likely to mount classic symptoms of hemodynamic instability. Head injuries of any severity may place geriatric patients at increased risk of mortality, but there are currently no geriatric-specific treatment recommendations that differ from usual adult guidelines. Our understanding of best practices in geriatric trauma and anesthesia care continues to expand, as it does in all other areas of medicine.

Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain.

Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70% nitrous oxide (N(2)O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2weeks and 3months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N(2)O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.

A fractionation of the physiological burden of the personal protective equipment worn by firefighters.

Load carriage increases physiological strain, reduces work capacity and elevates the risk of work-related injury. In this project, the separate and combined physiological consequences of wearing the personal protective equipment used by firefighters were evaluated. The overall impact upon performance was first measured in 20 subjects during a maximal, job-related obstacle course trial and an incremental treadmill test to exhaustion (with and without protective equipment). The fractional contributions of the thermal protective clothing, helmet, breathing apparatus and boots were then separately determined during steady-state walking (4.8 km h(-1), 0% gradient) and bench stepping (20 cm at 40 steps min(-1)). The protective equipment reduced exercise tolerance by 56% on a treadmill, with the ambulatory oxygen consumption reserve (peak minus steady-state walking) being 31% lower. For the obstacle course, performance declined by 27%. Under steady-state conditions, the footwear exerted the greatest relative metabolic impact during walking and bench stepping, being 8.7 and 6.4 times greater per unit mass than the breathing apparatus. Indeed, the relative influence of the clothing on oxygen cost was at least three times that of the breathing apparatus. Therefore, the most efficient way to reduce the physiological burden of firefighters' protective equipment, and thereby increase safety, would be to reduce the mass of the boots and thermal protective clothing.

AKT kinase activity is required for lithium to modulate mood-related behaviors in mice.

Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response-activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice-and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.

Unique Aspects of the Elderly Surgical Population: An Anesthesiologist's Perspective.

Increasing life expectancies paired with age-related comorbidities have resulted in the continued growth of the elderly surgical population. In this group, age-associated changes and decreased physiological reserve impede the body's ability to maintain homeostasis during times of physiological stress, with a subsequent decrease in physiological reserve. This can lead to age-related physiological and cognitive dysfunction resulting in perioperative complications. Changes in the cardiovascular, pulmonary, nervous, hepatorenal, endocrine, skin, and soft tissue systems are discussed as they are connected to the perioperative experience. Alterations affect both the pharmacodynamics and pharmacokinetics of administered drugs. Elderly patients with coexisting diseases are at a greater risk for polypharmacy that can further complicate anesthetic management. Consequently, the importance of conducting a focused preoperative evaluation and identifying potential risk factors is strongly emphasized. Efforts to maintain intraoperative normothermia have been shown to be of great importance. Procedures to maintain stable body temperature throughout the perioperative period are presented. The choice of anesthetic technique, in regard to a regional versus general anesthetic approach, is debated widely in the literature. The type of anesthesia to be administered should be assessed on a case-by-case basis, with special consideration given to the health status of the patient, the type of operation being conducted, and the expertise of the anesthesiologist. Specifically addressed in this article are age-related cognitive issues such as postoperative cognitive dysfunction and postoperative delirium. Strategies are suggested for avoiding these pitfalls.