Miles Berger

Postoperative Cognitive Dysfunction: Minding the Gaps in Our Knowledge of a Common Postoperative Complication in the Elderly.

Postoperative cognitive dysfunction (POCD) is a common complication associated with significant morbidity and mortality in elderly patients. There is much interest in and controversy about POCD, reflected partly in the increasing number of articles published on POCD recently. Recent work suggests surgery may also be associated with cognitive improvement in some patients, termed postoperative cognitive improvement (POCI). As the number of surgeries performed worldwide approaches 250 million per year, optimizing postoperative cognitive function and preventing/treating POCD are major public health issues. In this article, we review the literature on POCD and POCI, and discuss current research challenges in this area.

Molecular Determinants in the Second Intracellular Loop of the 5-Hydroxytryptamine-1A Receptor for G-Protein Coupling

This study provides the first comprehensive evidence that the second intracellular loop C-terminal domain (Ci2) is critical for receptor-G protein coupling to multiple responses. Although Ci2 is weakly conserved, its role in 5-hydroxytryptamine-1A (5-HT1A) receptor function was suggested by the selective loss of Gβγ-mediated signaling in the T149A-5-HT1A receptor mutant. More than 60 point mutant 5-HT1A receptors in the α-helical Ci2 sequence (143DYVNKRTPRR152) were generated. Most mutants retained agonist binding and were tested for Gβγ signaling to adenylyl cyclase II or phospholipase C and Gαi coupling to detect constitutive and agonist-induced Gi/Go coupling. Remarkably, most point mutations markedly attenuated 5-HT1A signaling, indicating that the entire Ci2 domain is critical for receptor G-protein coupling. Six signaling phenotypes were observed: wild-type-like, Gαi-coupled/weak Gβγ-coupled, Gβγ-uncoupled, Gβγ-selective coupled, uncoupled, and inverse coupling. Our data elucidate specific roles of Ci2 residues consistent with predictions based on rhodopsin crystal structure. The absolute coupling requirement for lysine, arginine, and proline residues is consistent with a predicted amphipathic α-helical Ci2 domain that is kinked at Pro150. Polar residues (Thr149, Asn146) located in the externally oriented positively charged face were required for Gβγ but not Gαi coupling, suggesting a direct interface with Gβγ subunits. The hydrophobic face includes the critical Tyr144 that directs the specificity of coupling to both Gβγ and Gαi pathways. The key coupling residues Tyr144/Lys147 (Ci2) are predicted to orient internally, forming hydrogen and ionic bonds with Asp133/Arg134 (Ni2 DRY motif) and Glu340 (Ci3) to stabilize the Gprotein coupling domain. Thus, the 5-HT1A receptor Ci2 domain determines Gβγ specificity and stabilizes Gαi-mediated signaling.

Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion

Significance This paper shows that a class of receptors known to modulate insulin release by pancreatic β cells also regulates the proliferation of these cells and restrains the perinatal β-cell expansion that establishes adult β-cell mass, suggesting that alterations in signaling by these receptors could contribute to the decreased β-cell numbers seen in patients with type 2 diabetes. Further, inhibition of signaling through these receptors potentially could be used to generate more β cells for people with diabetes. Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

General anesthetic and the risk of dementia in elderly patients: current insights.

In this review, we aim to provide clinical insights into the relationship between surgery, general anesthesia (GA), and dementia, particularly Alzheimer’s disease (AD). The pathogenesis of AD is complex, involving specific disease-linked proteins (amyloid-beta [Aβ] and tau), inflammation, and neurotransmitter dysregulation. Many points in this complex pathogenesis can potentially be influenced by both surgery and anesthetics. It has been demonstrated in some in vitro, animal, and human studies that some anesthetics are associated with increased aggregation and oligomerization of Aβ peptide and enhanced accumulation and hyperphosphorylation of tau protein. Two neurocognitive syndromes that have been studied in relation to surgery and anesthesia are postoperative delirium and postoperative cognitive dysfunction, both of which occur more commonly in older adults after surgery and anesthesia. Neither the route of anesthesia nor the type of anesthetic appears to be significantly associated with the development of postoperative delirium or postoperative cognitive dysfunction. A meta-analysis of case-control studies found no association between prior exposure to surgery utilizing GA and incident AD (pooled odds ratio =1.05, P=0.43). The few cohort studies on this topic have shown varying associations between surgery, GA, and AD, with one showing an increased risk, and another demonstrating a decreased risk. A recent randomized trial has shown that patients who received sevoflurane during spinal surgery were more likely to have progression of preexisting mild cognitive impairment compared to controls and to patients who received propofol or epidural anesthesia. Given the inconsistent evidence on the association between surgery, anesthetic type, and AD, well-designed and adequately powered studies with longer follow-up periods are required to establish a clear causal association between surgery, GA, and AD.

Neurological complications of cardiac surgery

As increasing numbers of elderly people undergo cardiac surgery, neurologists are frequently called upon to assess patients with neurological complications from the procedure. Some complications mandate acute intervention, whereas others need longer term observation and management. A large amount of published literature exists about these complications and guidance on best practice is constantly changing. Similarly, despite technological advances in surgical intervention and modifications in surgical technique to make cardiac procedures safer, these advances often create new avenues for neurological injury. Accordingly, rapid and precise neurological assessment and therapeutic intervention rests on a solid understanding of the evidence base and procedural variables.

Intraoperative Magnesium Administration Does Not Improve Neurocognitive Function After Cardiac Surgery

Background and Purpose— Neurocognitive decline occurs frequently after cardiac surgery and persists in a significant number of patients. Magnesium is thought to provide neuroprotection by preservation of cellular energy metabolism, blockade of the N-methyl-D-aspartate receptor, diminution of the inflammatory response, and inhibition of platelet activation. We therefore hypothesized that intraoperative magnesium administration would decrease postoperative cognitive impairment. Methods— After approval by the Duke University Health System Institutional Review Board, 389 patients undergoing cardiac surgery were enrolled in this prospective, randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive magnesium as a 50 mg/kg bolus followed by another 50 mg/kg infusion for 3 hours or placebo bolus and infusion. Cognitive function was assessed preoperatively and again at 6 weeks postoperatively using a standardized test battery. Mean CD11b fluorescence and percentage of platelets expressing CD62P, which are markers of leukocyte and platelet activation, respectively, were assessed by flow cytometry as a secondary outcome. The effect of magnesium on postoperative cognition was tested using multivariable regression modeling, adjusting for age, years of education, baseline cognition, sex, race, and weight. Results— Among the 389 allocated subjects (magnesium: n=198; placebo: n=191), the incidence of cognitive deficit in the magnesium group was 44.4% compared with 44.9% in the placebo group (P=0.93). The cognitive change score and platelet and leukocyte activation were also not different between the groups. Multivariable analysis revealed a marginal interaction between treatment group and weight such that heavier subjects receiving magnesium were less likely to have cognitive deficit (P=0.06). Conclusions— Magnesium administered intravenously during cardiac surgery does not reduce postoperative cognitive dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041392.

Precise pattern of recombination in serotonergic and hypothalamic neurons in a Pdx1-cre transgenic mouse line

BackgroundMulticellular organisms are characterized by a remarkable diversity of morphologically distinct and functionally specialized cell types. Transgenic techniques for the manipulation of gene expression in specific cellular populations are highly useful for elucidating the development and function of these cellular populations. Given notable similarities in developmental gene expression between pancreatic β-cells and serotonergic neurons, we examined the pattern of Cre-mediated recombination in the nervous system of a widely used mouse line, Pdx1-cre (formal designation, Tg(Ipf1-cre)89.1Dam), in which the expression of Cre recombinase is driven by regulatory elements upstream of the pdx1 (pancreatic-duodenal homeobox 1) gene.MethodsSingle (hemizygous) transgenic mice of the pdx1-creCre/0 genotype were bred to single (hemizygous) transgenic reporter mice (Z/EG and rosa26R lines). Recombination pattern was examined in offspring using whole-mount and sectioned histological preparations at e9.5, e10.5, e11.5, e16.5 and adult developmental stages.ResultsIn addition to the previously reported pancreatic recombination, recombination in the developing nervous system and inner ear formation was observed. In the central nervous system, we observed a highly specific pattern of recombination in neuronal progenitors in the ventral brainstem and diencephalon. In the rostral brainstem (r1-r2), recombination occurred in newborn serotonergic neurons. In the caudal brainstem, recombination occurred in non-serotonergic cells. In the adult, this resulted in reporter expression in the vast majority of forebrain-projecting serotonergic neurons (located in the dorsal and median raphe nuclei) but in none of the spinal cord-projecting serotonergic neurons of the caudal raphe nuclei. In the adult caudal brainstem, reporter expression was widespread in the inferior olive nucleus. In the adult hypothalamus, recombination was observed in the arcuate nucleus and dorsomedial hypothalamus. Recombination was not observed in any other region of the central nervous system. Neuronal expression of endogenous pdx1 was not observed.ConclusionsThe Pdx1-cre mouse line, and the regulatory elements contained in the corresponding transgene, could be a valuable tool for targeted genetic manipulation of developing forebrain-projecting serotonergic neurons and several other unique neuronal sub-populations. These results suggest that investigators employing this mouse line for studies of pancreatic function should consider the possible contributions of central nervous system effects towards resulting phenotypes.

Resting-State Functional Connectivity and Cognition After Major Cardiac Surgery in Older Adults without Preoperative Cognitive Impairment: Preliminary Findings.

To look for changes in intrinsic functional brain connectivity associated with postoperative changes in cognition, a common complication in seniors undergoing major surgery, using resting‐state functional magnetic resonance imaging.

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial

BACKGROUND Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimers disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). OBJECTIVE We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

Anesthetic neuroprotection: antecedents and an appraisal of preclinical and clinical data quality.

Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.