Deborah J. Culley - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] General anesthesia is one of the great advances of medicine but is not without risks. Subtle central nervous toxicity may be one of them. In neonatal animals, several general anesthetic agents have been implicated in neurodegeneration, hippocampal dysfunction, synaptic abnormalities, and learning impairment, with the period of the brain growth spurt and synaptogenesis being especially vulnerable. The mature brain, like the developing brain, contains immature cells that develop into neurons and get incorporated into functional neuronal circuits and has regions constantly remodeling synaptic connections in a rapid, highly dynamic process known as synaptic plasticity. Our central hypothesis, therefore, is that general anesthetic-mediated neurotoxicity is as much a function of the state of neural cellular development as it is the age of the animal. This implies that mitotically competent, immature-undifferentiated and immature-differentiating neural progenitors-whether they are in neonatal brain or "plastic" areas of mature brain-are targets of general anesthetic-mediated neurotoxicity. To test this hypothesis, we will use a few selected general anesthetic agents (ketamine, propofol, isoflurane) and a cell culture model that permits the maturity and differentiation state of the cells to be regulated and included as an independent variable. Immunocytochemically characterized immature-undifferentiated and immature-differentiating neural progenitors as well as terminally differentiated cells will be exposed to the anesthetics in vitro and various measures of cell death and injury used to assess survival, capacity for growth / replication, and differentiation / synaptogenesis. Furthermore, we will investigate mechanism of cell death and the role of neurotrophic support in neurotoxicity, as well as examine opportunities to modify or mitigate it with neurotrophins or other protective compounds that can be used in vivo. As such, this work will elucidate the neurotoxic properties of general anesthetics in neural cells at different stages of development and lead potentially to novel mechanism-directed therapies to mitigate it. Accordingly, this research has implications for understanding anesthetic-related neurotoxicity and behavioral impairments in the young as well as the old. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Approximately 1 in 3 surgical procedures nationally is performed on a patient = 65 years of age. These geriatric surgical patients have a high rate of perioperative complications and often do poorly, so there is intense interest in identifying predictors of adverse outcomes in this age group. Although preoperative assessment of major vital organs has been a routine part of preparation for surgery for decades, brain function is typically not evaluated. We propose that preexisting cognitive impairment is a strong predictor of poor medical-surgical and functional outcomes and that preoperative cognitive screening could identify those at risk. In a pilot study using the MiniCog, a brief, validated, structured cognitiv screening tool with high inter-rater reliability and patient acceptance, we found that 20-33% of older elective geriatric surgical patients are likely to be cognitively impaired preoperatively, findings consistent with community surveys of older adults. The goals of this proposal are to demonstrate that there is marginal benefit to preoperative cognitive screening for identifying cognitively impaired seniors (Aim 1) and that preoperative cognitive impairment predicts the risk of postoperative medical- surgical complications and poor functional outcomes (Aim 2). To this end, we will conduct a prospective observational study in which the MiniCog will be administered in the Center for Preoperative Evaluation at Brigham & Women's Hospital (Preop Center) to cognitively screen 250 patients = 65 years of age during the routine preoperative visit prior to elective total knee or hip replacement surgery. These surgical procedures are selected because they are common in this age group, reasonably uniform procedurally, and the underlying disease has no association beyond that of advancing age with cognitive function. Aim 1 will test the hypothesis that systematic chart review and patient/informant report of seeking medical advice about cognition/memory will improve the sensitivity of the standard preop evaluation but that many cases of likely impairment, and even severe impairment, based on MiniCog scores will go undetected without structured screening. In Aim 2 we will test the hypothesis that poor preoperative cognitive function as assessed by the MiniCog predicts medical- surgical complications and poor functional outcomes, with delirium and suboptimal change in the SF36 as the primary endpoints, respectively. We anticipate preoperative cognitive screening of seniors will prove to be better than current standard or systematic clinical practices for identifying patients with evidence of likely cognitive impairment and that evidence of such wil predict a poor outcome. The work has the potential for high clinical impact and is innovative because it brings together a cross disciplinary group to address new and important questions about the effect of cognition on surgical outcomes in seniors in a practical way that could transform the way we think about, evaluate, and manage the elderly brain and patient in a surgical setting.

Program Director/Principal Investigator (Last, First, Middle): Culley, Deborah J ABSTRACT Surgery triggers a cascade of humoral, cellular, and subcellular events involved in inflammation and its resolution. These profound immune responses have a major influence on postoperative outcomes, and many complications of surgery are due to dysregulated inflammation. Older persons have more surgery than younger ones and are especially prone to serious postoperative morbidity. The immune system becomes dysregulated with age and this dysfunction contributes to the pathogenesis of age-related diseases, including cognitive decline. Poor cognition is a potent and consistent risk factor for adverse surgical outcomes; we have shown it doubles the risk of postoperative delirium and halves the chance of being discharged home after elective joint replacement surgery. We have also demonstrated that between 22-40% of elective surgical patients ? 70 years of age are probably cognitively impaired at the time of surgery. Therefore, the combination of poor preoperative cognition and poor surgical outcomes is both common and clinically important. Yet, it is not known how poor cognition increases susceptibility to postoperative morbidity, and the situation is little studied. We propose that poor preoperative cognition signifies a state of immune disequilibrium / dysfunction that shapes the immune response to surgery and increases postoperative morbidity. We will test this proposition by examining humoral (plasma inflammatory and resolution mediators; Aim 1), cellular (monocyte transcriptome and function; Aim 2), and subcellular (circulating extracellular vesicle [EV] concentration, cargo, and function; Aim 3) components of inflammation in cognitively screened patients having surgical procedures common in old age (total joint replacement; spine surgery), with delirium and discharge to place other than home as clinical and patient- centered-outcomes, respectively. Preliminary results showing cognition- or outcome-related differences in the ratio of circulating proinflammatory and proresolution mediators, the transcriptome of blood-borne monocytes, and the distribution of plasma extracellular vesicles support our model. This research is innovative because the impact of preoperative cognition on the immunology of surgical recovery has not been studied previously, it will test novel pathogenic mechanisms (monocyte dysfunction, EVs) for preoperative cognition-driven risk and use state-of-the-art ex vivo and in vitro methods (multiplexed gene panels), and may identify a molecular signature for adverse postoperative outcomes and, thereby, potential therapeutic targets. Given the magnitude and importance of the clinical problem being addressed, this is a high impact proposal that may increase the precision and personalization of surgical care and improve outcomes for older patients. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page