Search

Introduction: Complex medication regimens are error prone and challenging for patients, which may impact medication adherence and safety. No universal method to assess the complexity of medication regimens (CMRx) exists. The authors aim to review literature for CMRx measurements to establish consistencies and, secondarily, describe CMRx impact on healthcare outcomes., Areas Covered: A search of EMBASE and PubMed for studies analyzing at least two medications and complexity components, among those self-managing medications, was conducted. Out of 1204 abstracts, 38 studies were included in the final sample. The majority (74%) of studies used one of five validated CMRx scales; their components and scoring were compared., Expert Opinion: Universal CMRx assessment is needed to identify and reduce complex regimens, and, thus, improve safety. The authors highlight commonalities among five scales to help build consensus. Common components (i.e., regimen factors) included dosing frequency, units per dose, and non-oral routes. Elements (e.g., twice daily) of these components (e.g., dosing frequency) and scoring varied. Patient-specific factors (e.g., dexterity, cognition) were not addressed, which is a shortcoming of current scales and a challenge for future scales. As CMRx has important outcomes, notably adherence and healthcare utilization, a standardized tool has potential for far-reaching clinical, research, and patient-safety impact.

Introduction: Older adults are generally considered to be at greater risk for medication non-adherence due to factors such as medication complexity, side effects, cost, and cognitive decline. However, this generalization may not apply to older adults with human immunodeficiency virus (HIV). Regardless of age, suboptimal adherence to antiretroviral therapy (ART) can lead to increased viral load, immunosuppression, drug-resistant viral strains, co-morbidities, and opportunistic infections. Understanding trends of adherence to ART among older adults is critical, especially as the population of people living with HIV grows older., Objectives: The purpose of this systematic review and meta-analysis is to determine if older individuals with HIV are less likely to be non-adherent to antiretroviral therapy than younger individuals with HIV., Design: A systematic search in PubMed, Embase, and PsycINFO was conducted to identify peer-reviewed articles evaluating adherence to ART in older adults. Two independent reviewers screened abstracts, applied inclusion criteria, and appraised study quality. The bibliographies of qualifying studies were searched. Data were abstracted from studies by two independent authors. Meta-analyses were conducted, and adherence levels were reported as the relative risk of non-adherence in older individuals compared to younger individuals., Results: The systematic search yielded 1,848 abstracts. Twelve studies met full inclusion criteria. The overall meta-analysis found that older age reduced risk for nonadherence by 27 % (relative risk (RR) 0.72, 95 % confidence interval (CI) 0.64–0.82). Studies assessing both short-term and long-term adherence demonstrated a significant reduction in non-adherence among older patients (RR 0.75, 95 % CI 0.64–0.87 and RR 0.65, 95 % CI 0.50–0.85, respectively)., Conclusions: Older adults with HIV have a reduced risk for non-adherence to ART than their younger counterparts. Future studies should seek to elucidate contributing factors of adherence among older individuals with HIV.

Delirium is an acute change in awareness and attention and is common, morbid, and costly for patients and health care systems. While hyperactive delirium is easily identifiable, the hypoactive form is more common and carries a higher mortality. Hospital systems to address delirium should consist of 3 critical steps. First, hospitals must identify patients who develop or are at intermediate or high risk for delirium. Delirium risk may be assessed using known patient-based and illness-based risk factors, including preexisting cognitive impairment. Delirium diagnosis remains a clinical diagnosis that requires a clinical assessment that can be structured using diagnostic criteria. Hospital systems may be useful to efficiently allocate delirium resources to prevent and manage delirium. Second, it is crucial to develop a systematic approach to prevent delirium using multimodal nonpharmacologic delirium prevention methods and to monitor all high-risk patients for its occurrence. Tools such as the modified Richmond Agitation and Sedation Scale can aid in monitoring for changes in mental status that could indicate the development of delirium. Third, hospital systems can utilize established methods to assess and manage delirium in a standardized fashion. The key lies in addressing the underlying cause/causes of delirium, which often involve medical conditions or medications. With a sustained commitment, standardized efforts to identify and prevent delirium can mitigate the long-term morbidity associated with this acute change. In the face of changes in health care funding, delirium serves as an example of a syndrome where care coordination can improve short-term and long-term costs.

Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43-87 years. Whole-brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol-associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular-related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults., (Copyright © 2012 Wiley Periodicals, Inc.)

Learning Objectives: After participating in this educational activity, the reader should be better able to measure the risk of depression before and after coronary artery bypass graft (CABG) surgery; examine the course of depression after CABG; and apply the results of the study to the treatment of patients., Objective: Depression is highly comorbid with coronary artery disease. Clinicians face the question of whether patients' depressive symptoms will improve after coronary artery bypass graft surgery (CABG). The objective of this meta-analysis is to determine the course of depressive symptoms after CABG., Methods: EMBASE, PubMed, and PsycINFO were searched for studies assessing depression before and after CABG. Meta-analyses were performed for depression at early (1-2 weeks), recovery (>2 weeks to 2 months), mid (>2 months to 6 months), and late (>6 months) postoperative time points. Heterogeneity and publication bias were analyzed., Results: Thirty-nine studies were included in the meta-analysis. Twelve reported dichotomous outcomes; 18 reported continuous outcomes; and 9 reported both. Risk of depression was increased early (relative risk [RR] = 1.27; 95% confidence interval [CI], 1.01-1.61). There was a significantly decreased risk of depression at recovery (RR = 0.78; 95% CI, 0.67-0.90), mid (RR = 0.64; 95% CI, 0.58-0.70), and late (RR = 0.68; 95% CI, 0.58-0.79) time points without heterogeneity. All studies reporting continuous depression scales had significant heterogeneity., Conclusions: The risk of depression decreased post-CABG when depression was measured dichotomously. While depression improves overall and remits for some patients after CABG, the majority of patients will not experience remission of depression. Preoperative and postoperative depression monitoring is important.

Background: Delirium (acute confusion), is a common, morbid, and costly complication of acute illness in older adults. Yet, researchers and clinicians lack short, efficient, and sensitive case identification tools for delirium. Though the Confusion Assessment Method (CAM) is the most widely used algorithm for delirium, the existing assessments that operationalize the CAM algorithm may be too long or complicated for routine clinical use. Item response theory (IRT) models help facilitate the development of short screening tools for use in clinical applications or research studies. This study utilizes IRT to identify a reduced set of optimally performing screening indicators for the four CAM features of delirium., Methods: Older adults were screened for enrollment in a large scale delirium study conducted in Boston-area post-acute facilities (n = 4,598). Trained interviewers conducted a structured delirium assessment that culminated in rating the presence or absence of four features of delirium based on the CAM. A pool of 135 indicators from established cognitive testing and delirium assessment tools were assigned by an expert panel into two indicator sets per CAM feature representing (a) direct interview questions, including cognitive testing, and (b) interviewer observations. We used IRT models to identify the best items to screen for each feature of delirium., Results: We identified 10 dimensions and chose up to five indicators per dimension. Preference was given to items with peak psychometric information in the latent trait region relevant for screening for delirium. The final set of 48 indicators, derived from 39 items, maintains fidelity to clinical constructs of delirium and maximizes psychometric information relevant for screening., Conclusions: We identified optimal indicators from a large item pool to screen for delirium. The selected indicators maintain fidelity to clinical constructs of delirium while maximizing psychometric information important for screening. This reduced item set facilitates development of short screening tools suitable for use in clinical applications or research studies. This study represents the first step in the establishment of an item bank for delirium screening with potential questions for clinical researchers to select from and tailor according to their research objectives.

This randomized clinical trial tested a new self-directed educational intervention to improve caregiver competence to create a safer home environment for persons with dementia living in the community. The sample included 108 patient/caregiver dyads: the intervention group (n = 60) received the Home Safety Toolkit (HST), including a new booklet based on health literacy principles, and sample safety items to enhance self-efficacy to make home safety modifications. The control group (n = 48) received customary care. Participants completed measures at baseline and at twelve-week follow-up. Multivariate Analysis of Covariance (MANCOVA) was used to test for significant group differences. All caregiver outcome variables improved in the intervention group more than in the control. Home safety was significant at P ≤ 0.001, caregiver strain at P ≤ 0.001, and caregiver self-efficacy at P = 0.002. Similarly, the care receiver outcome of risky behaviors and accidents was lower in the intervention group (P ≤ 0.001). The self-directed use of this Home Safety Toolkit activated the primary family caregiver to make the home safer for the person with dementia of Alzheimer's type (DAT) or related disorder. Improving the competence of informal caregivers is especially important for patients with DAT in light of all stakeholders reliance on their unpaid care.

Rit, along with Rin and Drosophila Ric, comprises the Rit subfamily of Ras-related small GTPases. Although the cellular functions of many Ras family GTPases are well established, the physiological significance of Rit remains poorly understood. Loss of Rit sensitizes multiple mammalian cell lines and mouse embryonic fibroblasts (MEFs) derived from Rit(-/-) mice to oxidative stress-mediated apoptosis. However, whether Rit-mediated pro-survival signaling extends to other cell types, particularly neurons, is presently unknown. Here, to examine these issues we generated a transgenic mouse overexpressing constitutively active Rit (Rit(Q79L)) exclusively in neurons, under control of the Synapsin I promoter. Active Rit-expressing hippocampal neurons display a dramatic increase in oxidative stress resistance. Moreover, pharmacological inhibitor studies demonstrate that p38 MAPK, rather than a MEK/ERK signaling cascade, is required for Rit-mediated protection. Together, the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To use an expert consensus process to identify indicators of delirium features to help enhance bedside recognition of delirium., Design: Modified Delphi consensus process to assign existing cognitive and delirium assessment items to delirium features in the Confusion Assessment Method (CAM) diagnostic algorithm., Setting: Meetings of expert panel., Participants: Panel of seven interdisciplinary clinical experts., Measurements: Panelists' assignments of each assessment item to indicate CAM features., Results: From an initial pool of 119 assessment items, the panel assigned 66 items to at least one CAM feature, and many items were assigned to more than one feature. Experts achieved a high level of consensus, with a postmeeting kappa for agreement of 0.98. The study staff compiled the assignment results to create a comprehensive list of CAM feature indicators, consisting of 107 patient interview questions, cognitive tasks, and interviewer observations, with some items assigned to multiple features. A subpanel shortened this list to 28 indicators of important delirium features., Conclusion: A systematic, well-described qualitative methodology was used to create a list of indicators for delirium based on the features of the CAM diagnostic algorithm. This indicator list may be useful as a clinical tool for enhancing delirium recognition at the bedside and for aiding in the development of a brief delirium screening instrument., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Objectives: Because delirium is a common yet frequently unrecognized condition, this study sought to design a brief screening tool for a core feature of mental status and to validate the instrument as a serial assessment for delirium., Design: Prospective cohort study., Setting: Tertiary VA Hospital in New England., Participants: A total of 95 veterans admitted to the medical service., Methods: A consensus panel developed a modified version of the Richmond Agitation and Sedation Scale (RASS) to capture alterations in consciousness. Upon admission, and daily thereafter, patients were screened with a modified RASS (mRASS) and independently underwent a comprehensive mental status interview by a geriatric expert, who determined whether the criteria for delirium were met. The sensitivity, specificity, and positive likelihood ratio (LR) of the mRASS for delirium are reported., Results: As a single assessment, the mRASS had a sensitivity of 64% and a specificity of 93% for delirium (LR, 9.4). When used to detect change, serial mRASS assessments had a sensitivity of 74% and a specificity of 92% (LR, 8.9) in both prevalent and incident delirium. When prevalent cases were excluded, any change in the mRASS had a sensitivity of 85% and a specificity of 92% for incident delirium (LR, 10.2), Conclusion: When administered daily, the mRASS has good sensitivity and specificity for incident delirium. Given the brevity of the instrument (<30 seconds), consideration should be given to incorporating the modified RASS as a daily screening measure for consciousness and delirium., (Copyright © 2012 Society of Hospital Medicine.)

Background: Although postoperative atrial fibrillation (AF) is prevalent after cardiac surgery, the corresponding medication burden associated with this postoperative arrhythmia is unknown., Methods: We conducted a prospective study of 204 patients aged 60 or older (median age 73) undergoing cardiac surgery at two academic medical centers. We defined "AF at discharge" as AF that developed after surgery and was present on the day of discharge. We evaluated the prevalence of anticoagulant and antiarrhythmic use at discharge, and out to 1 year post-discharge. We investigated the association between age and prescription of both classes of medications at discharge., Results: Ninety-one (45%) patients developed new postoperative AF, which persisted at discharge in 28 (14%) patients. Thirty-four percent of patients with postoperative AF were discharged on warfarin, 62% were discharged on antiarrhythmic medication, and 25% were discharged on both. Eighty-two percent of those discharged on both were older than 72 years of age. Patients with AF present at discharge were more likely to be discharged on anticoagulant agents than patients whose AF resolved prior to discharge (54% versus 26%, p=0.01), and more likely to be discharged on antiarrhythmic agents than patients whose AF resolved prior to discharge, though not significantly so (73% versus 57%, p=0.2). At 12 months, the proportion of patients on antiarrhythmic and anticoagulant medications had still not returned to preoperative rates., Conclusions: AF persists at hospital discharge in nearly one-third of affected patients. Cardiac surgery results in the initiation of anticoagulant and antiarrhythmic medications in many older patients annually, often concurrently. Our findings underscore the need for additional studies on the natural history of this arrhythmia and clinical trials investigating different management strategies after discharge. Such research will help to inform development of guidelines addressing duration of use for these medications, to aid physicians in these complicated post-discharge management decisions.

Prior studies have documented a range of brain changes that occur as a result of healthy aging as well as neural alterations due to profound dysregulation in vascular health such as extreme hypertension, cerebrovascular disease and stroke. In contrast, little information exists about the more transitionary state between the normal and abnormal physiology that contributes to vascular disease and cognitive decline. Specifically, little information exists with regard to the influence of systemic vascular physiology on brain tissue structure in older individuals with low risk for cerebrovascular disease and with no evidence of cognitive impairment. We examined the association between resting blood pressure and diffusion tensor imaging (DTI) indices of white matter microstructure in 128 healthy older adults (43-87 years) spanning the normotensive to moderate-severe hypertensive range. Mean arterial blood pressure (MABP) was related to diffusion measures in several regions of the brain with greatest associations in the anterior corpus callosum and lateral frontal, precentral, superior frontal, lateral parietal and precuneus white matter. Associations between white matter integrity and blood pressure remained when controlling for age, when controlling for white matter lesions, and when limiting the analyses to only normotensive, pharmacologically controlled and pre-hypertensive individuals. Of the diffusion measures examined, associations were strongest between MABP and radial diffusivity which may indicate that blood pressure has an influence on myelin structure. Associations between MABP and white matter integrity followed spatial patterns resembling those often attributed to the effects of chronological age, suggesting that systemic cerebrovascular health may play a role in neural tissue degeneration classically ascribed to aging. These results demonstrate the importance of the consideration of vascular physiology in studies of cognitive and neural aging, and that this significance extends to even the normotensive and medically controlled population. These data additionally suggest that optimal management of blood pressure may require consideration of the more subtle influence of vascular health on neural health in addition to the primary goal of prevention of a major cerebrovascular event., (Published by Elsevier Inc.)

Frailty and delirium, although seemingly distinct syndromes, both result in significant negative health outcomes in older adults. Frailty and delirium may be different clinical expressions of a shared vulnerability to stress in older adults, and future research will determine whether this vulnerability is age related, pathological, genetic, environmental, or most likely, a combination of all of these factors. This article explores the clinical overlap of frailty and delirium, describes possible pathophysiological mechanisms linking the two, and proposes research opportunities to further knowledge of the interrelationships between these important geriatric syndromes. Frailty, a diminished ability to compensate for stressors, is generally viewed as a chronic condition, whereas delirium is an acute change in attention and cognition, but there is a developing literature on transitions in frailty status around acute events, as well as on delirium as a chronic, persistent condition. If frailty predisposes an individual to delirium, and delirium delays recovery from a stressor, then both syndromes may contribute to a downward spiral of declining function, increasing risk, and negative outcomes. In addition, frailty and delirium may have shared pathophysiology, such as inflammation, atherosclerosis, and chronic nutritional deficiencies, which will require further investigation. The fields of frailty and delirium are rapidly evolving, and future research may help to better define the interrelationship of these common and morbid geriatric syndromes. Because of the heterogeneous pathophysiology and presentation associated with frailty and delirium, typical of all geriatric syndromes, multicomponent prevention and treatment strategies are most likely to be effective and should be developed and tested., (© 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.)

Objectives: To improve identification of patients at high risk for delirium, this study developed a chart abstraction tool for delirium risk and validated the tool against clinical expert diagnosis of delirium., Design: Prospective cohort study., Setting: Tertiary Veterans Affairs hospital in New England., Participants: One hundred veterans admitted to the medical service., Measurements: While admitted, each participant underwent serial assessments for delirium by a clinical expert. Using the four criteria of a validated delirium prediction rule (cognitive impairment, sensory deficit, severe illness, and dehydration), chart review terms were selected for each criterion, and delirium risk was the sum of criteria present (range: 0-4; 4 = worst). After discharge, a nurse blinded to the expert's diagnosis completed the chart tool., Results: The participants were mostly male (94%) and older (mean age 81 ± 7), and 23% developed overall delirium (14% incident). The rate of overall delirium was 11% in participants with zero risk factors, 18% in those with one or two, and 50% in those with three or four (P = .01; c-statistic 0.65, 95% confidence interval (CI) = 0.54-0.76). For incident delirium, the rates were 11%, 13%, and 25%, respectively (P = .53; c-statistic 0.56, 95% CI = 0.42-0.74). Discharge to a rehabilitation center or nursing home increased with increasing delirium risk (0%, 18%, 60%, P = .02)., Conclusion: A chart abstraction tool was effective at identifying overall delirium risk but not incident delirium risk. Although the tool cannot replace clinical assessment and diagnosis of delirium, the use of this tool as an educational, clinical, or quality measurement aid warrants additional study., (© 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.)

Objectives: To determine whether delirium after noncardiac surgery is associated with functional decline 3 months postoperatively., Design: Secondary analysis of a prospective study., Setting: Thirteen hospitals in eight countries., Participants: One thousand two hundred eighteen individuals aged 60 and older undergoing noncardiac surgery., Measurements: Participants were interviewed before surgery and 3 months postoperatively using six items pertaining to social and independent function. Functional decline was determined according to a loss in function in at least one item at the 3-month assessment from baseline. Postoperatively, a trained interviewer assessed delirium daily using a standardized battery. The primary outcome of this analysis was an examination of the risk of functional decline with delirium., Results: Of the 948 participants who completed functional assessment at 3 months, 20% (n = 189) had a decline in function. In unadjusted analysis, postoperative delirium increased the odds of functional decline (odds ratio (OR) = 2.4, 95% confidence interval (CI) = 1.4-4.2). After adjustment for age, sex, education, cognition, and surgery duration, delirium remained associated with functional decline (OR = 2.1, 95% CI = 1.2-3.8)., Conclusion: Although considered an acute event, delirium can have lasting functional consequences. Clinicians should give strong consideration to preoperative delirium risk assessment, delirium prevention strategies, and delirium surveillance programs after noncardiac surgery., (© 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.)

While it is relatively widely known that cardiovascular disease (CVD) can result in cognitive decline, it is becoming increasingly clearer that actual risk factors for CVD, such as high blood pressure, diabetes, and obesity are also associated with alterations to brain structure and cognition. The prevalence of CVD risk factors increase exponentially with age and are often overlooked as a source of cognitive changes that are otherwise thought to be part of the 'normal' aging process. Associated cognitive changes are observed even at levels of risk that would be considered subclinical by current diagnostic convention, and are often significant enough to interfere with daily functional abilities. More importantly, if not controlled, CVD risk can lead to further decline, including cerebrovacsular disease and dementia. Thus, it is critically important to consider these factors in the elderly and we recommend more routine cognitive screenings, particularly when CVD risk factors are involved.

Ras-related small GTP-binding proteins control a wide range of cellular processes by regulating a variety of effector pathways, including prominent roles in the control of mitogen-activated protein kinase (MAPK) cascades. Although the regulatory role(s) for many Ras family GTPases are well established, the physiological function for the Rit/Rin subfamily has been lacking. Here, using both knockout mice and Drosophila models, we demonstrate an evolutionarily conserved role for Rit subfamily GTPases (mammalian Rit and Rin, and the Drosophila RIC homologue) in governing survival in response to oxidative stress. Primary embryonic fibroblasts derived from Rit knockout mice display increased apoptosis and selective disruption of MAPK signaling following reactive oxygen species (ROS) exposure but not in response to endoplasmic reticulum stress or DNA damage. These deficits include a reduction in ROS-mediated stimulation of a p38-MK2-HSP27 signaling cascade that controls Akt activation, directing Bad phosphorylation to promote cell survival. Furthermore, D-RIC null flies display increased susceptibility to environmental stresses and reduced stress-dependent p38 signaling, extending the Rit-p38 survival pathway to Drosophila. Together, our studies establish the Rit GTPases as critical regulators of an evolutionarily conserved, p38 MAPK-dependent signaling cascade that functions as an important survival mechanism for cells in response to oxidative stress.

Objectives: To determine factors associated with proton pump inhibitor (PPI) discontinuation in long-term care., Design: Retrospective cohort analysis., Setting: Veterans Affairs (VA) long-term care facilities., Participants: Veterans admitted for nonhospice care in 2005 with a length of stay of 7 days or more who were prescribed a PPI within 7 days of admission (N = 10,371)., Measurements: Prescribed medications and comorbidities were determined from VA pharmacy and administrative databases and functional status from Minimum Data Set records. Associations between participant characteristics and PPI discontinuation were determined using Cox proportional hazard ratios (HRs), censoring at death, discharge, or 180 days after admission., Results: Participants were predominantly male (97%) and had a median age of 73 (interquartile range 60-81). There were 2,749 (27%) PPI discontinuations; 43% of these occurred within 28 days of admission. Hospitalizations (HR = 1.22, 95% confidence interval (CI) = 1.01-1.46), preadmission PPI use (HR = 1.35, 95% CI = 1.16-1.56), and lowest functional status (HR = 1.22, 95% CI = 1.03-1.45) were associated with early PPI discontinuation in adjusted models. Participants with gastric acid-related disease (HR = 0.53, 95% CI 0.46-0.61), diabetes mellitus (HR = 0.82, 95% CI 0.72-0.94), and those who were prescribed six or more medications (6-7 medications, HR = 0.78, 95% CI = 0.66-0.92; 8-10 medications, HR = 0.64, 95% CI = 0.54-0.76; ≥ 11 medications 0.51, 95% CI = 0.42-0.62) were less likely to have early discontinuation. No PPI discontinuer had PPIs resumed during the study, and few (9%) had histamine-2 receptor antagonist substitutions., Conclusion: Although there may be clinical uncertainty regarding PPI discontinuation, more than one-quarter of participants prescribed a PPI upon admission to long-term care had it discontinued within 180 days. Targeting individuals prescribed PPIs for medication appropriateness review may reduce prescribing of potentially nonindicated medications., (© 2011, Copyright the Authors. Journal compilation © 2011, The American Geriatrics Society.)

Background: The Clock-in-the-Box is a rapid (2-minute) cognitive screening tool. The purpose of this study was to compare the Clock-in-the-Box with the Mini-Mental State Exam and neuropsychologic tests; to determine Clock-in-the-Box score normative values by age and education group; and to determine if the Clock-in-the-Box score is associated with measures of physical function., Methods: Community-dwelling older participants in the Boston area were recruited for a prospective, longitudinal study in which they completed a variety of cognitive and functional assessments., Results: At baseline, participants (n=798; mean age [± standard deviation]=78.2 [±5.5] years; 14 [±3] mean years of education) completed in-home assessments of cognition (Clock-in-the-Box and Mini-Mental State Exam), measures of independent function (Activities of Daily Living and Instrumental Activities of Daily Living), and measures of physical function (Short Physical Performance Battery). The mean Mini-Mental State Exam score was 27.1 (±1.6; range 0-30 [0 worst]), and the mean Clock-in-the-Box score was 6.2 (±1.6; range 0-8 [0 worst]). Performance on the Clock-in-the-Box was correlated (Spearman) with the Mini-Mental State Exam (r=0.49, P<.001) and neuropsychologic measures (r=0.37-0.50; P<.001). Higher Clock-in-the-Box score was significantly associated with no difficulty in Activities of Daily Living (χ(2) = 39.6, P<.001) and Instrumental Activities of Daily Living (χ(2) = 35.5, P<.001). In addition, higher Clock-in-the-Box scores were associated with higher scores on the Short Physical Performance Battery (F=5.4, P<.001)., Conclusion: The Clock-in-the-Box is a brief cognitive screening test that is correlated with the Mini-Mental State Exam, neuropsychologic tests, and measures of independent and physical function in community-dwelling older adults., (Published by Elsevier Inc.)

Vital signs are objective measures of physiological function that are used to monitor acute and chronic disease and thus serve as a basic communication tool about patient status. The purpose of this analysis was to review age-related changes of traditional vital signs (blood pressure, pulse, respiratory rate, and temperature) with a focus on age-related molecular changes, organ system changes, systemic changes, and altered compensation to stressors. The review found that numerous physiological and pathological changes may occur with age and alter vital signs. These changes tend to reduce the ability of organ systems to adapt to physiological stressors, particularly in frail older patients. Because of the diversity of age-related physiological changes and comorbidities in an individual, single-point measurements of vital signs have less sensitivity in detecting disease processes. However, serial vital sign assessments may have increased sensitivity, especially when viewed in the context of individualized reference ranges. Vital sign change with age may be subtle because of reduced physiological ranges. However, change from an individual reference range may indicate important warning signs and thus may require additional evaluation to understand potential underlying pathological processes. As a result, individualized reference ranges may provide improved sensitivity in frail, older patients., (Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Delirium is an acute change in cognition and attention, which may include alterations in consciousness and disorganized thinking. Although delirium may affect any age group, it is most common in older patients, especially those with preexisting cognitive impairment. Patients with delirium after surgery recover more slowly than those without delirium and, as a result, have increased length of stay and hospital costs. The measured incidence of postoperative delirium varies with the type of surgery, the urgency of surgery, and the type and sensitivity of the delirium assessment. Although generally considered a short-term condition, delirium can persist for months and is associated with poor cognitive and functional outcomes beyond the immediate postoperative period. In this article, we provide a guide to assess delirium risk preoperatively and to prevent, diagnose, and treat this common and morbid condition. Care improvements such as identifying delirium risk preoperatively; training surgeons, anesthesiologists, and nurses to screen for delirium; implementing delirium prevention programs; and developing standardized delirium treatment protocols may reduce the risk of delirium and its associated morbidity., (© 2011 International Anesthesia Research Society)

Background: Among cardiac surgery patients, those with impaired cognitive status before surgery may have longer postoperative stays than do patients with normal status and may require additional care upon discharge., Objectives: To determine if preoperative scores on a screening measure for cognitive status (the Clock-in-the-Box), were associated with postoperative length of stay and discharge to a location other than home in patients who had cardiac surgery., Methods: A total of 181 consecutive patients scheduled for cardiac surgery at a single site were administered the Clock-in-the-Box as part of the preoperative evaluation. Scores on the Clock-in-the-Box tool, demographic and operative information, postoperative length of stay, and discharge location were collected retrospectively from medical records., Results: The mean age of the patients was 68.1 years (SD, 0.7), and 99% were men. Mean postoperative length of stay was 10.5 days (SD, 8.2), and 35 patients (19%) were discharged to a facility. Scores on the Clock-in-the-Box assessment were not associated with postoperative length of stay. Increasing age, living alone before surgery, and duration of cardiopulmonary bypass were associated with discharge to a facility and were used as covariates in adjusted analyses. After adjustment, better preoperative cognitive status reduced the risk of being discharged to a facility (adjusted relative risk, 0.93; 95% confidence interval, 0.89-0.98) after cardiac surgery., Conclusions: Cognitive screening before cardiac surgery can identify patients with impaired cognitive status who are less likely than patients with normal cognitive status to return home after cardiac surgery.

We examined how wide ranges in levels of risk factors for cerebrovascular disease are associated with thickness of the human cerebral cortex in 115 individuals ages 43-83 with no cerebrovascular or neurologic history. Cerebrovascular risk factors included blood pressure, cholesterol, body mass index, creatinine, and diabetes-related factors. Variables were submitted into a principal components analysis that confirmed four orthogonal factors (blood pressure, cholesterol, cholesterol/metabolic and glucose). T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness. Increasing blood pressure factor scores were associated with numerous regions of reduced thickness. Increasing glucose scores were modestly associated with areas of regionally decreased thickness. Increasing cholesterol scores, in contrast, were associated with thicker cortex across the whole brain. All findings were primarily independent of age. These results provide evidence that normal and moderately abnormal levels of parameters used to assess cerebrovascular health may impact brain structure, even in the absence of cerebrovascular disease. Our data have important implications for the clinical management of vascular health, as well as for what is currently conceptualized as "normal aging" as they suggest that subclinical levels of risk may impact cortical gray matter before a disease process is evident., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objectives: While a recent task force report recommended that remission from major depression be defined according to DSM criteria, most previous work has used depressive symptom rating scales. The current study sought to identify baseline factors associated with treatment outcome in major depression, diagnosed according to DSM-IV criteria., Methods: Data from the Primary Care Research in Substance Abuse and Mental Health for the Elderly (PRISM-E) study were utilized. This analysis focused on 792 geriatric primary care patients with major depression at baseline, which was randomized to services by a mental health professional in primary care or specialty settings. Major depression was diagnosed according to DSM-IV criteria based on a structured interview at baseline and 6 months. The primary outcome was the absence of any DSM-IV depressive disorder at six-month follow-up. Association with baseline demographic characteristics, comorbid anxiety disorder, 'at risk' drinking, number of co-occurring medical conditions, and depressive symptom severity was examined using multiple logistic regression modeling., Results: Remission occurred in 228 (29%) patients with completed follow-up assessments, while 564 (71%) did not remit. Factors which increased the odds of non-remission included comorbid anxiety (OR=1.60, 95% CI 1.11-2.31), female sex (OR=1.49, 95% CI 1.04-2.15), general medical comorbidity (OR=1.15, 95% CI 1.07-1.24), and increased baseline depressive symptom severity (OR=1.04, 95% CI 1.03-1.06)., Conclusions: The findings underscore the importance of using DSM criteria to define remission from major depression, and suggest that concurrent measurement of depression severity, comorbid anxiety, and medical comorbidity are important in identifying patients requiring targeted interventions to optimize remission from major depression., (Copyright © 2010 John Wiley & Sons, Ltd.)

The objective of this analysis was to develop a measure of neuropsychological performance for cardiac surgery and to assess its psychometric properties. Older patients (n = 210) underwent a neuropsychological battery using nine assessments. The number of factors was identified with variable reduction methods. Factor analysis methods based on item response theory were used to evaluate the measure. Modified parallel analysis supported a single factor, and the battery formed an internally consistent set (coefficient alpha = .82). The developed measure provided a reliable, continuous measure (reliability > .90) across a broad range of performance (-1.5 SDs to +1.0 SDs) with minimal ceiling and floor effects.

Objectives: To examine the rates of and risk factors for acute hospitalization in a prospective cohort of older community-dwelling patients with Alzheimer's disease (AD)., Design: Longitudinal patient registry., Setting: AD research center., Participants: Eight hundred twenty-seven older persons with AD., Measurements: Acute hospitalization after AD research center visit was determined from a Medicare database. Risk factor variables included demographics, dementia-related, comorbidity and diagnoses and were measured in interviews and according to Medicare data., Results: Of the 827 eligible patients seen at the ADRC during 1991 to 2006 (median follow-up 3.0 years), 542 (66%) were hospitalized at least once, and 389 (47%) were hospitalized two or more times, with a median of 3 days spent in the hospital per person-year. Leading reasons for admission were syncope or falls (26%), ischemic heart disease (17%), gastrointestinal disease (9%), pneumonia (6%), and delirium (5%). Five significant independent risk factors for hospitalization were higher comorbidity (hazard ratio (HR)=1.87, 95% confidence interval (CI)=1.57-2.23), previous acute hospitalization (HR=1.65, 95% CI=1.37-1.99), older age (HR=1.51, 95% CI=1.26-1.81), male sex (HR=1.27, 95% CI=1.04-1.54), and shorter duration of dementia symptoms (HR=1.26, 95% CI=1.02-1.56). Cumulative risk of hospitalization increased with number of risk factors present at baseline: 38% with zero factors, 57% with one factor, 70% with two or three factors, and 85% with four or five factors (P(trend) <.001)., Conclusion: In a community-dwelling population with generally mild AD, hospitalization is frequent, occurring in two-thirds of participants over a median follow-up time of 3 years. With these results, clinicians may be able to identify dementia patients at high risk for hospitalization., (© 2010, Copyright the Authors. Journal compilation © 2010, The American Geriatrics Society.)

Post-operative cognitive dysfunction (POCD) is a decline in cognitive function from pre-operative levels, which has been frequently described after cardiac surgery. The purpose of this study was to examine the variability in the measurement and definitions for POCD using the framework of a 1995 Consensus Statement on measurement of POCD. Electronic medical literature databases were searched for the intersection of the search terms 'thoracic surgery' and 'cognition, dementia, and neuropsychological test.' Abstracts were reviewed independently by two reviewers. English articles with >50 participants published since 1995 that performed pre-operative and post-operative psychometric testing in patients undergoing cardiac surgery were reviewed. Data relevant to the measurement and definition of POCD were abstracted and compared with the recommendations of the Consensus Statement. Sixty-two studies of POCD in patients undergoing cardiac surgery were identified. Of these studies, the recommended neuropsychological tests were carried out in less than half of the studies. The cognitive domains measured most frequently were attention (n=56; 93%) and memory (n=57; 95%); motor skills were measured less frequently (n=36; 60%). Additionally, less than half of the studies examined anxiety and depression, performed neurological exam, or accounted for learning. Four definitions of POCD emerged: per cent decline (n=15), standard deviation decline (n=14), factor analysis (n=13), and analysis of performance on individual tests (n=12). There is marked variability in the measurement and definition of POCD. This heterogeneity may impede progress by reducing the ability to compare studies on the causes and treatment of POCD.

Objectives: To determine whether patients who developed delirium after cardiac surgery were at risk of functional decline., Design: Prospective cohort study., Setting: Two academic hospitals and a Veterans Affairs Medical Center., Participants: One hundred ninety patients aged 60 and older undergoing elective or urgent cardiac surgery., Measurements: Delirium was assessed daily and was diagnosed according to the Confusion Assessment Method. Before surgery and 1 and 12 months postoperatively, patients were assessed for function using the instrumental activities of daily living (IADL) scale. Functional decline was defined as a decrease in ability to perform one IADL at follow-up., Results: Delirium occurred in 43.1% (n=82) of the patients (mean age 73.7+/-6.7). Functional decline occurred in 36.3% (n=65/179) at 1 month and in 14.6% (n=26/178) at 12 months. Delirium was associated with greater risk of functional decline at 1 month (relative risk (RR)=1.9, 95% confidence interval (CI)=1.3-2.8) and tended toward greater risk at 12 months (RR=1.9, 95% CI=0.9-3.8). After adjustment for age, cognition, comorbidity, and baseline function, delirium remained significantly associated with functional decline at 1 month (adjusted RR=1.8, 95% CI=1.2-2.6) but not at 12 months (adjusted RR=1.5, 95% CI=0.6-3.3)., Conclusion: Delirium was independently associated with functional decline at 1 month and had a trend toward association at 12 months. These findings provide justification for intervention trials to evaluate whether delirium prevention or treatment strategies might improve postoperative functional recovery.

Although hypertension is a major risk factor for cerebrovascular disease (CVD) and is highly prevalent in African Americans, little is known about how blood pressure (BP) affects brain-behavior relationships in this population. In predominantly Caucasian populations, high BP is associated with alterations in frontal-subcortical white matter and in executive functioning aspects of cognition. We investigated associations among BP, brain structure, and neuropsychological functioning in 52 middle-older-age African Americans without diagnosed history of CVD. All participants underwent diffusion tensor imaging for examination of white matter integrity, indexed by fractional anisotropy (FA). Three regions of interest were derived in the anterior (genu) and posterior (splenium) corpus callosum and across the whole brain. A brief neuropsychological battery was administered from which composite scores of executive function and memory were derived. Blood pressure was characterized by mean arterial blood pressure (MABP). When controlling for age, higher MABP was associated with lower FA in the genu, and there was a trend for this same relationship with regard to whole-brain FA. When the sample was broken into groups on the basis of treatment for BP regulation (medicated vs. nonmedicated), MABP was related to genu and whole-brain FA only in the nonmedicated group. Neither MABP nor FA was significantly related to either neuropsychological composite score regardless of medication use. These data provide important evidence that variation in BP may contribute to significant alterations in specific neural regions of white matter in nonmedicated individuals without symptoms of overt CVD., (Copyright 2010 APA, all rights reserved)

Delirium is an acute change in cognition which occurs frequently after coronary artery bypass graft (CABG) surgery. Cerebral microemboli, from plaque, air, or thrombus, have been hypothesized to contribute to delirium and cognitive decline after CABG. The purpose of this study was to determine if there was an association between cerebral microemboli and delirium after cardiac surgery. Non-delirious patients (n=68) were prospectively enrolled and underwent intraoperative monitoring of the middle cerebral arteries with transcranial Doppler (TCD). TCD signals were saved and analyzed postoperatively for microemboli manually, according to established criteria. Postoperatively, patients were assessed for delirium with a standardized battery. Thirty-three patients (48.5%) developed delirium after surgery. Microemboli counts (mean + or - SD) were not significantly different in those with and without delirium (303 + or - 449 vs. 299 + or - 350; p=0.97). While intraoperative microemboli were not associated with delirium after CABG, further investigation into the source and composition of microemboli can further elucidate the long-term clinical impact of microemboli.

Background: Brief cognitive screening measures are valuable tools for both research and clinical applications. The most widely used instrument, the Mini-Mental State Examination (MMSE), is limited in that it must be administered face-to-face, cannot be used in participants with visual or motor impairments, and is protected by copyright. Screening instruments such as the Telephone Interview for Cognitive Status (TICS) were developed to provide a valid alternative, with comparable cut-point scores to rate global cognitive function., Methods: The MMSE, TICS-30, and TICS-40 scores from 746 community-dwelling elders who participated in the Aging, Demographics, and Memory Study (ADAMS) were analyzed with equipercentile equating, a statistical process of determining comparable scores based on percentile equivalents for different forms of an examination., Results: Scores from the MMSE and TICS-30 and TICS-40 corresponded well, and clinically relevant cut-point scores were determined. For example, an MMSE score of 23 is equivalent to 17 and 20 on the TICS-30 and TICS-40, respectively., Conclusions: These findings indicate that TICS and MMSE scores can be linked directly. Clinically relevant and important MMSE cut points and the respective ADAMS TICS-30 and TICS-40 cut-point scores are included, to identify the degree of cognitive impairment among respondents with any type of cognitive disorder. These results will help in the widespread application of TICS in both research and clinical practice.

Carotid stenosis is a frequent coexisting condition in patients undergoing coronary artery bypass graft (CABG) surgery. The impact of carotid stenosis on cerebral perfusion is not fully understood. The purpose of this study was to determine the impact of carotid stenosis on cerebral blood flow velocity in patients undergoing CABG. Seventy-three patients undergoing CABG were prospectively recruited and underwent preoperative Duplex carotid ultrasound to evaluate the degree of carotid stenosis. Intraoperatively, transcranial Doppler ultrasound was used to record the mean flow velocity (MFV) within the bilateral middle cerebral arteries. In addition, during the period of cardiopulmonary bypass, regulators of cerebral hemodynamics such as hematocrit, partial pressure of carbon dioxide and temperature were recorded. The ipsilateral middle cerebral artery mean flow velocity was compared in arteries with and without carotid stenosis using a repeated measures analysis. Seventy-three patients underwent intraoperative monitoring during CABG and 30% (n=22) had carotid stenosis. Overall, MFV rose throughout the duration of CABG including when the patient was on cardiopulmonary bypass. However, there was no significant MFV difference between those arteries with and without stenosis (F=1.2, p=.21). Further analysis during cardiopulmonary bypass, demonstrated that hemodilution and partial pressure of carbon dioxide may play a role in cerebral autoregulation during CABG. Carotid stenosis did not impact mean cerebral blood flow velocity during CABG. The cerebrovascular regulatory process appears to be largely intact during CABG.

Background: Delirium is an acute confusional state that is common, preventable, and life-threatening., Objective: The authors investigated the phenomenology of delirium severity as measured with the Memorial Delirium Assessment Scale among 441 older patients (age 65 and older) admitted with delirium in post-acute care., Methods: Using latent class analysis, they identified four classes of psychomotor-severity subtypes of delirium: 1) hypoactive/mild; 2) hypoactive/severe; 3) mixed, with hyperactive features/severe; and 4) normal/mild., Results: Among those with dementia (N=166), the hypoactive/mild class was associated with a higher risk of mortality. Among those without dementia (N=275), greater severity was associated with mortality, regardless of psychomotor features, when compared with the normal/mild class., Conclusion: The data suggest that instruments measuring delirium severity and psychomotor features provide important prognostic information and should be integrated into the assessment of delirium.

Background: Much attention in the literature has focused on the relationship between perioperative microemboli during cardiac and vascular surgery and postoperative cognitive decline. Transcranial Doppler ultrasonography (TCD) has been used to measure high-intensity transient signals (HITS), which represent microemboli during cardiac, vascular, and orthopedic surgery. The purpose of this study was to systematically examine the literature with respect to HITS and postoperative cognitive function., Methods: Systematic PubMed searches identified articles related to the use of TCD and cognitive function in the surgical setting., Results: The literature remains largely undecided on the role of HITS and cognitive impairment after surgery, with most studies being underpowered to show a relationship. Although the cognitive effects of HITS may be difficult to detect, subclinical microemboli present potential harm, which may be modifiable., Conclusions: TCD represents a tool for intraoperative cerebral monitoring to reduce the number of HITS during surgery.

In the inpatient setting, dysphagia is a common, morbid, and costly condition. Antipsychotic medications in older patients have been associated with dysphagia. The purpose of this study was to determine if hospitalized patients who were exposed to antipsychotic medications had worse swallowing function than those who were not exposed. Retrospectively, all patients referred for swallowing difficulty who underwent a videofluoroscopic swallowing study during the course of their hospital care were considered eligible. We excluded patients younger than 50 years and those with a history of dysphagia, a medical cause for dysphagia, or chronic antipsychotic medication usage. Patients exposed to antipsychotics (n = 17) were matched at a 3:1 ratio to patients without exposure (n = 51) for age, comorbidity, and anticholinergic risk. Videofluoroscopic swallowing study was scored according to the Dysphagia Severity Rating Scale (range, 0-6; 6 = worst). Patients who were given antipsychotic medications scored significantly worse on the Dysphagia Severity Rating Scale compared with matched controls (4.1 +/- 1.0 vs 3.0 +/- 1.4; P < 0.01). Using the medication and dosage, the antipsychotic exposure was quantified by converting to chlorpromazine equivalency units. Higher doses of antipsychotic medication were associated with worse swallowing function (P = 0.04). Thus, the potential impact on swallow functions should be considered when prescribing antipsychotic medications in older patients.

The purpose of this analysis was to determine if postoperative delirium was associated with early postoperative cognitive dysfunction (at 7 days) and long-term postoperative cognitive dysfunction (at 3 months). The International Study of Postoperative Cognitive Dysfunction recruited 1218 subjects >or= 60 years old undergoing elective, non-cardiac surgery. Postoperatively, subjects were evaluated for delirium using the criteria of the Diagnostic and Statistical Manual. Subjects underwent neuropsychological testing pre-operatively and postoperatively at 7 days (n = 1018) and 3 months (n = 946). Postoperative cognitive dysfunction was defined as a composite Z-score > 2 across tests or at least two individual test Z-scores > 2. Subjects with delirium were significantly less likely to participate in postoperative testing. Delirium was associated with an increased incidence of early postoperative cognitive dysfunction (adjusted risk ratio 1.6, 95% CI 1.1-2.1), but not long-term postoperative cognitive dysfunction (adjusted risk ratio 1.3, 95% CI 0.6-2.4). Delirium was associated with early postoperative cognitive dysfunction, but the relationship of delirium to long-term postoperative cognitive dysfunction remains unclear.

Background: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort., Methods: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis., Results: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77)., Conclusion: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.

Background: Delirium has been hypothesized to be a central nervous system response to systemic inflammation during a state of blood-brain barrier compromise. The purpose of this study was to compare postoperative changes in groups of inflammatory markers in persons who developed delirium following cardiac surgery and matched controls without delirium., Methods: Serum samples were drawn from 42 patients undergoing cardiac surgery preoperatively and postoperatively at 6 hours and postoperative day 4. The serum concentrations of 28 inflammatory markers were determined with a microsphere flow cytometer. A priori, inflammatory markers were assigned to five classes of cytokines. A class z score was calculated by averaging the standardized, normalized levels of the markers in each class. Beginning on postoperative day 2, patients underwent a daily delirium assessment., Results: Twelve patients with delirium were matched by surgical duration, age, and baseline cognition to 12 patients without delirium. At the 6-hour time point, patients who went on to develop delirium had higher increases of chemokines compared to matched controls (class z score 0.3 +/- 1.0, p <.05). Among the five classes of cytokines, there were no other significant differences between patients with or without delirium at either the 6 hour or postoperative day 4 assessments., Conclusion: After cardiac surgery, chemokine levels were elevated in patients who developed delirium in the early postoperative period. Because chemokines are capable of disrupting blood-brain barrier integrity in vitro, future studies are needed to define the relationship of these inflammatory mediators to delirium pathogenesis.

Rit is a novel member of the Ras superfamily of small GTP-binding proteins that regulates signaling pathways controlling cellular fate determination. Constitutively activated mutants of Rit induce terminal differentiation of pheochromocytoma (PC6) cells resulting in a sympathetic neuron-like phenotype characterized by the development of highly-branched neurites. Rit signaling has been found to activate several downstream pathways including MEK/ERK, p38 MAPK, Ral-specific guanine nucleotide exchange factors (GEFs), and Rit associates with the Par6 cell polarity machinery. In this study, a series of Rit effector loop mutants was generated to test the importance of these cellular targets to Rit-mediated neuronal differentiation. We find that Rit-mediated neuritogenesis is dependent upon MEK/ERK MAP kinase signaling but independent of RalGEF activation. In addition, in vivo binding studies identified a novel mechanism of Par6 interaction, suggesting that the cell polarity machinery may serve to spatially restrict Rit signaling.

Objectives: Neurologic injury after cardiac surgery, often manifested as neurocognitive decline, is a common postoperative complication without clear cause. We studied acute variations in gene-expression profiles of patients with neurocognitive decline (NCD group) compared with those without neurocognitive decline (NORM group) after cardiopulmonary bypass., Methods: Forty-two patients undergoing coronary artery bypass grafting, valve procedures, or both by using cardiopulmonary bypass were administered a validated neurocognitive battery preoperatively and postoperatively at day 4. Neurocognitive decline was defined as 1 standard deviation from baseline on 25% or greater of tasks. Whole-blood mRNA was isolated preoperatively and at 6 hours after surgical intervention for fold-change calculation. Relative gene expression in the NCD versus the NORM group was assessed by using Affymetrix GeneChip U133 Plus 2.0 (>40,000 genes) from mRNA samples collected. Differential expression, clustering, gene ontology, and canonical pathway analysis were performed. Validation of microarray gene expression was performed with SYBR Green real-time polymerase chain reaction., Results: Patients with neurocognitive decline (17/42 [40.5%] patients) were associated with a significantly different gene-expression response compared with that of healthy patients. Compared with preoperative samples, 6-hour samples had 531 upregulated and 670 downregulated genes uniquely in the NCD group compared with 2214 upregulated and 558 downregulated genes uniquely in the NORM group (P < .001; lower confidence bound, > or =1.2). Compared with patients in the NORM group, patients with neurocognitive decline had significantly different gene-expression pathways involving inflammation (including FAS, IL2RB, and CD59), antigen presentation (including HLA-DQ1, TAP1, and TAP2), and cellular adhesion (including ICAM2, ICAM3, and CAD7) among others., Conclusions: Patients with neurocognitive decline have inherently different genetic responses to cardiopulmonary bypass compared with those of patients without neurocognitive decline Genetic variations in inflammatory, cell adhesion, and apoptotic pathways might be important contributors to the pathophysiology of neurologic injury after cardiopulmonary bypass and could become a target for prevention and risk stratification.

Background: Delirium is a common, morbid, and costly syndrome that occurs frequently after surgery for atherosclerosis. We hypothesized that vascular risk factors and mildly impaired cognitive performance would independently predispose nondemented patients to develop delirium after noncardiac surgery., Methods: The International Study of Postoperative Cognitive Dysfunction recruited patients undergoing noncardiac surgery from 8 countries. Subjects provided detailed medical history and underwent preoperative testing of multiple cognitive domains with a neuropsychologic battery. Postoperatively, subjects (n=1161) were assessed daily for delirium., Results: Ninety-nine subjects (8%) developed delirium. In bivariable analysis, several vascular risk factors were significantly associated with the likelihood of delirium, including male sex, exposure to tobacco, previous myocardial infarction, and vascular surgery. After adjustment for age, tobacco exposure and vascular surgery were independent vascular risk factors for delirium (adjusted relative risk [RR] 3.2, 95% confidence interval [CI], 2.1-4.9). In addition, mildly impaired cognitive performance, defined as performance 1.5 standard deviation below the mean on either of 2 neuropsychologic tests, was independently associated with delirium (adjusted RR 2.2, 95% CI, 1.4-3.6). Subjects with both vascular risk factors and mildly impaired cognitive performance were at double the risk of delirium (RR 2.2, 95% CI, 1.2-4.2) compared with those with either of these risk factors alone., Conclusions: Vascular risk and mildly impaired cognitive performance independently predispose patients to delirium after noncardiac surgery. These factors will help to identify high-risk patients for delirium and to design and target future intervention strategies.

This narrative review examines serum biomarkers for the diagnosis and monitoring of delirium. Serum biomarkers for delirium fall into three major groups: 1) those that are present or elevated prior to disease onset-risk markers, 2) those that rise with onset and fall with recovery-disease markers, and 3) those that rise in proportion to the consequences of disease-end products. As risk markers, we examine serum chemistries and genetic risk markers. As disease markers, we examine serum anticholinergic activity, amino acids, melatonin, cytokines, cortisol, and gene expression. As end products of delirium, we examine markers of neuronal injury. Finally, we discuss methodological and biostatistical considerations for future biomarker studies. Identifying accurate biomarkers for delirium may shed further light into its pathophysiology and on the interrelationship between delirium and dementia.

Objective: To examine the association between biochemical markers of brain injury (MBI) and the inflammatory response in relation to neurocognitive deficiency (NCD) after cardiopulmonary bypass (CPB)., Summary Background Data: In cardiac surgery, NCD is a common but underdiagnosed complication with an unclear pathophysiology leading to significant morbidity. Despite extensive investigation, identification of a MBI for clinical use and clarifying the pathophysiology of NCD have not been achieved., Methods: Forty patients undergoing CABG and/or valve procedures using CPB were administered a validated neurocognitive battery preoperatively and postoperatively at day 4 and 3 months. S-100b, neuron specific enolase (NSE), and tau protein were assayed as MBIs preoperatively and postoperatively at 6 hours and day 4. C-reactive protein (CRP), interleukin (IL)-6, C3a, and total peroxide levels were also quantified from serum. Impact of cardiotomy suction and antifibrinolytics on markers of brain injury was assessed., Results: The incidence of early NCD was 40% (16 of 40). NSE and tau protein at the 6-hour time point were both significantly elevated in the presence of NCD (NCD group) compared with those without NCD (NORM group) (8.69 +/- 0.82 vs. 5.98 +/- 0.61; P = 0.018 and 68.8 vs. 29.2%; P = 0.015; respectively). S-100b increase was not different between the NCD and NORM groups. Cardiotomy suction significantly elevated S-100b levels, whereas NSE and tau were not significantly influenced. Aprotinin did not have an effect on NCD or levels of MBIs. Also, the NCD group had significantly elevated CRP and peroxide levels compared with the NORM group at postoperative day 4 while C3a was significantly elevated at 6 hours., Conclusion: NSE and tau are better associated with NCD and less influenced by cardiotomy suction compared with S-100beta. Inflammatory and oxidative stress is associated with NCD post-CPB.

Background: It has been recognized that neurocognitive decline (NCD) often occurs as a complication in cardiac surgery. The early inflammatory response and C-reactive protein (CRP) was examined in relation to NCD and to a marker of axonal central nervous system (CNS) injury after cardiopulmonary bypass., Methods: A cohort of patients undergoing coronary artery bypass grafting and/or valve procedures using cardiopulmonary bypass were administered a neurocognitive battery preoperatively and postoperatively at 6 hours and day 4. CRP, interleukin 1 beta, and interleukin 10 were quantified from serum. Increase of serum tau protein after surgery was used as a marker of axonal CNS damage., Results: The rate of NCD was found to be 40.5% in this group. Surprisingly, known predictors of NCD did not differ significantly between patients with/without NCD. Patients with NCD had an early increase of CRP of a significantly higher magnitude than those without NCD (38.01 +/- 11.4 vs 16.49 +/- 3.5 mg/L, P = .042), interleukin 1ss (2.35 +/- 0.3 vs 1.20 +/- 0.2 pg/mL, P = .002), and interleukin 10 (29.77 +/- 4.7 vs 12.94 +/- 2.2 pg/mL, P < .001). Increase in serum Tau protein was significantly correlated to NCD (r = 0.50, P = .02)., Conclusion: Perioperative increases in CRP and inflammatory cytokines are associated with NCD in patients after cardiopulmonary bypass. Thus, it appears that inflammation plays a key role in NCD pathophysiology, likely via axonal CNS injury, and could become a target for prevention.

Objectives: To determine the extent to which preoperative performance on tests of executive function and memory was associated with delirium after coronary artery bypass graft (CABG) surgery., Design: Prospective observational cohort study., Setting: Two academic medical centers and one Department of Veterans Affairs medical center in Massachusetts., Participants: Eighty subjects without preoperative delirium undergoing CABG or CABG-valve surgery completed baseline neuropsychological assessments with validated measures of memory and executive function., Measurements: Beginning on postoperative Day 2, a battery to diagnose delirium was administered daily. Confirmatory factor analysis (CFA) was used to define two cognitive domain composites (memory and executive function). The loading pattern of neuropsychological measures onto the latent cognitive domains was determined a priori. Poisson regression was used to model the association between neuropsychological performance and cognitive domain composite scores and risk of postoperative delirium. The association was expressed as the difference between impaired (0.5 standard deviations (SDs) below mean) and nonimpaired (0.5 SDs above mean) performers., Results: Forty subjects (50%) developed delirium. Measures of memory function were not significantly related to delirium. Of the executive function measures, verbal fluency, category fluency, Hopkins Verbal Learning Test learning, and backward recounting of days and months were significantly related to delirium. Preoperative mental status was a strong predictor of postoperative delirium. After controlling for age, sex, education, medical comorbidity, mental status, and the other cognitive domain, CFA cognitive domain composites suggest that risk for delirium is specific for executive functioning impairment (relative risk (RR) = 2.77, 95% confidence interval (CI) = 1.12-6.87) but not for memory impairment (RR = 0.49, 95% CI = 0.19-1.25)., Conclusion: Worse preoperative performance in executive function was independently associated with greater risk of developing delirium after CABG.