A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aß42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

Application of Postcolonial Feminist Theory, Chicana Feminist Thought, and Black Feminist Thought in Analyzing the Mental Health Needs of Latina Migrant Farmworkers: A Shared Legacy.

The purpose of this theoretical article is to analyze the utility of postcolonial, Black, and Chicana feminist frameworks to inform nursing research and practice specific to mental health needs of Latina women migrant farmworkers. Twentieth-century Western feminist narratives overlooked the intersecting systems of oppression experienced by women of color, including Latina women. Feminist epistemologies are useful in understanding the complex sociopolitical contexts that have impacted women's health outcomes and well-being. This analysis is critical to shaping nursing care that meets the unique health needs of migrant farmworker women while considering their sociopolitical realities.

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.

Race and Blackness: A Thematic Review of Communication Challenges Confronting the Black Community Within the U.S. Health Care System.

Effective communication is integral to the patient-provider relationship. Yet, as a result of structural factors that ignore the unique health care needs of different populations of patients who identify as Black-both African American and African immigrants-are confronted with communication challenges during health care seeking encounters. Using cultural safety as a framework, in this article, we thematically review communication challenges specifically experienced by patients of African descent in the U.S. health care system. In our review, we focus on complications that might arise from discrimination, mistrust, health literacy, and impacts of culture and language barriers on health literacy. In conclusion, we offer recommendations for improving the health care experiences and potential health outcomes for this population, through nursing care and health care delivery.

Racial Disparity in Cerebrospinal Fluid Amyloid and Tau Biomarkers and Associated Cutoffs for Mild Cognitive Impairment.

Importance: Prior evidence suggests that racial differences exist in tau biomarkers in mild cognitive impairment (MCI) and Alzheimer disease (AD). Whether this reported disparity is associated with a differential level of neurodegeneration and disease stage or with underlying mechanisms separate from amyloid or tau is unclear. Objectives: To compare cerebrospinal fluid (CSF) biomarkers in African American and white individuals with normal cognition and MCI, to estimate race-based cutoffs for these biomarkers that maximize diagnostic discrimination between normal cognition and MCI, and to study the association of demographic characteristics, cognitive performance, and common vascular risk factors with these differences. Design, Setting, and Participants: This case-control study conducted from March 1, 2016, through January 31, 2019, included participants in the Brain Stress Hypertension and Aging Research Program cohort undergoing baseline assessment. Participants were 50 years or older and recruited from the Atlanta, Georgia, area. Exposures: Self-reported race and cognitive status categorized using modified Petersen criteria and clinical consensus diagnosis. Main Outcomes and Measures: Levels of ß-amyloid 1-42 (Aß1-42), tau, and phosphorylated tau 181 (pTau181), the ratio of tau or pTau181 to Aß1-42, and hippocampal volume on magnetic resonance imaging of the brain. Results: Data from 362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years), of whom 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjustment for demographic characteristics and cognitive performance, lower mean (SE) levels were observed in African American vs white individuals with MCI for tau (52.40 [5.90] vs 78.98 [5.02] pg/mL; P = .001) and pTau181 (15.42 [2.06] vs 25.24 [1.75] pg/mL; P = .001) and a lower pTau181 to Aß1-42 ratio (0.07 [0.02] vs 0.14 [0.01]; P = .003). There were no racial differences in the normal cognition group or in hippocampal volumes in the MCI group. Cutoffs for CSF biomarkers were higher for Aß1-42 in African American relative to white individuals (208 [95% CI, 126-321] vs 197 [95% CI, 183-245] pg/mL) and lower for tau (51 [95% CI, 31-59] vs 59 [95% CI, 56-92] pg/mL) and pTau181 (12 [95% CI, 12-19] vs 20 [95% CI, 12-27] pg/mL) levels. Cutoffs for the pTau181 to Aß1-42 ratio were 0.05 (95% CI, 0.03-0.12) for African American participants and 0.05 (95% CI, 0.05-0.13) for white participants. Conclusions and Relevance: This study found that African American individuals had lower levels of tau-based biomarkers that were not likely explained by the degree of disease stage or neurodegeneration reflected by hippocampal volumes. This study suggests that race is an important factor when interpreting CSF biomarkers, especially in the clinical diagnosis of prodromal AD. It appears that using the pTau181 to Aß1-42 ratio may ameliorate these differences.

The Assessment of Self-Determination in Spanish and American Adolescents: The Self-Determination Inventory: Student Report.

The purpose of this study was to explore the cross-cultural validity of the Self-Determination Inventory: Student Report, a newly developed measure of self-determination grounded in Causal Agency Theory. The tool was translated to Spanish and administered to American and Spanish adolescents. The sample was structured to include adolescents with and without intellectual disability in both cultural contexts. More than 3,000 students in the U.S. and Spain aged 13 to 22 completed the assessment. Findings suggest that the same set of items can be used across cultural contexts and in youth with and without intellectual disability, although there are some specific differences in item functioning across students with and without intellectual disability in Spain that must be further researched. There were specific patterns of differences in latent self-determination means, with students with intellectual disability scoring lower in the U.S. and Spain. Implications for assessment research and practice in diverse cultural contexts are explored.

An Emancipatory Approach to Cultural Competency: The Application of Critical Race, Postcolonial, and Intersectionality Theories.

Nurses teach, work, and conduct research in an increasingly hostile sociopolitical climate where health inequities persist among marginalized communities. Current approaches to cultural competency do not adequately equip nurses to address these complex factors and risk perpetuating stereotypes and discrimination. A theory-driven emancipatory approach to cultural competency will instead lead to lasting change and uphold the core nursing value of commitment to social justice. This article explicates key tenets of critical race, postcolonial feminist, and intersectionality theories and then applies them, using an emancipatory approach to cultural competency that can reshape nursing education, research, and practice.

Design of comprehensive Alzheimer's disease centers to address unmet national needs.

The problem of Alzheimer's disease (AD) exemplifies the challenges of dealing with a broad range of aging-related chronic disorders that require long-term, labor-intensive, and expensive care. As the baby boom generation ages and brain diseases become more prevalent, the need to confront the pending health care crisis is more urgent than ever before. Indeed, there is now a critical need to expand significantly the national effort to solve the problem of AD, with special focus on prevention. The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020) aims to create a new paradigm for planning and supporting the organization of worldwide cooperative research networks to develop new technologies for early detection and treatments of aging-related memory and motor impairments. PAD 2020 is developing an implementation plan to justify (1) increasing the federal budget for research, (2) developing novel national resources to discover new interventions for memory and motor disorders, and (3) creating innovative and streamlined decision-making processes for selecting and supporting new ideas. Since 1978 the National Institute on Aging or National Institute of Health (NIH) established an extensive national network of AD research facilities at academic institutions including AD Centers (ADCs), Consortium to Establish a Registry for AD, AD Cooperative Study (ADCS), AD Drug Discovery Program, National Alzheimer's Coordinating Center, National Cell Repository for AD, and AD Neuroimaging Initiative. However, despite the success of these programs and their critical contributions, they are no longer adequate to meet the challenges presented by AD. PAD 2020 is designed to address these changes by improving the efficiency and effectiveness of these programs. For example, the ADCs (P30s and P50s) can be enhanced by converting some into Comprehensive Alzheimer's Disease Centers (CADCs) to support not only research, but also by being demonstration projects on care/treatment, clinical trials, and education as well as by seamlessly integrating multisite collaborative studies (ADCS, AD Neuroimaging Initiative, Patient Registries, Clinical Data Banks, etc) into a cohesive structure that further enhances the original mission of the National Institute on Aging ADCs. Regional CADCs offer greater efficiency and cost savings while serving as coordinating hubs of existing ADCs, thereby offering greater economies of scale and programmatic integration. The CADCs also broaden the scope of ADC activities to include research on interventions, diagnosis, imaging, prevention trials, and other longitudinal studies that require long-term support. Thus, CADCs can address the urgent need to identify subjects at high risk of AD for prevention trials and very early in the course of AD for clinical trials of disease modification. The enhanced CADCs will allow more flexibility among ADCs by supporting collaborative linkages with other institutions and drawing on a wider expertise from different locations. This perspective article describes the University of Pennsylvania (Penn) CADC Model as an illustrative example of how an existing ADC can be converted into a CADC by better utilization of Penn academic resources to address the wide range of problems concerning AD. The intent of this position paper is to stimulate thinking and foster the development of other or alternative models for a systematic approach to the study of dementia and movement disorders.

Review of the newest HPLC methods with mass spectrometry detection for determination of immunosuppressive drugs in clinical practice.

High performance liquid chromatography coupled with electrospray mass spectrometry is widely used for quantitative determination of immunosuppressive drugs (sirolimus, tacrolimus, everolimus, CsA and MPA) in biological fluids. The growth in volume for testing these drugs and economic constraints in clinical laboratories has led to heightened demand for high throughput methods. Fast-flow on-line extraction with switching valve technique and implementation of automation accelerates sample preparation. For on-line purification the combination of fast flow of washing solution and narrow-bore extraction column provides a clean sample in a very short time without compromising precision and accuracy. The unique feature of multireactant monitoring tandem mass spectrometry reduces significantly the need for chromatographic separation, as long as matrix effects are not detected, and permits simultaneous measurement of several drugs in one run when they are present in the same specimen. Additionally, the same method together with the identical sample preparation and HPLC-MS conditions and setting can be used for measurement of all five immunosuppressants, four of them in blood, MPA in plasma. Thanks to the high sensitivity of LC-MS only a small volume of biological sample is required for analysis. However for MPA quantitation, mass interference attributable to in-source fragmentation of its glucuronide metabolite can be a problem if the latter is not chromatographically separated from the parent drug before introduction of the sample into the ion source. Thus, chromatographic separation is extremely important for MPA analysis. In conclusion, important features of LC-MS methodology for immunosuppressive drugs include: shortened analysis time, increased throughput, selectivity and lower cost of analysis.

HPLC-atmospheric pressure chemical ionization MS/MS for quantification of 15-F2t-isoprostane in human urine and plasma.

BACKGROUND: Quantification of F(2)-Isoprostanes is considered a reliable index of the oxidative stress status in vivo and is valuable in the diagnosis and monitoring of a variety of diseases. Because of complex and lengthy sample preparation procedures, current chromatography/mass spectrometry and immunoassays are impractical for measuring larger numbers of samples. Thus, we developed and validated a semiautomated high-throughput HPLC tandem mass spectrometry assay for the quantification of F(2)-Isoprostane F(2t) in human urine and plasma. METHODS: After protein precipitation (500 microL methanol/zinc sulfate added to 500 microL plasma), samples were injected into the HPLC system and extracted online. The extracts were then back-flushed onto the analytical column and detected with an atmospheric pressure chemical ionization-triple quadrupole mass spectrometer monitoring the deprotonated molecular ions [M-H](-) of 15-F(2t)-IsoP (m/z = 353-->193) and the internal standard 15-F(2t)-IsoP-d(4) (m/z = 357-->197). RESULTS: In human urine, the assay was linear from 0.025 to 80 microg/L and in human plasma from 0.0025 to 80 microg/L (r(2)>0.99). Interday accuracy and precision for concentrations above the lower limit of quantification were <10%. Concentrations of 15-F(2t)-IsoP in urine of 16 healthy individuals ranged from 55-348 ng/g creatinine. In 16 plasma samples from healthy individuals, free 15-F(2t)-IsoP was detectable in all samples and concentrations were 3-25 ng/L. CONCLUSIONS: Our assay meets all predefined method performance criteria, allows for analysis of >80 samples/day, and has sufficient sensitivity for quantifying 15-F(2t)-IsoP concentrations in plasma and urine from healthy individuals. It is, thus, suitable for clinical routine monitoring and the analysis of samples from larger clinical trials.

Efficacy and time-efficiency of a "sonographer-driven" contrast echocardiography protocol in a high-volume echocardiography laboratory.

BACKGROUND: Contrast echocardiography (CE) has not gained widespread use despite numerous studies demonstrating its efficacy in the assessment of left ventricular (LV) function. METHODS: We sought to determine whether CE could be used in a high-volume echocardiography laboratory in a clinically effective and time efficient manner. We implemented a protocol with a feasibility phase and an established phase. Cost-benefit analyses were done on the basis of time use. RESULTS: During the feasibility and established phases, data on 119 and 672 patients, respectively, were obtained. After a "sonographer-driven" protocol, contrast studies represented 7% to 8% of the total number of routine transthoracic and stress studies. Stress studies accounted for only 15% of the total number of contrast studies. Obesity was the most common indication for contrast use. LV visualization indices and wall thickening assessment, as evaluated by 2 blinded readers, were significantly improved with CE compared with second harmonic imaging alone. The time to make the decision to use CE and the time taken to administer contrast decreased significantly from the feasibility phase to the established phase (8.3 +/- 5 vs 7.6 +/- 5 min, P <.01, and 13.4 +/- 10 vs 10.2 +/- 5 min, P <.001, respectively). On the basis of time use only, a cost analysis indicated that savings were obtained at a 10-minute reduction in study time. CONCLUSIONS: A "sonographer-driven" CE protocol for LV assessment is feasible in high-volume echocardiography laboratories. It is clinically effective because it significantly improves LV global and regional wall motion visualization. A "sonographer-driven" CE protocol can reduce decision and administration times substantially, thus making CE time-efficient.