Charting the cellular landscape of pulmonary arterial hypertension through single-cell omics.

This review examines how single-cell omics technologies, particularly single-cell RNA sequencing (scRNAseq), enhance our understanding of pulmonary arterial hypertension (PAH). PAH is a multifaceted disorder marked by pulmonary vascular remodeling, leading to high morbidity and mortality. The cellular pathobiology of this heterogeneous disease, involving various vascular and non-vascular cell types, is not fully understood. Traditional PAH studies have struggled to resolve the complexity of pathogenic cell populations. scRNAseq offers a refined perspective by detailing cellular diversity within PAH, identifying unique cell subsets, gene networks, and molecular pathways that drive the disease. We discuss significant findings from recent literature, summarizing how scRNAseq has shifted our understanding of PAH in human, rat, and mouse models. This review highlights the insights gained into cellular phenotypes, gene expression patterns, and novel molecular targets, and contemplates the challenges and prospective paths for research. We propose ways in which single-cell omics could inform future research and translational efforts to combat PAH.

Impact of COVID status and blood group on complications in patients in hemorrhagic shock.

Objective: Among critically injured patients of various blood groups, we sought to compare survival and complication rates between COVID-19-positive and COVID-19-negative cohorts. Background: SARS-CoV-2 infections have been shown to cause endothelial injury and dysfunctional coagulation. We hypothesized that, among patients with trauma in hemorrhagic shock, COVID-19-positive status would be associated with increased mortality and inpatient complications. As a secondary hypothesis, we suspected group O patients with COVID-19 would experience fewer complications than non-group O patients with COVID-19. Methods: We evaluated all trauma patients admitted 4/2020-7/2020. Patients 16 years or older were included if they presented in hemorrhagic shock and received emergency release blood products. Patients were dichotomized by COVID-19 testing and then divided by blood groups. Results: 3281 patients with trauma were evaluated, and 417 met criteria for analysis. Seven percent (29) of patients were COVID-19 positive; 388 were COVID-19 negative. COVID-19-positive patients experienced higher complication rates than the COVID-19-negative cohort, including acute kidney injury, pneumonia, sepsis, venous thromboembolism, and systemic inflammatory response syndrome. Univariate analysis by blood groups demonstrated that survival for COVID-19-positive group O patients was similar to that of COVID-19-negative patients (79 vs 78%). However, COVID-19-positive non-group O patients had a significantly lower survival (38%). Controlling for age, sex and Injury Severity Score, COVID-19-positive patients had a greater than 70% decreased odds of survival (OR 0.28, 95% CI 0.09 to 0.81; p=0.019). Conclusions: COVID-19 status is associated with increased major complications and 70% decreased odds of survival in this group of patients with trauma. However, among patients with COVID-19, blood group O was associated with twofold increased survival over other blood groups. This survival rate was similar to that of patients without COVID-19.

Patients with both traumatic brain injury and hemorrhagic shock benefit from resuscitation with whole blood.

BACKGROUND: Hemorrhagic shock in the setting of traumatic brain injury (TBI) reduces cerebral blood flow and doubles mortality. The optimal resuscitation strategy for hemorrhage in the setting of TBI is unknown. We hypothesized that, among patients presenting with concomitant hemorrhagic shock and TBI, resuscitation including whole blood (WB) is associated with decreased overall and TBI-related mortality when compared with patients receiving component (COMP) therapy alone. METHODS: An a priori subgroup of prospective, observational cohort study of injured patients receiving emergency-release blood products for hemorrhagic shock is reported. Adult trauma patients presenting November 2017 to September 2020 with TBI, defined as a Head Abbreviated Injury Scale of ≥3, were included. Whole blood group patients received any cold-store low-titer Group O WB units. The COMP group received fractionated blood components alone. Overall and TBI-related 30-day mortality, favorable discharge disposition (home or rehabilitation), and 24-hour blood product utilization were assessed. Univariate and inverse probabilities of treatment-weighted multivariable analyses were performed. RESULTS: Of 564 eligible patients, 341 received WB. Patients who received WB had a higher injury severity score (median, 34 vs. 29), lower scene blood pressure (104 vs. 118), and higher arrival lactate (4.3 vs. 3.6, all p < 0.05). Univariate analysis noted similar overall mortality between WB and COMP; however, weighted multivariable analyses found WB was associated with decreased overall mortality and TBI-related mortality. There were no differences in discharge disposition between the WB group and COMP group. CONCLUSION: In patients with concomitant hemorrhagic shock and TBI, WB transfusion was associated with decreased overall mortality and TBI-related mortality. Whole blood should be considered a first-line therapy for hemorrhage in the setting of TBI. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Surgical management of spontaneous bowel perforation and fascial dehiscence in a patient on bevacizumab and pembrolizumab in the setting of active Clostridium difficile infection.

Immunotherapy such as bevacizumab and pembrolizumab is used to treat an increasing number of malignancies. These medications have been associated with poor wound healing and several gastrointestinal complications, including intestinal perforations in rare cases. We present a unique case of a patient with metastatic cervical cancer on pembrolizumab and recent bevacizumab therapy, presenting with a colonic perforation requiring urgent exploratory laparotomy, in the setting of active Clostridium difficile infection. She required a second laparotomy shortly after due to fascial dehiscence, where a synthetic absorbable mesh was used for fascial approximation. We review the factors that led to these events and describe the surgical technique used for safe abdominal closure.

Is Low-Titer Group O Whole Blood Truly a Universal Blood Product?

BACKGROUND: Whole blood was historically transfused as a type-specific product. Given recent advocacy for low-titer group O whole blood (LTOWB) as a universal blood product, we examined outcomes after LTOWB transfusion stratified by recipient blood groups. STUDY DESIGN: Adult trauma patients receiving prehospital or in-hospital transfusion of LTOWB (November 2017 to July 2020) at a single trauma center were prospectively evaluated. The patients were divided into blood type groups (O, A, B, and AB). Major complications and survival to 30 days were compared. Univariate analyses among blood groups were followed by purposeful regression modeling, reflecting 6 variables of significance: male sex, White race, injury severity, arrival lactate, arrival systolic blood pressure, and emergency department blood products. RESULTS: Of 1,075 patients receiving any LTOWB, 539 (50.1%) were Group O, 340 (31.6%) were Group A, 150 (14.0%) were Group B, and 46 (4.3%) were Group AB. There were no statistically significant differences in demographics, injury severity, hemolysis panels, prehospital vitals, or resuscitation parameters (all p > 0.05). However, arrival systolic pressure was lower (91 vs 102, p = 0.034) and lactate was worse (5.5 vs 4.1, p = 0.048) in Group B patients compared to other groups. While survival and most major complications did not differ across recipient groups, acute kidney injury (AKI) initially appeared higher for Group B. Stepwise regression did not show a difference in AKI rates. This analysis was repeated in patients receiving only component products. Group B again showed no significantly increased risk of AKI (13%) compared to other groups (O 7%, A 7%, AB 5%; p = 0.091). CONCLUSIONS: LTOWB appears to be a safe product for universal use across all blood groups. Group B recipients arrived with worse physiologic values associated with hemorrhagic shock whether receiving LTOWB or standard component products.

Exploration of the external and internal factors that affected learning effectiveness for the students: a questionnaire survey.

Learning effectiveness may be affected by internal and external factors, including personal attitude, motivations, learning skills, learning environment and peer pressure. This study sought to explore potential factors on students who majored in medical technology. The 106 students who completed their internship at Chang Gung Memorial Hospital were enrolled in this study. A written questionnaire was analyzed to explore the relationship between potential factors and learning effectiveness. The strength of relationship between the outcome and each factor was evaluated using Spearman correlation coefficients. A multiple linear regression model was constructed to assess how those factors affected learning effectiveness altogether. The results indicated that the learning effectiveness of the students mainly depended on three factors: the "extracurricular studies" and "willingness to cooperate" were positively associated with learning effectiveness. However, the "weakened motivation due to uncertainty" is negatively associated with learning effectiveness. We suggested that the educators can understand the uncertainty of students about the future. Additionally, the projects that require joint cooperation and discussion need to be given. The most important thing is that students should be able to integrate the learning content instead of rote.

Tm4sf1-marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension.

The identification and role of endothelial progenitor cells in pulmonary arterial hypertension (PAH) remain controversial. Single-cell omics analysis can shed light on endothelial progenitor cells and their potential contribution to PAH pathobiology. We aim to identify endothelial cells that may have stem/progenitor potential in rat lungs and assess their relevance to PAH. Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA sequencing of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic data sets. Rat lung endothelial cells were visualized by immunofluorescence in situ, analyzed by flow cytometry, and assessed for tubulogenesis in vitro. A subpopulation of endothelial cells (endothelial arterial type 2 [EA2]) marked by Tm4sf1 (transmembrane 4 L six family member 1), a gene strongly implicated in cancer, harbored a distinct transcriptomic signature enriched for angiogenesis and CXCL12 signaling. Trajectory analysis predicted that EA2 has a less differentiated state compared with other endothelial subpopulations. Analysis of independent data sets revealed that TM4SF1 is downregulated in lungs and endothelial cells from patients and PAH models, is a marker for hematopoietic stem cells, and is upregulated in PAH circulation. TM4SF1+CD31+ rat lung endothelial cells were visualized in distal pulmonary arteries, expressed hematopoietic marker CD45, and formed tubules in coculture with lung fibroblasts. Our study uncovered a novel Tm4sf1-marked subpopulation of rat lung endothelial cells that may have stem/progenitor potential and demonstrated its relevance to PAH. Future studies are warranted to further elucidate the role of EA2 and Tm4sf1 in PAH.

Impact of Incorporating Whole Blood into Hemorrhagic Shock Resuscitation: Analysis of 1,377 Consecutive Trauma Patients Receiving Emergency-Release Uncrossmatched Blood Products.

BACKGROUND: Use of whole blood (WB) for trauma resuscitation has seen a resurgence. The purpose of this study was to investigate survival benefit of WB across a diverse population of bleeding trauma patients. STUDY DESIGN: A prospective observational cohort study of injured patients receiving emergency-release blood products was performed. All adult trauma patients resuscitated between November 2017 and September 2020 were included. The WB group included patients receiving any group O WB units. The component (COMP) group received no WB units, instead relying on fractionated blood (red blood cells, plasma, and platelets). Univariate and multivariate analyses were performed. Given large observed differences in our regression model, post hoc adjustments with inverse probability of treatment were conducted and a propensity score created. Propensity scoring and Poisson regression supported these findings. RESULTS: Of 1,377 patients receiving emergency release blood products, 840 received WB and 537 remained in the COMP arm. WB patients had higher Injury Severity Score (ISS; 27 vs 20), lower field blood pressure (103 vs 114), and higher arrival lactate (4.2 vs 3.5; all p < 0.05). Postarrival transfusions and complications were similar between groups, except for sepsis, which was lower in the WB arm (25 vs 30%, p = 0.041). Although univariate analysis noted similar survival between WB and COMP (75 vs 76%), logistic regression found WB was independently associated with a 4-fold increased survival (odds ratio [OR] 4.10, p < 0.001). WB patients also had a 60% reduction in overall transfusions (OR 0.38, 95% CI 0.21-0.70). This impact on survival remained regardless of location of transfusion, ISS, or presence of head injury. CONCLUSION: In patients experiencing hemorrhagic shock, WB transfusion is associated with both improved survival and decreased overall blood utilization.

Barriers to Transition to Home From the Neonatal Intensive Care Unit: A Qualitative Perspectives of Parents and Healthcare Providers.

The objective of this study was to explore the challenges faced by parents of former neonatal intensive care unit (NICU) patients in transitioning home from parents' and healthcare providers' perspective. We conducted semistructured individual and group interviews with parents of former NICU patients and healthcare providers. Themes from the individual interviews framed the group interviews' contents. The group interviews were recorded and transcribed, and thematic analysis was performed to identify themes. We conducted individual and group interviews with 16 parents and 33 inpatient and outpatient providers from November 2017 to June 2018. Individual interview participants identified several barriers experienced by parents when transitioning their infant home from the NICU including parental involvement and engagement during NICU stay and during the discharge process. Further exploration within group interviews revealed opportunities to improve discharge communication and processes, standardization of parental education that was lacking due to NICU resource constraints, support for parents' emotional state, and use of technology for infant care in the home. Parents of NICU patients face serious emotional, logistical, and knowledge challenges when transitioning their infant home from the NICU. Understanding and mitigating the challenges of transitioning infants from NICU to home require multistakeholder input from both parents and providers.

Double Dissociation of Auditory Attention Span and Visual Attention in Long-Term Survivors of Childhood Cerebellar Tumor: A Deterministic Tractography Study of the Cerebellar-Frontal and the Superior Longitudinal Fasciculus Pathways.

OBJECTIVE: Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation. METHODS: Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment. RESULTS: A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = -.50, p = .01) and was not associated with visual attention (FA: r = -.11, p = .59; RD: r = -.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = -.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = -.10, p = .62). CONCLUSIONS: The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

Programmatic and Administrative Barriers to High-Risk Infant Follow-Up Care.

OBJECTIVE: This article characterizes programmatic features of a population-based network of high-risk infant follow-up programs and identifies potential challenges associated with attendance from the providers' perspective. STUDY DESIGN: A web-based survey of high-risk infant follow-up program directors, coordinators, and providers of a statewide high-risk infant follow-up system. Frequencies and percentages were used to describe the survey responses. RESULTS: Of the 68 high-risk infant follow-up programs in California, 56 (82%) responded to the survey. The first visit no-show rate between 10 and 30% was estimated by 44% of programs with higher no-show rates for subsequent visits. Common strategies to remind families of appointments were phone calls and mailings. Most programs (54%) did not have a strategy to help families who lived distant to the high-risk infant follow-up clinic. CONCLUSION: High-risk infant follow-up programs may lack resources and effective strategies to enhance follow-up, particularly for those living at a distance.

* Glioblastoma Exosomes for Therapeutic Angiogenesis in Peripheral Ischemia.

Peripheral ischemia as a result of occlusive vascular disease is a widespread problem in patients older than the age of 65. Angiogenic therapies that can induce microvascular growth have great potential for providing a long-lasting solution for patients with ischemia and would provide an appealing alternative to surgical and percutaneous interventions. However, many angiogenic therapies have seen poor efficacy in clinical trials, suggesting that patients with long-term peripheral ischemia have considerable therapeutic resistance to angiogenic stimuli. Glioblastoma is one of the most angiogenic tumor types, inducing robust vessel growth in the area surrounding the tumor. One major angiogenic mechanism used by the tumor cells to induce blood vessel growth is the production of exosomes and other extracellular vesicles that can carry pro-angiogenic and immunomodulatory signals. Here, we explored whether the pro-angiogenic aspects of glioblastoma-derived exosomes could be harnessed to promote angiogenesis and healing in the context of peripheral ischemic disease. We demonstrate that the exosomes derived from glioblastoma markedly enhance endothelial cell proliferation and increase endothelial tubule formation in vitro. An analysis of the microRNA expression using next generation sequencing identified that exosomes contained a high concentration of miR-221. In addition, we found that glioblastoma exosomes contained significant amounts of the proteoglycans glypican-1 and syndecan-4, which can serve as co-receptors for angiogenic factors, including fibroblast growth factor-2 (FGF-2). In a hindlimb ischemia model in mice, we found that the exosomes promoted enhanced revascularization in comparison to control alginate gels and FGF-2 treatment alone. Taken together, our results support the fact that glioblastoma-derived exosomes have powerful effects in increasing revascularization in the context of peripheral ischemia.

Missed opportunities in the referral of high-risk infants to early intervention.

OBJECTIVE: Using a statewide population-based data source, we describe current neonatal follow-up referral practices for high-risk infants with developmental delays throughout California. METHODS: From a cohort analysis of quality improvement data from 66 neonatal follow-up programs in the California Children's Services and California Perinatal Quality Care Collaborative High-Risk Infant Follow-Up Quality of Care Initiative, 5129 high-risk infants were evaluated at the first visit between 4 and 8 months of age in neonatal follow-up. A total of 1737 high-risk infants were evaluated at the second visit between 12 and 16 months of age. We calculated referral rates in relation to developmental status (high versus low concern) based on standardized developmental testing or screening. RESULTS: Among infants with low concerns (standard score >70 or passed screen) at the first visit, 6% were referred to early intervention; among infants with high concerns, 28% of infants were referred to early intervention. Even after including referrals to other (private) therapies, 34% infants with high concerns did not receive any referrals. These rates were similar for the second visit. CONCLUSIONS: In spite of the specialization of neonatal follow-up programs to identify high-risk infants with developmental delays, a large proportion of potentially eligible infants were not referred to early intervention.

Severe feeding disorder and malnutrition in 2 children with autism.

Leanna, a 10-year-old girl with autism, was hospitalized for severe malnutrition and 20 pound weight loss secondary to reduced intake over 4 months. Her food choices became increasingly restrictive to the point where she only ate certain types and brands of foods. She gradually stopped drinking and developed severe constipation and encopresis. A new behavior of collecting saliva in her mouth and spitting onto napkins also emerged. Vital signs and electrolytes were normal on admission. A nasogastric tube was placed because she refused to eat. A behavior modification plan was implemented that awarded points for completing specific tasks related to feeding, which could later be redeemed for specific rewards, such as computer time. Although her ideal body weight increased from 68% to 75% (due to continuous nasogastric tube feeds), her refusal to eat persisted. Upon further data gathering, the staff learned that she moved and changed schools 5 months ago. She was cared for by either a family friend or paid caregiver while her mother worked. Although she could conduct basic self-care activities without assistance and write and draw at a third-grade level, she functioned cognitively at a 4-year-old level. The behavior plan was modified, breaking the tasks into shorter components with immediate and tangible rewards. She soon began eating small portions of food and spitting less frequently. Toileting was later incorporated into this plan. She was referred to a behavioral therapist in the community to work with her at home and school. Weekly visits with her pediatrician and appointments with a child psychiatrist and dietician were made. Orlando, a 3-year-old boy with autism, was evaluated in the emergency room for lethargy and generalized edema for 6 weeks. The history revealed a restrictive diet of commercial pureed fruit and coconut juice for 2 years. He only ate a particular brand and with specific containers; the limited food intake occurred only with his favorite blanket. He refused to eat other types of food. Outpatient treatments were unsuccessful. On physical examination, he was irritable with an erythematous, scaly rash throughout his body. His hair was thin, coarse, and blonde. He had nonpitting edema in his arms, legs, and periorbital region. The laboratory evaluation was significant for anemia, hypoalbuminemia, and hypoproteinemia. He was admitted to the pediatric service where nutritional formula feedings were initiated through a nasogastric tube. Weight gain was adequate, and the hemoglobin, serum albumen, and protein became normal. The rash improved with zinc supplementation. He was transferred to an inpatient feeding disorders unit where a team of occupational therapists implemented a behavioral modification program to overcome his severe food aversion.

Delayed recognition of profound hearing loss in a 7-year-old girl with a neurological condition.

CASE: Kelly is a 7-year-old girl with a complex medical history including asthma, mild spastic diplegia, and seizure disorder that is controlled with carbamazepine. She had a significant receptive and expressive language impairment and milder delays in gross and fine motor skills. Kelly is currently repeating first grade in a self-contained classroom; she receives speech, occupational, and physical therapy. At the 7-year-old well child visit, her mother is worried about Kelly's poor progress in school, and she expresses concern about her daughter's hearing. Her pediatrician observes that Kelly is withdrawn, uses minimal language, and is fearful of the examination. Kelly was born full-term by Cesarean section because of placental abruption. She was in the neonatal intensive care nursery for 2 weeks with metabolic acidosis because of acute tubular necrosis. One day after arriving home, she had a cardiopulmonary arrest followed by emergency open-heart surgery for critical pulmonary hypertension. Her postoperative course was significant for renal failure, extracorporal membrane oxygenation, ventilator dependency, tracheostomy, and gastrostomy. By 3 years of age her medical condition stabilized, and the tracheostomy and gastrostomy tubes were removed. A review of Kelly's previous audiological tests revealed a failed otoacoustic emission test at 5 months. An auditory brain stem response test at 8 months recorded normal hearing in the right ear. At 4 years, behavioral audiometry was attempted but not completed because Kelly cried throughout the session. At 5 years, testing with ear inserts showed normal hearing bilaterally. Because of the concerns raised by Kelly's mother at the pediatric visit, she was referred to audiology for a reevaluation. Testing at this time revealed moderate to profound sensorineural hearing loss in both the ears, which was confirmed on subsequent examinations. Kelly was promptly fitted for hearing aids. Her individual education plan was changed to reflect the diagnosis of hearing impairment, and hearing services were implemented in the classroom. On a recent follow-up visit, Kelly was talkative, engaging, and cheerful.

Delayed recognition of profound hearing loss in a 7-year-old girl with a neurological condition.

Kelly is a 7-year-old girl with a complex medical history including asthma, mild spastic diplegia, and seizure disorder that is controlled with carbamazepine. She had a significant receptive and expressive language impairment and milder delays in gross and fine motor skills. Kelly is currently repeating first grade in a self-contained classroom; she receives speech, occupational, and physical therapy. At the 7-year-old well child visit, her mother is worried about Kelly's poor progress in school, and she expresses concern about her daughter's hearing. Her pediatrician observes that Kelly is withdrawn, uses minimal language, and is fearful of the examination.Kelly was born full-term by Cesarean section because of placental abruption. She was in the neonatal intensive care nursery for 2 weeks with metabolic acidosis because of acute tubular necrosis. One day after arriving home, she had a cardiopulmonary arrest followed by emergency open-heart surgery for critical pulmonary hypertension. Her postoperative course was significant for renal failure, extracorporal membrane oxygenation, ventilator dependency, tracheostomy, and gastrostomy. By 3 years of age her medical condition stabilized, and the tracheostomy and gastrostomy tubes were removed.A review of Kelly's previous audiological tests revealed a failed otoacoustic emission test at 5 months. An auditory brain stem response test at 8 months recorded normal hearing in the right ear. At 4 years, behavioral audiometry was attempted but not completed because Kelly cried throughout the session. At 5 years, testing with ear inserts showed normal hearing bilaterally.Because of the concerns raised by Kelly's mother at the pediatric visit, she was referred to audiology for a reevaluation. Testing at this time revealed moderate to profound sensorineural hearing loss in both the ears, which was confirmed on subsequent examinations. Kelly was promptly fitted for hearing aids. Her individual education plan was changed to reflect the diagnosis of hearing impairment, and hearing services were implemented in the classroom. On a recent follow-up visit, Kelly was talkative, engaging, and cheerful.

A sub-neighborhood scale land use regression model for predicting NO(2).

This study set out to develop a land use regression model at sub-neighborhood scale (0.01-1 km) for Portland, Oregon using passive measurements of NO(2) at 77 locations. Variables used to develop the model included road and railroad density, traffic volume, and land use with buffers of 50 to 750 m surrounding each measurement site. An initial regression model was able to predict 66% of the variation in NO(2). Including wind direction in the regression model increased predictive power by 15%. Iterative random exclusion of 11 sites during model calibration resulted in a 3% variation in predictive power. The regression model was applied to the Portland metropolitan area using 10 m gridded land use layers. This study further validates land use regression for use in North America, and identifies important considerations for their use, such as inclusion of railways, open spaces and meteorological patterns.

Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease.

CONTEXT: Alzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) beta-amyloid1-42 and tau proteins. OBJECTIVES: To compare CSF beta-amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF beta-amyloid and tau levels in AD patients and controls. DESIGN: Cross-sectional study of the comparison of baseline CSF beta-amyloid1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF beta-amyloid and 34 studies of CSF tau. SETTING: Clinical research unit of the National Institute of Mental Health, Bethesda, Md. PATIENTS: The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls. MAIN OUTCOME MEASURES: Levels of CSF beta-amyloid1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay. RESULTS: Levels of CSF beta-amyloid1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Levels of CSF tau were significantly higher in AD patients (mean [SD], 587 [365] pg/mL vs 244 [156] pg/mL; P<.001). The cutpoints of 444 pg/mL for CSF beta-amyloid1-42 and 195 pg/mL for CSF tau gave a sensitivity and specificity of 92% and 89%, respectively, to distinguish AD patients from controls, which is comparable with rates with clinical diagnosis. Meta-analyses of studies comparing CSF beta-amyloid and tau levels in AD participants and controls confirmed an overall difference between levels in these 2 groups. CONCLUSIONS: Alzheimer disease is associated with a significant decrease in CSF beta-amyloid1-42 levels along with an increase in CSF tau levels. These findings suggest that the 2 measures are biological markers of AD pathophysiology. While these CSF measures may have a potential clinical utility as biomarkers of disease, the preliminary and retrospective nature of the findings, the absence of assay standardization, and the lack of comparison patient populations must be addressed in future studies testing the usefulness of these CSF measures for predictive, diagnostic, or treatment evaluation purposes.