Pan-Cancer Proteomics Analysis to Identify Tumor-Enriched and Highly Expressed Cell Surface Antigens as Potential Targets for Cancer Therapeutics.

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) provides unique opportunities for cancer target discovery using protein expression. Proteomics data from CPTAC tumor types have been primarily generated using a multiplex tandem mass tag (TMT) approach, which is designed to provide protein quantification relative to reference samples. However, relative protein expression data are suboptimal for prioritization of targets within a tissue type, which requires additional reprocessing of the original proteomics data to derive absolute quantitation estimation. We evaluated the feasibility of using differential protein analysis coupled with intensity-based absolute quantification (iBAQ) to identify tumor-enriched and highly expressed cell surface antigens, employing tandem mass tag (TMT) proteomics data from CPTAC. Absolute quantification derived from TMT proteomics data was highly correlated with that of label-free proteomics data from the CPTAC colon adenocarcinoma cohort, which contains proteomics data measured by both approaches. We validated the TMT-iBAQ approach by comparing the iBAQ value to the receptor density value of HER2 and TROP2 measured by flow cytometry in about 30 selected breast and lung cancer cell lines from the Cancer Cell Line Encyclopedia. Collections of these tumor-enriched and highly expressed cell surface antigens could serve as a valuable resource for the development of cancer therapeutics, including antibody-drug conjugates and immunotherapeutic agents.

Tutorial on Firth's Logistic Regression Models for Biomarkers in Preclinical Space.

Preclinical studies are broad and can encompass cellular research, animal trials, and small human trials. Preclinical studies tend to be exploratory and have smaller datasets that often consist of biomarker data. Logistic regression is typically the model of choice for modeling a binary outcome with explanatory variables such as genetic, imaging, and clinical data. Small preclinical studies can have challenging data that may include a complete separation or quasi-complete separation issue that will result in logistic regression inflated coefficient estimates and standard errors. Penalized regression approaches such as Firth's logistic regression are a solution to reduce the bias in the estimates. In this tutorial, a number of examples with separation (complete or quasi-complete) are illustrated and the results from both logistic regression and Firth's logistic regression are compared to demonstrate the inflated estimates from the standard logistic regression model and bias-reduction of the estimates from the penalized Firth's approach. R code and datasets are provided in the supplement.

Statistical Models for the Analysis of Isobaric Tags Multiplexed Quantitative Proteomics.

Mass spectrometry is being used to identify protein biomarkers that can facilitate development of drug treatment. Mass spectrometry-based labeling proteomic experiments result in complex proteomic data that is hierarchical in nature often with small sample size studies. The generalized linear model (GLM) is the most popular approach in proteomics to compare protein abundances between groups. However, GLM does not address all the complexities of proteomics data such as repeated measures and variance heterogeneity. Linear models for microarray data (LIMMA) and mixed models are two approaches that can address some of these data complexities to provide better statistical estimates. We compared these three statistical models (GLM, LIMMA, and mixed models) under two different normalization approaches (quantile normalization and median sweeping) to demonstrate when each approach is the best for tagged proteins. We evaluated these methods using a spiked-in data set of known protein abundances, a systemic lupus erythematosus (SLE) data set, and simulated data from multiplexed labeling experiments that use tandem mass tags (TMT). Data are available via ProteomeXchange with identifier PXD005486. We found median sweeping to be a preferred approach of data normalization, and with this normalization approach there was overlap with findings across all methods with GLM being a subset of mixed models. The conclusion is that the mixed model had the best type I error with median sweeping, whereas LIMMA had the better overall statistical properties regardless of normalization approaches.

Comparison of brain structural variables, neuropsychological factors, and treatment outcome in early-onset versus late-onset late-life depression.

OBJECTIVE: To compare differences in gray matter volumes, white matter and subcortical gray matter hyperintensities, neuropsychological factors, and treatment outcome between early- and late-onset late-life depressed (LLD) subjects. METHODS: We conducted a prospective, nonrandomized, controlled trial at the outpatient clinics at Washington University and Duke University on 126 subjects, aged 60 years or older, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received neuropsychological testing and magnetic resonance imaging. Subjects were excluded for cognitive impairment or severe medical disorders. After 12 weeks of sertraline treatment, subjects' MADRS scores over time and neuropsychological factors were studied. RESULTS: Left anterior cingulate thickness was significantly smaller in the late-onset depressed group than in the early-onset LLD subjects. The late-onset group also had more hyperintensities than the early-onset LLD subjects. No differences were found in neuropsychological factor scores or treatment outcome between early-onset and late-onset LLD subjects. CONCLUSION: Age at onset of depressive symptoms in LLD subjects are associated with differences in cortical thickness and white matter and subcortical gray matter hyperintensities, but age at onset did not affect neuropsychological factors or treatment outcome.

Serotonin signaling is associated with lower amyloid-ß levels and plaques in transgenic mice and humans.

Aggregation of amyloid-ß (Aß) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aß levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aß metabolism. We assessed the ability of serotonin signaling to alter brain Aß levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aß levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aß levels. Serotonin-dependent reductions in Aß were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aß plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aß accumulation in cognitively normal individuals.

Application of copulas to improve covariance estimation for partial least squares.

Dimension reduction techniques, such as partial least squares, are useful for computing summary measures and examining relationships in complex settings. Partial least squares requires an estimate of the covariance matrix as a first step in the analysis, making this estimate critical to the results. In addition, the covariance matrix also forms the basis for other techniques in multivariate analysis, such as principal component analysis and independent component analysis. This paper has been motivated by an example from an imaging study in Alzheimer's disease where there is complete separation between Alzheimer's and control subjects for one of the imaging modalities. This separation occurs in one block of variables and does not occur with the second block of variables resulting in inaccurate estimates of the covariance. We propose the use of a copula to obtain estimates of the covariance in this setting, where one set of variables comes from a mixture distribution. Simulation studies show that the proposed estimator is an improvement over the standard estimators of covariance. We illustrate the methods from the motivating example from a study in the area of Alzheimer's disease.

Bootstrapping GEE models for fMRI regional connectivity.

An Alzheimer's fMRI study has motivated us to evaluate inter-regional correlations during rest between groups. We apply generalized estimating equation (GEE) models to test for differences in regional correlations across groups. Both the GEE marginal model and GEE transition model are evaluated and compared to the standard pooling Fisher-z approach using simulation studies. Standard errors of all methods are estimated both theoretically (model-based) and empirically (bootstrap). Of all the methods, we find that the transition models have the best statistical properties. Overall, the model-based standard errors and bootstrap standard errors perform about the same. We also demonstrate the methods with a functional connectivity study in a healthy cognitively normal population of ApoE4+ participants and ApoE4- participants who are recruited from the Adult Children's Study conducted at the Washington University Knight Alzheimer's Disease Research Center.

Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease.

OBJECTIVE: There is a growing need to identify cerebrospinal fluid (CSF) markers that can detect Alzheimer's disease (AD) pathology in cognitively normal individuals because it is in this population that disease-modifying therapies may have the greatest chance of success. While AD pathology is estimated to begin ~10-15 years prior to the onset of cognitive decline, substantial neuronal loss is present by the time the earliest signs of cognitive impairment appear. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. Here we investigate CSF VILIP-1 and VILIP-1/amyloid-ß42 (Aß42) ratio as diagnostic and prognostic markers in early AD. METHODS: We assessed CSF levels of VILIP-1, tau, phosphorylated-tau181 (p-tau181), and Aß42 in cognitively normal controls (CNC) (n = 211), individuals with early symptomatic AD (n = 98), and individuals with other dementias (n = 19). Structural magnetic resonance imaging (n = 192) and amyloid imaging with Pittsburgh Compound-B (n = 156) were obtained in subsets of this cohort. Among the CNC cohort, 164 individuals had follow-up annual cognitive assessments for 2-3 years. RESULTS: CSF VILIP-1 levels differentiated individuals with AD from CNC and individuals with other dementias. CSF VILIP-1 levels correlated with CSF tau, p-tau181, and brain volumes in AD. VILIP-1 and VILIP-1/Aß42 predicted future cognitive impairment in CNC over the follow-up period. Importantly, CSF VILIP-1/Aß42 predicted future cognitive impairment at least as well as tau/Aß42 and p-tau181/Aß42. INTERPRETATION: These findings suggest that CSF VILIP-1 and VILIP-1/Aß42 offer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normal individuals similarly to tau and tau/Aß42, respectively.

APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aß42.

Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-ß (Aß) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aß plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aß plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.

Preexisting statin use is associated with greater reperfusion in hyperacute ischemic stroke.

BACKGROUND AND PURPOSE: Statin pretreatment has been associated with improved outcomes in patients with ischemic stroke. Although several mechanisms have been examined in animal models, few have been examined in patients. We hypothesized that patients using statins before stroke onset may have greater reperfusion than patients not using statins. METHODS: Acute ischemic stroke patients underwent 2 MR scans: within 4.5 (tp1) and at 6 hours (tp2) after stroke onset. Regions of reperfusion were defined by prolonged mean transit time (MTT) at tp1, which normalized at tp2. Four MTT thresholds were assessed to ensure that results were not spuriously based on an arbitrary threshold. Baseline characteristics, relative reperfusion, and change in NIHSS between tp1 and 1-month follow-up (ΔNIHSS) were compared between patients who were using statins at stroke onset and those who were not. RESULTS: Thirty-one stroke patients were prospectively enrolled; 12 were using statins and 19 were not. Baseline characteristics did not differ between the 2 groups except the statin group had greater coronary artery disease (P=0.03). Patients using statins showed significantly greater reperfusion compared to untreated patients across all MTT thresholds. For MTT of 4 seconds, median relative reperfusion was 50% (interquartile range, 30%-56%) in the preexisting statin group versus 13% (interquartile range, 5%-36%) in the untreated group (P=0.014). The statin group had greater ΔNIHSS (8.8±4.0 points) compared to the untreated group (4.4±5.7 points; P=0.028). CONCLUSIONS: Statin use before ischemic stroke onset was associated with greater early reperfusion and NIHSS improvement. Further studies in larger populations are required to confirm our preliminary findings.

A Likelihood-Based Approach for Missing Genotype Data.

Missing genotype data in a candidate gene association study can make it difficult to model the effects of multiple genetic variants simultaneously. In particular, when regression models are used to model phenotype as a function of SNP genotypes in several different genes, the most common approach is a complete case analysis, in which only individuals with no missing genotypes are included. But this can lead to substantial reduction in sample size and thus potential bias and loss in efficiency. A number of other methods for handling missing data are applicable, but have rarely been used in this context. The purpose of this paper is to describe how several standard methods for handling missing data can be applied or adapted to this problem, and to compare their performance using a simulation study. We demonstrate these techniques using an Alzheimer's disease association study. We show that the expectation-maximization algorithm and multiple imputation with a bootstrapped expectation-maximization sampling algorithm have the best properties of all the estimators studied.

Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR.

Resistance to antibody-drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance.

Do hospitals provide lower quality of care to black patients for pneumonia?

OBJECTIVES: Recent studies reported lower quality of care for black vs. white patients with community-acquired pneumonia and suggested that disparities persist at the individual hospital level. We examined racial differences in emergency department and intensive care unit care processes to determine whether differences persist after adjusting for case-mix and variation in care across hospitals. DESIGN: Prospective, observational cohort study. SETTING: Twenty-eight U.S. hospitals. PATIENTS: Patients with community-acquired pneumonia: 1738 white and 352 black patients. INTERVENTIONS: None. MEASUREMENTS: We compared care quality based on antibiotic receipt within 4 hrs and adherence to American Thoracic Society antibiotic guidelines, and intensity based on intensive care unit admission and mechanical ventilation use. Using random effects and generalized estimating equations models, we adjusted for case-mix and clustering of racial groups within hospitals and estimated odds ratios for differences in care within and across hospitals. MAIN RESULTS: Black patients were less likely to receive antibiotics within 4 hrs (odds ratio, 0.55; 95% confidence interval, 0.43-0.70; p < .001) and less likely to receive guideline-adherent antibiotics (odds ratio, 0.72; 95% confidence interval, 0.57-0.91; p = .006). These differences were attenuated after adjusting for casemix (odds ratio, 0.59; 95% confidence interval; 0.46-0.76 and 0.84; 95% confidence interval, 0.66 -1.09). Within hospitals, black and white patients received similar care quality (odds ratio, 1; 95% confidence interval, 0.97-1.04 and 1; 95% confidence interval, 0.97-1.03). However, hospitals that served a greater proportion of black patients were less likely to provide timely antibiotics (odds ratio, 0.84; 95% confidence interval, 0.78-0.90). Black patients were more likely to receive mechanical ventilation (odds ratio, 1.57; 95% confidence interval, 1.02-2.42; p = .042). Again, within hospitals, black and white subjects were equally likely to receive mechanical ventilation (odds ratio, 1; 95% confidence interval, .94-1.06) and hospitals that served a greater proportion of black patients were more likely to institute mechanical ventilation (odds ratio, 1.13; 95% confidence interval, 1.02-1.25). CONCLUSIONS: Black patients appear to receive lower quality and higher intensity of care in crude analyses. However, these differences were explained by different case-mix and variation in care across hospitals. Within the same hospital, no racial differences in care were observed.

Differences in immune response may explain lower survival among older men with pneumonia.

OBJECTIVE: Lower life expectancy in men is generally attributed to higher likelihood of risky behavior and because men develop chronic conditions earlier. If sex-related differences in survival are independent of preinfection chronic health and health behavior, it would suggest that survival differences may occur because of sex differences in quality of care and biological response to infection, and these differences may contribute to sex differences in life expectancy. We assessed if sex-related survival difference following community-acquired pneumonia (CAP) is due to differences in clinical characteristics, quality of care, or immune response. DESIGN, SETTING, AND SUBJECTS: Prospective observational cohort of 2183 subjects with CAP. MEASUREMENTS AND MAIN RESULTS: Mean age was 64.9 years. Men were more likely to smoke and had more comorbidity compared with women. At emergency department presentation, men had different biomarker patterns, as evidenced by higher inflammation (tumor necrosis factor, interleukin [IL]-6, and IL-10) and fibrinolysis (d-dimer), and lower coagulation biomarkers (antithrombin-III and factor IX) (p < 0.05). Small differences in favor of men were seen in care quality, including antibiotic timing and compliance with American Thoracic Society guidelines. Men had lower survival at 30, 90, and 365 days. The higher 1-year mortality was not attenuated when adjusted for differences in demographics, smoking, resuscitation, insurance, and vaccination status, comorbidity, hospital characteristics, and illness severity (unadjusted hazard ratio [HR] = 1.35, p = 0.003; and adjusted HR = 1.29, p = 0.004). HR was no longer statistically significant when additionally adjusted for differences in emergency department concentrations of tumor necrosis factor, IL-6, IL-10, d-dimer, antithrombin-III, and factor IX (adjusted HR = 1.27, p = 0.17). Patterns of biomarkers observed in men were associated with worse survival for 1 year. CONCLUSIONS: Lower survival among men following CAP was not explained by differences in chronic diseases, health behaviors, and quality of care. Patterns of inflammatory, coagulation, and fibrinolysis biomarkers among men may explain reduced short-term and long-term survival.

Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis.

RATIONALE: Survivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown. OBJECTIVES: To investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes. METHODS: Prospective cohort study at 28 sites. MEASUREMENTS AND MAIN RESULTS: We used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008). CONCLUSIONS: Despite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.

Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients.

Data are limited on the attributable outcomes of Clostridium difficile-associated disease (CDAD), particularly in CDAD-endemic settings. We conducted a retrospective cohort study of nonsurgical inpatients admitted for >/=48 hours in 2003 (N = 18,050). The adjusted hazard ratios for readmission (hazard ratio 2.19, 95% confidence interval [CI] 1.87-2.55) and deaths within 180 days (hazard ratio 1.23, 95% CI 1.03-1.46) were significantly different among CDAD case-patients and noncase patients. In a propensity score matched-pairs analysis that used a nested subset of the cohort (N = 706), attributable length of stay attributable to CDAD was 2.8 days, attributable readmission at 180 days was 19.3%, and attributable death at 180 days was 5.7%. CDAD patients were significantly more likely than controls to be discharged to a long-term-care facility or outside hospital. Even in a nonoutbreak setting, CDAD had a statistically significant negative impact on patient illness and death, and the impact of CDAD persisted beyond hospital discharge.

Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.

IMPORTANCE: Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. OBJECTIVE: To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. MAIN OUTCOMES AND MEASURES: Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. RESULTS: A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: ß estimate, 0.29; P = .001; global composite scores: ß estimate, -0.11; P = .001; episodic memory scores: ß estimate, -0.18; P < .001; and semantic memory scores: ß estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181. CONCLUSIONS AND RELEVANCE: The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.

Susceptibility-weighted imaging helps to discriminate pediatric multiple sclerosis from acute disseminated encephalomyelitis.

BACKGROUND: Susceptibility-weighted imaging is a relatively new magnetic resonance imaging sequence that can identify lesions of multiple sclerosis in adults. This study was designed to determine if susceptibility-weighted imaging is a useful discriminator between children who develop multiple sclerosis and children with monophasic acute disseminated encephalomyelitis. METHODS: Eighteen children who presented with acute central nervous system demyelination and had a brain magnetic resonance imaging study including susceptibility-weighted imaging within 6 months of the first clinical attack were studied. Final diagnosis was based on international consensus definitions. Brain lesions detected on the fluid-attenuated inversion recovery sequence were assessed for abnormal signal on susceptibility-weighted imaging. The burden of susceptibility abnormalities was then analyzed for differences between the multiple sclerosis and acute disseminated encephalomyelitis groups. RESULTS: Eight patients had a final diagnosis of acute disseminated encephalomyelitis and ten had multiple sclerosis. Twenty-two percent of fluid-attenuated inversion recovery lesions were identified on susceptibility-weighted imaging. The percentage of fluid-attenuated inversion recovery lesions identified on susceptibility-weighted imaging differed between the multiple sclerosis and acute disseminated encephalomyelitis groups (P = 0.04). The median percentage (minimum-maximum) of lesions identified on susceptibility-weighted imaging in the multiple sclerosis group was 0.22 (0-0.68) and in the acute disseminated encephalomyelitis group was 0.0 (0-0.17). CONCLUSION: Susceptibility-weighted imaging may be a useful technique in differentiating acute disseminated encephalomyelitis from multiple sclerosis at initial presentation.

Elective neck dissection and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx.

OBJECTIVE/HYPOTHESIS: The utility of elective neck dissection in the management of patients with oral cavity and oropharyngeal cancer who present without neck metastases remains controversial. The study addressed the question of whether elective neck dissection improves regional control and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx presenting with T1/T2 node-negative disease. STUDY DESIGN: A nonrandomized, uncontrolled retrospective chart review. METHODS: A nonrandomized, uncontrolled retrospective chart review was performed. Resection of the primary tumor was performed in all patients. The neck was observed in one group, and elective neck dissection was performed for patients in another group. RESULTS: The study data indicated that elective neck dissection significantly improves regional control and regional recurrence-free survival. Elective neck dissection when compared with observation of the neck did not improve overall survival. CONCLUSION: Elective neck dissection reduces regional recurrence and may extend disease-free survival.