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The addition of the ATR inhibitor, AZD6738, did not show synergistic cytotoxicity with SG3199 or ADCs in parental MDA-MB-361 cells

Differentially expressed proteins identified in the 361-PBDr cell line

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: β estimate, 0.29; P = .001; global composite scores: β estimate, −0.11; P = .001; episodic memory scores: β estimate, −0.18; P 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.

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. The methods are illustrated from the motivating example from a study in the area of Alzheimer’s disease.

Objectives To test the hypothesis that the degree of vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late-life depression. Design Measurement of cognition both before and following 12 weeks of treatment with sertraline. Setting University medical centers (Washington University and Duke University). Participants One hundred sixty-six individuals with late-life depression. Intervention Sertraline treatment. Measurements The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2-based white matter hyperintensities using the Fazekas criteria. Results Both episodic memory and executive function demonstrated significant improvement among adults with late-life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental State Examination scores predicted less change in working memory. Furthermore, older age, later age of onset, and higher vascular risk scores predicted less change in executive function. Conclusions These results have important clinical implications in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.

Aggregation of amyloid-β (Aβ) 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 Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ 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 Aβ levels. Serotonin-dependent reductions in Aβ 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 Aβ 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 Aβ accumulation in cognitively normal individuals.

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-β42 (Aβ42) ratio as diagnostic and prognostic markers in early AD. Methods: We assessed CSF levels of VILIP-1, tau, phosphorylated-tau181 (p-tau181), and Aβ42 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/Aβ42 predicted future cognitive impairment in CNC over the follow-up period. Importantly, CSF VILIP-1/Aβ42 predicted future cognitive impairment at least as well as tau/Aβ42 and p-tau181/Aβ42. Interpretation: These findings suggest that CSF VILIP-1 and VILIP-1/Aβ42 offer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normal individuals similarly to tau and tau/Aβ42, respectively. ANN NEUROL 2011

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.

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-β (Aβ) 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 Aβ 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 Aβ 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.

Background Disease-modifying therapies for Alzheimer's disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. Methods AD-associated changes in cerebrospinal fluid (CSF) were measured using two-dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry. Subsequently, CSF YKL-40 was measured by enzyme-linked immunosorbent assay in the discovery cohort (n = 47), validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (PSP; n = 9), and progressive supranuclear palsy (PSP; n = 6). Immunohistochemistry was performed to identify source(s) of YKL-40 in human AD brain. Results Discovery and validation cohorts, showed higher mean CSF YKL-40 in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) versus control subjects (CDR 0) and PSP subjects. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion), as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau 181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 versus CDR 0, and correlated with CSF levels. YKL-40 immunoreactivity labeled astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. Conclusions These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD and, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

Previous studies report that black patients compared to white patients receive lower quality of care for severe infections, such as community-acquired pneumonia (CAP) and sepsis (1–5), and that these disparities may persist at individual hospitals (3). Despite these recent efforts to understand racial disparities in pneumonia care, several issues remain unsolved. First, there is no standard definition of quality of care. Examining only evidence-based processes of care as quality indicators does not necessarily capture “true” treatment quality, because other factors such as patient preferences may influence treatment (6). Depending on the process measure, we might draw different conclusions about treatment quality. For example, black patients with CAP are less likely to receive timely and guideline adherent antibiotics in the emergency department (ED) (1–3) but may be treated more intensely, as evidenced by a higher likelihood of receiving intensive care unit (ICU) services during hospitalization (7). Second, black subjects reside in different neighborhoods and seek care at different hospitals (3). As suggested by disparity research in other fields (8, 9), racial disparities may be explained by variation in care among hospitals. Black patients often receive care at hospitals that provide lower quality of care, whereas within the same hospital, black and white patients are treated similarly. Statistical methods to account for within-center correlation and confounding attributable to variation in care across centers have been described (10, 11). Most previous studies examining care differences for pneumonia did not account for either of these effects (2–4), and a single study showed that black patients received lower quality of care despite accounting for these effects (5). Third, it is unclear whether reported racial differences in process of care for CAP lead to disparities in outcomes, such as incidence of severe sepsis. Understanding the reasons for disparities is critical to direct quality-improvement initiatives and to control for differences when exploring mechanisms of disease and effects of treatment interventions. We therefore sought to examine racial differences in CAP treatment by evaluating processes of care in the ED and utilization of different therapeutic interventions in the ICU. We used a large observational cohort of CAP patients recruited from four geographic regions in the US with detailed individual-level measures of illness severity and used robust statistical methods to adjust for differences in case-mix, the confounding effect of variation in care among hospitals, and clustering of black and white patients within hospitals.

Background Many recent studies have identified white matter abnormalities in late life depression (LLD). These abnormalities include an increased volume of discrete white matter hyperintensities on T2-weighted imaging (WMH) and changes in the diffusion tensor properties of water. However, no study of LLD to date has examined the integrity of white matter outside of WMH (i.e., in normal-appearing white matter). Methods We performed T1- and T2-weighted imaging as well as diffusion tensor imaging (DTI) in depressed elderly subjects ( n = 73) and nondepressed control subjects ( n = 23) matched for age and cerebrovascular risk factors. The structural images were segmented into white matter, gray matter, cerebrospinal fluid, and WMH. The DTI parameters were calculated in white matter regions of interest after excluding the WMH. Results Compared with control subjects, in the LLD group there were widespread abnormalities in DTI parameters, particularly in prefrontal regions. From a comprehensive neuropsychological battery, the strongest correlations were observed between cognitive processing speed and DTI abnormalities. Conclusions These results suggest that further investigation is warranted to determine potential reversibility and/or prognosis in LLD.

CDAD led to significantly worse outcomes in these 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.

According to the American Cancer Society, there are currently 2 million breast cancer (BC) survivors in the USA and 20% of them cope with lymphedema (LE). The primary aim of this study was to determine the predictive factors of BC-related LE. The secondary aim was to investigate the impact of predictors on the severity of LE. The study design was intended to be a 1:2 matched case-control study. Instead, we stratified on age (+/-10 years), radiation therapy (y/n), and type of operation (SM/MRM/MRM with tram). Patients who underwent BC surgery between 1990 and 2000 at UPMC Magee-Womens Hospital were reviewed for LE. Data were collected on 52 women with LE and 104 female controls. Logistic regression was utilized to assess the relationship between risk factors and LE. Ordinal logistic regression was performed to determine the association between risk factors and severity of LE. Severity was defined according to the volume difference between affected and unaffected limbs. Risk factors considered were occupation/hobby (hand use), TNM stage, number of dissected nodes, number of positive nodes, tumor size, infection, allergy, diabetes mellitus, hypertension, hypothyroidism, chronic obstructive pulmonary disease, and body mass index (BMI). LE was mild in 43 patients and was moderate/severe in nine patients. The level of hand use in the control group was categorized as low in 56 (54%), medium in 15 (14%), and high in 33 (32%) patients. The corresponding frequencies were 14 (33%), 6 (14%) and 23 (53%) for patients with mild LE and 3 (33%), 1 (11%), 5 (56%) for patients with moderate/severe LE (p < 0.05). Infection of the operated side arm was reported by two (2%) patients in the control group, 14 (33%) patients with mild LE and five (56%) patients with moderate/severe LE (p < 0.05). The mean BMI was 26.1 kg/m(2) (SD 4.9) for the control group, 29.0 kg/m(2) (SD 5.9) for the mild LE group and 30.9 kg/m(2) (SD 7.5) for patients with moderate/severe LE (p < 0.05). The results of this stratified case-control study demonstrated that the risk and severity of LE was statistically related to infection, BMI, and level of hand use.

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.

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.

In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.

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.

In the dementia area it is often of interest to study relationships among regional brain measures; however, it is often necessary to adjust for covariates. Partial correlations are frequently used to correlate two variables while adjusting for other variables. Complete case analysis is typically the analysis of choice for partial correlations with missing data. However, complete case analysis will lead to biased and inefficient results when the data are missing at random. We have extended the partial correlation coefficient in the presence of missing data using the expectation-maximization (EM) algorithm, and compared it with a multiple imputation method and complete case analysis using simulation studies. The EM approach performed the best of all methods with multiple imputation performing almost as well. These methods were illustrated with regional imaging data from an Alzheimer’s disease study.

In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial.In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time.Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyper-intensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not.These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.

An Alzheimer's fMRI study has motivated us to evaluate inter-regional correlations between groups. The overall objective is to assess inter-regional correlations at a resting-state with no stimulus or task. We propose using a generalized estimating equation (GEE) transition model and a GEE marginal model to model the within-subject correlation for each region. Residuals calculated from the GEE models are used to correlate brain regions and assess between group differences. The standard pooling approach of group averages of the Fisher-z transformation assuming temporal independence is a typical approach used to compare group correlations. The GEE approaches and standard Fisher-z pooling approach are demonstrated with an Alzheimer's disease (AD) connectivity study in a population of AD subjects and healthy control subjects. We also compare these methods using simulation studies and show that the transition model may have better statistical properties.

Research on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity.To evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression.Two-site, prospective, nonrandomized controlled trial.Outpatient clinics at Washington University and Duke University.A total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time.Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P.001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRSor =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores.Comprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.clinicaltrials.gov Identifier: NCT00045773.

Variable selection in genome-wide association studies can be a daunting task and statistically challenging because there are more variables than subjects. We propose an approach that uses principal-component analysis (PCA) and least absolute shrinkage and selection operator (LASSO) to identify gene-gene interaction in genome-wide association studies. A PCA was used to first reduce the dimension of the single-nucleotide polymorphisms (SNPs) within each gene. The interaction of the gene PCA scores were placed into LASSO to determine whether any gene-gene signals exist. We have extended the PCA-LASSO approach using the bootstrap to estimate the standard errors and confidence intervals of the LASSO coefficient estimates. This method was compared to placing the raw SNP values into the LASSO and the logistic model with individual gene-gene interaction. We demonstrated these methods with the Genetic Analysis Workshop 16 rheumatoid arthritis genome-wide association study data and our results identified a few gene-gene signals. Based on our results, the PCA-LASSO method shows promise in identifying gene-gene interactions, and, at this time we suggest using it with other conventional approaches, such as generalized linear models, to narrow down genetic signals.

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.

Objective To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid levels. Design, Setting, and Participants Uptake of carbon 11–labeled Pittsburgh Compound B ([ 11 C]PiB) was measured for participants assessed between August 15, 2003, and January 8, 2008, at the Washington University Alzheimer's Disease Research Center and diagnosed either as nondemented (n = 161) or with dementia of the Alzheimer type (n = 37). Multiple regression was used to determine whether [ 11 C]PiB uptake interacted with level of educational attainment to predict cognitive function. Main Outcome Measures Scores on the Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, and Short Blessed Test and individual measures from a psychometric battery. Results Uptake of [ 11 C]PiB interacted with years of education in predicting scores on the Clinical Dementia Rating sum of boxes ( P = .003), the Mini-Mental State Examination ( P P = .03), and a measure of verbal abstract reasoning and conceptualization ( P = .02) such that performance on these measures increased with increasing education for participants with elevated PiB uptake. Education was unrelated to global cognitive functioning scores among those with lower PiB uptake. Conclusion The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition.

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.

Prothrombotic conditions, like myocardial infarction and pulmonary embolism, are more common after respiratory infections, but underlying mechanisms are unclear. We hypothesized that the imbalance between procoagulant and fibrinolytic response during community-acquired pneumonia (CAP) persists at hospital discharge and increases the risk of 1-year mortality.