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BACKGROUND - Late-life depression (LLD) is associated with a fragile antidepressant response and high recurrence risk. This study examined what measures predict recurrence in remitted LLD.
METHODS - Individuals of age 60 years or older with a Diagnostic and Statistical Manual - IV (DSM-IV) diagnosis of major depressive disorder were enrolled in the neurocognitive outcomes of depression in the elderly study. Participants received manualized antidepressant treatment and were followed longitudinally for an average of 5 years. Study analyses included participants who remitted. Measures included demographic and clinical measures, medical comorbidity, disability, life stress, social support, and neuropsychological testing. A subset underwent structural magnetic resonance imaging (MRI).
RESULTS - Of 241 remitted elders, approximately over 4 years, 137 (56.8%) experienced recurrence and 104 (43.2%) maintained remission. In the final model, greater recurrence risk was associated with female sex (hazard ratio [HR] = 1.536; confidence interval [CI] = 1.027-2.297), younger age of onset (HR = 0.990; CI = 0.981-0.999), higher perceived stress (HR = 1.121; CI = 1.022-1.229), disability (HR = 1.060; CI = 1.005-1.119), and less support with activities (HR = 0.885; CI = 0.812-0.963). Recurrence risk was also associated with higher Montgomery-Asberg Depression Rating Scale (MADRS) scores prior to censoring (HR = 1.081; CI = 1.033-1.131) and baseline symptoms of suicidal thoughts by MADRS (HR = 1.175; CI = 1.002-1.377) and sadness by Center for Epidemiologic Studies-Depression (HR = 1.302; CI, 1.080-1.569). Sex, age of onset, and suicidal thoughts were no longer associated with recurrence in a model incorporating report of multiple prior episodes (HR = 2.107; CI = 1.252-3.548). Neither neuropsychological test performance nor MRI measures of aging pathology were associated with recurrence.
CONCLUSIONS - Over half of the depressed elders who remitted experienced recurrence, mostly within 2 years. Multiple clinical and environmental measures predict recurrence risk. Work is needed to develop instruments that stratify risk.
© 2018 Wiley Periodicals, Inc.
BACKGROUND - Determine the prognostic impact of magnetic resonance imaging (MRI)-defined diffuse axonal injury (DAI) after traumatic brain injury (TBI) on functional outcomes, quality of life, and 3-year mortality.
METHODS - This retrospective single center cohort included adult trauma patients (age > 17 years) admitted from 2006 to 2012 with TBI. Inclusion criteria were positive head computed tomography with brain MRI within 2 weeks of admission. Exclusion criteria included penetrating TBI or prior neurologic condition. Separate ordinal logistic models assessed DAI's prognostic value for the following scores: (1) hospital-discharge Functional Independence Measure, (2) long-term Glasgow Outcome Scale-Extended, and (3) long-term Quality of Life after Brain Injury-Overall Scale. Cox proportional hazards modeling assessed DAI's prognostic value for 3-year survival. Covariates included age, sex, race, insurance status, Injury Severity Score, admission Glasgow Coma Scale Score, Marshall Head computed tomography Class, clinical DAI on MRI (Y/N), research-level anatomic DAI Grades I-III (I, cortical; II, corpus callosum; III, brainstem), ventilator days, time to follow commands, and time to long-term follow-up (for logistic models).
RESULTS - Eligibility criteria was met by 311 patients, who had a median age of 40 years (interquartile range [IQR], 23-57 years), Injury Severity Score of 29 (IQR, 22-38), intensive care unit stay of 6 days (IQR, 2-11 days), and follow-up of 5 years (IQR, 3-6 years). Clinical DAI was present on 47% of MRIs. Among 300 readable MRIs, 56% of MRIs had anatomic DAI (25% Grade I, 18% Grade II, 13% Grade III). On regression, only clinical (not anatomic) DAI was predictive of a lower Functional Independence Measure score (odds ratio, 2.5; 95% confidence interval, 1.28-4.76], p = 0.007). Neither clinical nor anatomic DAI were related to survival, Glasgow Outcome Scale-Extended, or Quality of Life after Brain Injury-Overall Scale scores.
CONCLUSION - In this longitudinal cohort, clinical evidence of DAI on MRI may only be useful for predicting short-term in-hospital functional outcome. Given no association of DAI and long-term TBI outcomes, providers should be cautious in attributing DAI to future neurologic function, quality of life, and/or survival.
LEVEL OF EVIDENCE - Epidemiological, level III; Therapeutic, level IV.
OBJECTIVES - To examine the effect of late-life body mass index (BMI) and rapid weight loss on incident mild cognitive impairment (MCI) and Alzheimer's disease (AD).
DESIGN - Prospective longitudinal cohort study.
SETTING - National Alzheimer's Coordinating Center (NACC) Uniform Data Set, including 34 past and current National Institute on Aging-funded AD Centers across the United States.
PARTICIPANTS - 6940 older adults (n=5061 normal cognition [NC]; n=1879 MCI).
MEASUREMENTS - BMI (kg/m2) and modified Framingham Stroke Risk Profile (FSRP) score (sex, age, systolic blood pressure, anti-hypertension medication, diabetes mellitus, cigarette smoking, prevalent cardiovascular disease, atrial fibrillation) were assessed at baseline. Cognition and weight were assessed annually.
RESULTS - Multivariable binary logistic regression, adjusting for age, sex, race, education, length of follow-up, and modified FSRP related late-life BMI to risk of diagnostic conversion from NC to MCI or AD and from MCI to AD. Secondary analyses related late-life BMI to diagnostic conversion in the presence of rapid weight loss (>5% decrease in 12 months) and apolipoprotein E (APOE) ε4. During a mean 3.8-year follow-up period, 12% of NC participants converted to MCI or AD and 49% of MCI participants converted to AD. Higher baseline BMI was associated with a reduced probability of diagnostic conversion, such that for each one-unit increase in baseline BMI there was a reduction in diagnostic conversion for both NC (OR=0.977, 95%CI 0.958-0.996, p=0.015) and MCI participants (OR=0.962, 95%CI 0.942-0.983, p<0.001). The protective effect of higher baseline BMI did not persist in the setting of rapid weight loss but did persist when adjusting for APOE ε4.
CONCLUSIONS - Higher late-life BMI is associated with a lower risk of incident MCI and AD but is not protective in the presence of rapid weight loss.
OBJECTIVE - To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults.
METHODS - Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), ε4 status, cognitive diagnosis, and regional tissue volume.
RESULTS - Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, = 0.001) and right (β = 2.5, = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, = 0.003; right temporal lobe β = 2.5, = 0.003). Cardiac index was unrelated to CBF in other regions assessed ( > 0.25) and CVR in all regions ( > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left ( < 0.0001) and right ( < 0.0001) temporal lobes.
CONCLUSIONS - Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.
© 2017 American Academy of Neurology.
Importance - Pulmonary hypertension (PH) is diagnosed by a mean pulmonary arterial pressure (mPAP) value of at least 25 mm Hg during right heart catheterization (RHC). While several studies have demonstrated increased mortality in patients with mPAP less than that threshold, little is known about the natural history of borderline PH.
Objective - To test the hypothesis that patients with borderline PH have decreased survival compared with patients with lower mPAP and frequently develop overt PH and to identify clinical correlates of borderline PH.
Design, Setting, and Participants - Retrospective cohort study from 1998 to 2014 at Vanderbilt University Medical Center, comprising all patients undergoing routine RHC for clinical indication. We extracted demographics, clinical data, invasive hemodynamics, echocardiography, and vital status for all patients. Patients with mPAP values of 18 mm Hg or less, 19 to 24 mm Hg, and at least 25 mm Hg were classified as reference, borderline PH, and PH, respectively.
Exposures - Mean pulmonary arterial pressure.
Main Outcome and Measures - Our primary outcome was all-cause mortality after adjusting for clinically relevant covariates in a Cox proportional hazards model. Our secondary outcome was the diagnosis of overt PH in patients initially diagnosed with borderline PH. Both outcomes were determined prior to data analysis.
Results - We identified 4343 patients (mean [SD] age, 59  years, 51% women, and 86% white) among whom the prevalence of PH and borderline PH was 62% and 18%, respectively. Advanced age, features of the metabolic syndrome, and chronic heart and lung disease were independently associated with a higher likelihood of borderline PH compared with reference patients in a logistic regression model. After adjusting for 34 covariates in a Cox proportional hazards model, borderline PH was associated with increased mortality compared with reference patients (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = .001). The hazard of death increased incrementally with higher mPAP, without an observed threshold. In the 70 patients with borderline PH who underwent a repeated RHC, 43 (61%) had developed overt PH, with a median increase in mPAP of 5 mm Hg (interquartile range, -1 to 11 mm Hg; P < .001).
Conclusions and Relevance - Borderline PH is common in patients undergoing RHC and is associated with significant comorbidities, progression to overt PH, and decreased survival. Small increases in mPAP, even at values currently considered normal, are independently associated with increased mortality. Prospective studies are warranted to determine whether early intervention or closer monitoring improves clinical outcomes in these patients.
Background - Primary aldosteronism is recognized as a severe form of renin-independent aldosteronism that results in excessive mineralocorticoid receptor (MR) activation.
Objective - To investigate whether a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons.
Design - Cohort study.
Setting - National community-based study.
Participants - 850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA).
Measurements - Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and MR activity, assessed via serum potassium and urinary fractional excretion of potassium.
Results - A suppressed renin phenotype was associated with a higher rate of incident hypertension than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed.
Limitation - Sodium and potassium were measured several years before renin and aldosterone.
Conclusion - Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension.
Primary Funding Source - National Institutes of Health.
INTRODUCTION - Patients with SCLC have a poor prognosis and limited treatment options. Because access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden.
METHODS - We developed a liquid biopsy assay that quantifies somatic variants in cfDNA. The assay detects single nucleotide variants, copy number alterations, and insertions or deletions in 14 genes that are frequently mutated in SCLC, including tumor protein p53 gene (TP53), retinoblastoma 1 gene (RB1), BRAF, KIT proto-oncogene receptor tyrosine kinase gene (KIT), notch 1 gene (NOTCH1), notch 2 gene (NOTCH2), notch 3 gene (NOTCH3), notch 4 gene (NOTCH4), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), phosphatase and tensin homolog gene (PTEN), fibroblast growth factor receptor 1 gene (FGFR1), v-myc avian myelocytomatosis viral oncogene homolog gene (MYC), v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog gene (MYCL1), and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog gene (MYCN).
RESULTS - Over the course of 26 months of peripheral blood collection, we examined 140 plasma samples from 27 patients. We detected disease-associated mutations in 85% of patient samples with mutant allele frequencies ranging from 0.1% to 87%. In our cohort, 59% of the patients had extensive-stage disease, and the most common mutations occurred in TP53 (70%) and RB1 (52%). In addition to mutations in TP53 and RB1, we detected alterations in 10 additional genes in our patient population (PTEN, NOTCH1, NOTCH2, NOTCH3, NOTCH4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed allele frequencies and copy number alterations tracked closely with treatment responses. Notably, in several cases analysis of cfDNA provided evidence of disease relapse before conventional imaging.
CONCLUSIONS - These results suggest that liquid biopsies are readily applicable in patients with SCLC and can potentially provide improved monitoring of disease burden, depth of response to treatment, and timely warning of disease relapse in patients with this disease.
Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
It has been proposed that early differences in sensory responsiveness arise from atypical neural function and produce cascading effects on development across domains. This longitudinal study prospectively followed infants at heightened risk for autism spectrum disorder (ASD) based on their status as younger siblings of children diagnosed with ASD (Sibs-ASD) and infants at relatively lower risk for ASD (siblings of typically developing children; Sibs-TD) to examine the developmental sequelae and possible neurophysiological substrates of a specific sensory response pattern: unusually intense interest in nonsocial sensory stimuli or "sensory seeking." At 18 months, sensory seeking and social orienting were measured with the Sensory Processing Assessment, and a potential neural signature for sensory seeking (i.e., frontal alpha asymmetry) was measured via resting state electroencephalography. At 36 months, infants' social symptomatology was assessed in a comprehensive diagnostic evaluation. Sibs-ASD showed elevated sensory seeking relative to Sibs-TD, and increased sensory seeking was concurrently associated with reduced social orienting across groups and resting frontal asymmetry in Sibs-ASD. Sensory seeking also predicted later social symptomatology. Findings suggest that sensory seeking may produce cascading effects on social development in infants at risk for ASD and that atypical frontal asymmetry may underlie this atypical pattern of sensory responsiveness.
Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
BACKGROUND & AIMS - Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). Moderate drinking (vs abstinence) is associated with lower risk of CVD in the general population. We assessed whether alcohol use is associated with CVD risk in patients with NAFLD.
METHODS - We analyzed data from participants in the Coronary Artery Risk Development in Young Adults longitudinal cohort study of 5115 black and white young adults, 18-30 years old, recruited from 4 cities in the United States from 1985 through 1986. Participants self-reported alcohol use at study entry and then again after 15, 20, and 25 years. At year 25 (2010-2011), participants underwent computed tomography examination of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking. Coronary artery calcification was defined as an Agatston score above 0. NAFLD was defined as liver attenuation <51 Hounsfield Units after exclusions. Drinkers reported 1-21 (men) or 1-14 (women) standard drinks/week at years 15, 20, or 25. Nondrinkers reported no alcohol use at years 15, 20, and 25.
RESULTS - Of the 570 participants with NAFLD (mean age, 50 years; 54% black; 46% female), 332 (58%) were drinkers; significantly higher proportions of drinkers were white, male, and with higher levels of education compared with nondrinkers (P < .05 for all). Higher proportions of drinkers had obesity, diabetes, and metabolic syndrome compared with nondrinkers (P < .01). There was no difference in liver attenuation between groups (P = .12). After multivariable adjustment, there was no association between alcohol use and CVD risk factors (diabetes, hypertension, hyperlipidemia) or subclinical CVD measures (coronary artery calcification, early transmitral velocity/late (atrial) transmitral velocity (E/A) ratio, global longitudinal strain).
CONCLUSIONS - In a population-based sample of individuals with NAFLD in midlife, prospectively assessed alcohol use is not associated with significant differences in risk factors for CVD or markers of subclinical CVD. In contrast to general population findings, alcohol use may not reduce the risk of CVD in patients with NAFLD.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
RATIONALE - Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied.
OBJECTIVE - To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults.
METHODS - This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants.
MEASUREMENTS - In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome.
RESULTS - Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised β 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement.
CONCLUSIONS - Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.