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1.  A Prospective Comparison of Informant- and Performance-Based Dementia Screening Tools to Predict In-hospital Delirium 
Dementia is an important risk factor for delirium, but the optimal strategy for incorporating cognitive impairment into delirium risk assessment at the time of hospital admission is unknown. We compared two informant-based screening tools for dementia and mild cognitive impairment (AD8 and D=(MC)2) to the Mini Mental State Exam (MMSE) and Mini-cog in predicting hospital-acquired delirium. This prospective cohort study at an academic medical center consisted of 162 medical inpatients over age 50 without delirium upon admission. Each participant was evaluated using the MMSE, Mini-cog, AD8, and D=(MC)2 upon admission and was assessed daily for delirium. An MMSE ≤ 24 carried a 5.5 (95% CI 2.7 – 11.1) relative risk for delirium, whereas cognitive impairment detected by the Mini-cog, D=(MC)2 or AD8 carried a 2-fold risk. Adding the D=(MC)2 to the MMSE increased the sensitivity for predicting delirium from 52% (32 – 73) for the MMSE alone to 65% (46 – 85) if either test was positive. If both were positive, specificity was maximized at 97% (94 – 100) but sensitivity was 17% (2 – 33). The MMSE and Mini-cog identify a large proportion of patients at risk for hospital-acquired delirium, but the combination of performance- and an informant-based screens may maximize specificity and sensitivity.
PMCID: PMC4411195  PMID: 25350550
Delirium; dementia; screening; prediction
2.  A comparison of depression and anxiety symptom trajectories between women who had an abortion and women denied one 
Psychological medicine  2015;45(10):2073-2082.
This study prospectively assesses the mental health outcomes among women seeking abortions, by comparing women having later abortions to women denied abortions, up to two years post-abortion seeking.
We present the first two years of a 5-year telephone interview study that is following 956 women who sought an abortion from 30 facilities throughout the U.S. We use adjusted linear mixed effects regression analyses to assess whether symptoms of depression and anxiety, as measured by the BSI-short form and Prime-MD, differ over time among women denied an abortion due to advanced gestational age, compared to women who received abortions.
Baseline predicted mean depressive symptom scores for women denied abortion (3.07) were similar to women receiving an abortion just below the gestational limit (2.86). Depressive symptoms declined over time with no difference between groups. Initial predicted mean anxiety symptoms were higher among women denied care (2.59) than among women who had an abortion just below the gestational limit (1.91). Anxiety levels in the two groups declined and converged after one year.
Women who received an abortion had similar or lower levels of depression and anxiety than women denied an abortion. Our findings do not support the notion that abortion is a cause of mental health problems.
PMCID: PMC5004731  PMID: 25628123
3.  Influence of neighbourhood socioeconomic position on the transition to type II diabetes in older Mexican Americans: the Sacramento Area Longitudinal Study on Aging 
BMJ Open  2016;6(8):e010905.
To examine the influence of neighbourhood socioeconomic position (NSEP) on development of diabetes over time.
A longitudinal cohort study.
The data reported were from the Sacramento Area Latino Study on Aging, a longitudinal study of the health of 1789 older Latinos.
Community-dwelling older Mexican Americans residing in the Sacramento Metropolitan Statistical Area.
Main outcome
Multistate Markov regression were used to model transitions through four possible states over time: 1=normal; 2=pre-diabetic; 3=diabetic; and 4=death without diabetes.
At baseline, nearly 50% were non-diabetic, 17.5% were pre-diabetic and nearly 33% were diabetic. At the end of follow-up, there were a total of 824 people with type 2 diabetes. In a fully adjusted MSM regression model, among non-diabetics, higher NSEP was not associated with a transition to pre-diabetes. Among non-diabetics, higher NSEP was associated with an increased risk of diabetes (HR=1.66, 95% CI 1.14 to 2.42) and decreased risk of death without diabetes (HR: 0.56, 95% CI 0.33 to 0.96). Among pre-diabetics, higher NSEP was significantly associated with a transition to non-diabetic status (HR: 1.22, 95% CI 0.99 to 1.50). Adjusting for BMI, age, education, physical activity, smoking, alcohol consumption, medical insurance and nativity did not affect this relationship.
Our findings show that high NSEP poses higher risk of progression from normal to diabetes compared with a lower risk of death without diabetes. This work presents a possibility that these associations are modified by nativity or culture.
PMCID: PMC4985827  PMID: 27515749
4.  Does type 2 diabetes increase rate of cognitive decline in older Mexican Americans? 
Estimating effects of diabetes on cognitive change among older Mexican Americans is important, yet challenging because diabetes and cognitive decline both predict mortality, which can induce survival bias. Older Mexican Americans in the Sacramento Area Latino Study on Aging (n=1,634) completed Modified Mini-Mental State Exams (3MSE) and diabetes assessments up to seven times (1998-2007). We examined baseline and new onset diabetes and cognitive decline with joint longitudinal-survival models to account for death. At baseline, 32.4% of participants had diabetes and 15.8% developed diabetes during the study. Over the study, 22.8% of participants died. In joint longitudinal-survival models, those with baseline diabetes experienced faster cognitive decline (p=0.003) and higher mortality (HR=1.88, 95% CI 1.48-2.38) than those without diabetes. Cognitive decline and mortality were similar for those with new onset diabetes and those without diabetes. For a typical person, 3MSE scores declined by 2.3 points among those without diabetes and 4.3 points among those with baseline diabetes during the last 6 years of study. Ignoring the impact of death yielded a 17.0% smaller estimate of the effect of baseline diabetes on cognitive decline. Analyses that overlook the association between cognitive decline and mortality may underestimate the effect of diabetes on cognitive aging.
PMCID: PMC4543443  PMID: 25650694
5.  Declines in inflammation predict greater white matter microstructure in older adults 
Neurobiology of aging  2014;36(2):948-954.
Protracted, systemic inflammation has been associated with adverse effects on cognition and brain structure, and may accelerate neurodegenerative disease processes; however, it is less clear whether changes in inflammation are associated with brain structure.
We studied 276 black and white older adults (mean age=83 years at time of imaging) enrolled in a prospective study of aging. Inflammation (measured with CRP) was assessed repeatedly over 6 years (i.e. Year 2, 4, 6, & 8). Brain MRIs were obtained at years 10–11 with DTI; regions of interest included late-myelinating areas vulnerable to aging, including frontal-parietal [superior longitudinal fasciculus (SLF)-dorsal] and temporal (SLF-temporal; uncinate) white matter tracts.
Mean CRP values significantly declined (t=−5.54, p<.0001) over 6 years, and subject-specific slopes (BLUPs) all showed a decline (mean=−.57, SD=.53) for our participant sample. More than 50% of study participants were still in the moderate to high cardiovascular risk range based on CRP values at Year 8. After controlling for demographics, vascular risk factors and MRI white matter hyperintensities, larger decreases in CRP values over time were significantly associated with higher fractional anisotropy in the SLF-dorsal [Beta=−0.0052, standard error (SE)=0.003; 95% confidence interval (CI)= −0.0103 to −0.0025, p=.04], SLF-temporal (Beta=−0.0109, SE=0.004; 95%CI=−0.0189 to −0.0029, p=.008), and uncinate (Beta=−0.0067, SE=0.003; 95%CI=−0.0132 to −0.0001, p=.05) fasciculi.
Results suggest that in a prospective cohort of older individuals, faster declines in inflammation over time are related to indicators of white matter health, even after accounting for vascular risk factors.
PMCID: PMC4339188  PMID: 25554492
CRP; pro-inflammatory; diffusion tensor imaging; longitudinal
6.  Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study 
Critical Care  2015;19:435.
The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS.
We conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates.
Plasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman’s rho = 0.37, p < 0.01). Overall mortality was 16 %. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury.
Elevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-1145-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4699329  PMID: 26652251
Persistent pain following breast cancer surgery is well-documented. However, it is not well characterized in terms of the anatomic site effected (i.e., breast, arm). In two separate growth mixture modeling analyses, we identified subgroups of women (n=398) with distinct breast pain and arm pain trajectories. Based on the fact that these latent classes differed by anatomic site, types if tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. Purposes of this companion study were to identify demographic and clinical characteristics that differed between the two arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection (ALND) sites, pain qualities, pain interference, and hand and arm function; as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the Moderate Arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and ALND site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility.
Perspective: For persistent breast and arm pain, changes in sensation following breast cancer surgery were notable. Persistent arm pain was associated with sustained interference with daily functioning and upper body mobility impairments. Long-term management of persistent pain following breast cancer surgery is warranted to improve the quality of survivorship for these women.
PMCID: PMC4254679  PMID: 25439319
arm pain; breast cancer surgery; pain qualities; pain interference; range of motion; grip strength; sensory changes; persistent pain; chronic pain
8.  Type 2 diabetes and cognitive decline over 14 years in middle-aged African Americans and whites: The ARIC Brain MRI Study 
Neuroepidemiology  2014;43(0):220-227.
Diabetes predicts late-life dementia, but the association with rate of cognitive decline is inconsistent and has rarely been examined in non-white populations, despite the high prevalence of diabetes in African-Americans. We evaluated the effect of diabetes on cognitive decline in middle-aged African Americans and whites.
Atherosclerosis Risk in Communities (ARIC) Brain MRI Study participants (n=1,886, mean age=60, 49% African American) underwent assessments of verbal memory, processing speed, and verbal fluency four times over 14 years. Using race-stratified mixed linear effects models, we examined cognitive change for participants with prevalent (baseline) diabetes and incident (diagnosed after baseline) diabetes.
African Americans had more advanced diabetes, as indicated by fasting blood glucose levels, anti-diabetes medication use, and cardiovascular risk profiles. African Americans with prevalent diabetes experienced 41% greater annual decline in processing speed scores (p=0.048) and 50% greater annual decline in verbal fluency scores (p=0.042) than those without diabetes; incident diabetes was not associated with cognitive decline. Among whites, diabetes was not associated with cognitive decline.
Prevalent diabetes was associated with greater cognitive decline in middle-aged African Americans, possibly reflecting adverse effects of longer duration and more advanced diabetes.
PMCID: PMC4370220  PMID: 25402639
diabetes; cognitive decline; ethnicity; epidemiology
9.  Predictors of Initial Levels and Trajectories of Anxiety in Women Prior to and For Six Months Following Breast Cancer Surgery 
Cancer nursing  2014;37(6):406-417.
The diagnosis of breast cancer in combination with the anticipation of surgery evokes fear, uncertainty, and anxiety in most women.
In patients who underwent breast cancer surgery, study purposes were to examine how ratings of state anxiety changed from the time of the preoperative assessment to 6 months after surgery and to investigate whether specific demographic, clinical, symptom, and psychosocial adjustment characteristics predicted the preoperative levels of state anxiety and/or characteristics of the trajectories of state anxiety.
Patients (n=396) were enrolled preoperatively and completed the Spielberger State Anxiety inventory monthly for six months. Using hierarchical linear modeling, demographic, clinical, symptom, and psychosocial adjustment characteristics were evaluated as predictors of initial levels and trajectories of state anxiety.
Patients experienced moderate levels of anxiety prior to surgery. Higher levels of depressive symptoms and uncertainty about the future, as well as lower levels of life satisfaction, less sense of control, and greater difficulty coping predicted higher preoperative levels of state anxiety. Higher preoperative state anxiety, poorer physical health, decreased sense of control, and more feelings of isolation predicted higher state anxiety scores over time.
Moderate levels of anxiety persist in women for six months following breast cancer surgery.
Implications for Practice
Clinicians need to implement systematic assessments of anxiety to identify high risk women who warrant more targeted interventions. In addition, ongoing follow-up is needed in order to prevent adverse postoperative outcomes and to support women to return to their preoperative levels of function.
PMCID: PMC4162864  PMID: 24633334
10.  Development and validation of a brief dementia screening indicator for primary care 
Detection of “any cognitive impairment” is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.
We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.
The final Dementia Screening Indicator included age (1 point/year; ages, 65–79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m2 (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell’s C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).
The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.
PMCID: PMC4119094  PMID: 24491321
Dementia; Screening; Risk prediction modeling; Primary care
11.  More than Memory Impairment in Voltage-Gated Potassium Channel Complex Encephalopathy 
Autoimmune encephalopathies (AE) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AE inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with voltage-gated potassium channel complex antibodies (VGKCC-Abs) in order to delineate cognitive strengths and weaknesses.
We assessed serial VGKCC-Abs AE subjects (n=12) with a comprehensive evaluation of memory, executive functions, visuospatial skills, and language. Clinical MRI (n=10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change.
Subjects demonstrated mild to moderate impairment in memory (mean Z=−1.9) and executive functions (mean Z=−1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients.
This study augments prior neuropsychological analyses in VGKCC-Ab AE by identifying not only memory and executive function deficits, but also language impairments, with preservation of visuospatial functioning. This study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC-Ab AE.
PMCID: PMC4162838  PMID: 24981998
autoimmune; cognitive; LGI1
12.  Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease 
Neurology: Clinical Practice  2015;5(2):116-125.
We assessed the diagnostic utility of 3 CSF biomarkers—14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)—from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92–1.00) and a diagnostic accuracy of 97% (CI 90%–100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03).
PMCID: PMC4404282  PMID: 26137420
13.  Clinical, Biologic, and Prognostic Differences on the Basis of Primary Tumor Site in Neuroblastoma: A Report From the International Neuroblastoma Risk Group Project 
Journal of Clinical Oncology  2014;32(28):3169-3176.
Neuroblastoma (NB) is a heterogeneous tumor arising from sympathetic tissues. The impact of primary tumor site in influencing the heterogeneity of NB remains unclear.
Patients and Methods
Children younger than age 21 years diagnosed with NB or ganglioneuroblastoma between 1990 and 2002 and with known primary site were identified from the International Neuroblastoma Risk Group database. Data were compared between sites with respect to clinical and biologic features, as well as event-free survival (EFS) and overall survival (OS).
Among 8,369 children, 47% had adrenal tumors. All evaluated clinical and biologic variables differed statistically between primary sites. The features that were > 10% discrepant between sites were stage 4 disease, MYCN amplification, elevated ferritin, elevated lactate dehydrogenase, and segmental chromosomal aberrations, all of which were more frequent in adrenal versus nonadrenal tumors (P < .001). Adrenal tumors were more likely than nonadrenal tumors (adjusted odds ratio, 2.09; 95% CI, 1.67 to 2.63; P < .001) and thoracic tumors were less likely than nonthoracic tumors (adjusted odds ratio, 0.20; 95% CI, 0.11 to 0.39; P < .001) to have MYCN amplification after controlling for age, stage, and histologic grade. EFS and OS differed significantly according to the primary site (P < .001 for both comparisons). After controlling for age, MYCN status, and stage, patients with adrenal tumors had higher risk for events (hazard ratio, 1.13 compared with nonadrenal tumors; 95% CI, 1.03 to 1.23; P = .008), and patients with thoracic tumors had lower risk for events (HR, 0.79 compared with nonthoracic; 95% CI, 0.67 to 0.92; P = .003).
Clinical and biologic features show important differences by NB primary site, with adrenal and thoracic sites associated with inferior and superior survival, respectively. Future studies will need to investigate the biologic origin of these differences.
PMCID: PMC4171360  PMID: 25154816
14.  Side of Cancer Does Not Influence Limb Volumes in Women Prior to Breast Cancer Surgery 
Lymphatic Research and Biology  2014;12(3):189-193.
Background: Understanding normal volume asymmetry is essential for accurate assessment of limb volume changes following breast cancer (BC) treatment in which lymphatic function is disrupted. The purposes of this study were to evaluate for differences in dominant and nondominant limb volumes and to evaluate for interactions between the effects of dominance and side of cancer on limb volume.
Methods and Results: This study evaluated preoperative limb volumes of 397 women enrolled in a prospective, longitudinal study of neuropathic pain and lymphedema. Volume was calculated from circumference. Limb resistance was measured with bioimpedance. Women were dichotomized into two groups: those whose cancer was on their dominant side and those whose cancer was on their nondominant side. Analyses of variance were used to evaluate for differences. In 47%, BC occurred on the side of the dominant limb. Except for the 30 to 40 centimeter (cm) limb volume segment, a main effect of dominance was found for all measures. The volume of the dominant limb was significantly greater than that of the nondominant limb. No main effects were found for side of cancer. A statistically significant interaction was found only at the 0 to 10 cm limb volume segment.
Conclusions: Prior to BC treatment, the dominant limb demonstrated lower bioimpedance resistance (−2.09%) and greater total limb volume (1.12%) than the nondominant limb. Segmental volume differences were greatest at the proximal forearm segment (2.31%) and least at the proximal arm segment (0.21%). This study provides evidence that preoperative volume assessment is important due to normal variability associated with limb dominance.
PMCID: PMC4171111  PMID: 24834791
15.  Decision Rightness and Emotional Responses to Abortion in the United States: A Longitudinal Study 
PLoS ONE  2015;10(7):e0128832.
Arguments that abortion causes women emotional harm are used to regulate abortion, particularly later procedures, in the United States. However, existing research is inconclusive. We examined women’s emotions and reports of whether the abortion decision was the right one for them over the three years after having an induced abortion.
We recruited a cohort of women seeking abortions between 2008-2010 at 30 facilities across the United States, selected based on having the latest gestational age limit within 150 miles. Two groups of women (n=667) were followed prospectively for three years: women having first-trimester procedures and women terminating pregnancies within two weeks under facilities’ gestational age limits at the same facilities. Participants completed semiannual phone surveys to assess whether they felt that having the abortion was the right decision for them; negative emotions (regret, anger, guilt, sadness) about the abortion; and positive emotions (relief, happiness). Multivariable mixed-effects models were used to examine changes in each outcome over time, to compare the two groups, and to identify associated factors.
The predicted probability of reporting that abortion was the right decision was over 99% at all time points over three years. Women with more planned pregnancies and who had more difficulty deciding to terminate the pregnancy had lower odds of reporting the abortion was the right decision (aOR=0.71 [0.60, 0.85] and 0.46 [0.36, 0.64], respectively). Both negative and positive emotions declined over time, with no differences between women having procedures near gestational age limits versus first-trimester abortions. Higher perceived community abortion stigma and lower social support were associated with more negative emotions (b=0.45 [0.31, 0.58] and b=-0.61 [-0.93, -0.29], respectively).
Women experienced decreasing emotional intensity over time, and the overwhelming majority of women felt that termination was the right decision for them over three years. Emotional support may be beneficial for women having abortions who report intended pregnancies or difficulty deciding.
PMCID: PMC4496083  PMID: 26154386
16.  The Impact of Neighborhood Socioeconomic Position on Prevalence of Diabetes and Pre-diabetes in Older Latinos: The Sacramento Area Latino Study on Aging 
Diabetes is a leading cause of morbidity and mortality in Latinos, but few studies of disease risk in this subpopulation examine both area-level socioeconomic position and its association with individual-level risk factors. This study sought to examine the cross-sectional relationship between neighborhood socioeconomic position (NSEP) and prevalent diabetes and pre-diabetes status among older Latinos. Longitudinal health data were collected from 1,789 participants in the Sacramento Area Latino Study on Aging (SALSA). Among SALSA participants, higher NSEP was associated with lower diabetes prevalence (p = 0.001). Adjustment for BMI and other individual-level factors did not affect this relationship. No association was observed between NSEP and pre-diabetes in both unadjusted and adjusted models. Neighborhoods with higher SEP had a lower prevalence of diabetes. This study highlights the importance of considering neighborhood factors that may place older Latinos at high risk for this disease.
PMCID: PMC4470296  PMID: 26078026
neighborhood; diabetes; Latinos; aging
Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within-subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject-specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are `missing at random' (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between- and within-cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy-to-use approach to simultaneously protect against bias from both cluster-level confounding and MAR missingness in assessments of change.
PMCID: PMC4456042  PMID: 26052246
bias; conditional likelihood; confounding; consistent estimation
18.  Metacognition in the behavioral variant of frontotemporal dementia and Alzheimer’s disease 
Neuropsychology  2014;28(3):436-447.
Impaired self-awareness is characteristic of nearly all dementias, including Alzheimer’s disease (AD), but the deficit is most severe in the behavioral variant of frontotemporal dementia (bvFTD). The prominence of frontal pathology in bvFTD suggests that failure of online monitoring, the process by which individuals monitor their own cognitive processing in real time, is an important contributor. Metacognitive research offers several approaches to measure self-assessment, some more and others less sensitive to online monitoring. The goal of this study was to assess metacognition in bvFTD using several approaches, and compare the results with those in AD.
We examined metacognition in 12 patients with bvFTD, 14 with AD and 35 healthy controls using Feeling of Knowing (FOK), Ease of Learning (EOL), Judgment of Learning (JOL), and Retrospective Confidence Rating (CR) tasks, as well as response to feedback about performance.
BvFTD and AD were both impaired at FOK compared with controls, although AD showed some sparing. Both groups were similarly impaired at CR and neither group was impaired at JOL after accounting for memory performance. Most strikingly, bvFTD patients failed to appropriately adjust their predictions about future memory performance even after receiving explicit feedback that they had performed worse than they expected.
Both bvFTD and AD show deficits in online monitoring, although the deficit appears more severe in bvFTD. The insensitivity of bvFTD patients to overt feedback may point to unique mechanisms, possibly frontally mediated, that add to their severe lack of self-awareness.
PMCID: PMC4085356  PMID: 24548124
Feeling of knowing; Judgment of Learning; Metamemory; Dementia; Frontal lobe
19.  Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery 
Lymphatic Research and Biology  2014;12(1):10-22.
Background: Lymphedema (LE) is a frequent complication following breast cancer treatment. While progress is being made in the identification of phenotypic risk factors for the development of LE, little information is available on the molecular characterization of LE. The purpose of this study was to determine if variations in pro- and anti-inflammatory cytokine genes were associated with LE following breast cancer treatment.
Methods and Results: Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n=155) and without LE (n=387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease, and a higher number of lymph nodes removed. Genetic associations were identified for three genes (i.e., interleukin (IL4) 4 (rs2227284), IL 10 (rs1518111), and nuclear kappa factor beta 2 (NFKB2 (rs1056890)) associated with inflammatory responses.
Conclusions: These genetic associations suggest a role for a number of pro- and anti-inflammatory genes in the development of LE following breast cancer treatment.
PMCID: PMC3961780  PMID: 24502445
Journal of neurogenetics  2014;28(0):122-135.
Preoperative breast pain in women with breast cancer may result from a number of causes. Previous work from our team found that breast pain occurred in 28.2% of women (n=398) who were about to undergo breast cancer surgery. The occurrence of preoperative breast pain was associated with a number of demographic and clinical characteristics, as well as variation in two cytokine genes. Given that ion channels regulate excitability of sensory neurons, we hypothesized that variations in potassium channel genes would be associated with preoperative breast pain in these patients. Therefore, in this study we evaluated for associations between single nucleotide polymorphisms and inferred haplotypes among 10 potassium channel genes and the occurrence of preoperative breast pain in patients scheduled to undergo breast cancer surgery. Multivariable logistic regression analyses were used to identify those genetic variations that were associated with the occurrence of preoperative breast pain while controlling for age and genomic estimates of and self-reported race/ethnicity. Variations in four potassium channel genes: 1) potassium voltage-gated channel, delayed rectifier, subfamily S, member 1 (KCNS1); 2) potassium inwardly-rectifying channel, subfamily J, member 3 (KCNJ3); 3) KCNJ6; and 4) potassium channel, subfamily K, member 9 (KCNK9) were associated with the occurrence of breast pain. Findings from this study warrant replication in an independent sample of women who report breast pain following one or more breast biopsies.
PMCID: PMC4035357  PMID: 24392765
breast pain; preoperative pain; potassium channel genes; breast cancer; candidate genes
21.  Longitudinal gray matter contraction in three variants of primary progressive aphasia: A tenser-based morphometry study 
NeuroImage : Clinical  2015;8:345-355.
The present study investigated the pattern of longitudinal changes in cognition and anatomy in three variants of primary progressive aphasia (PPA). Eight patients with the non-fluent variant of PPA (nfvPPA), 13 patients with the semantic variant (svPPA), seven patients with the logopenic variant (lvPPA), and 29 age-matched, neurologically healthy controls were included in the study. All participants underwent longitudinal MRI, neuropsychological and language testing at baseline and at a 1-year follow-up. Tenser-based morphometry (TBM) was applied to T1-weighted MRI images in order to map the progression of gray and white matter atrophy over a 1-year period. Results showed that each patient group was characterized by a specific pattern of cognitive and anatomical changes. Specifically, nfvPPA patients showed gray matter atrophy progression in the left frontal and subcortical areas as well as a decline in motor speech and executive functions; svPPA patients presented atrophy progression in the medial and lateral temporal lobe and decline in semantic memory abilities; and lvPPA patients showed atrophy progression in lateral/posterior temporal and medial parietal regions with a decline in memory, sentence repetition and calculations. In addition, in all three variants, the white matter fibers underlying the abovementioned cortical areas underwent significant volume contraction over a 1-year period.
Overall, these results indicate that the three PPA variants present distinct patterns of neuroanatomical contraction, which reflect their clinical and cognitive progression.
•PPA variants present distinct patterns of neuroanatomical contraction.•Non-fluent variant of PPA shows GM contraction in left frontal and subcortical areas.•Semantic variant of PPA shows GM contraction in medial and lateral temporal lobe.•Logopenic variant of PPA shows GM contraction in lateral/posterior temporal and medial parietal regions.
PMCID: PMC4473099  PMID: 26106560
22.  Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease 
Neurology  2013;81(23):2015-2023.
To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD).
This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2.
Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months.
This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials.
Classification of evidence:
This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.
PMCID: PMC4211922  PMID: 24122181
23.  Impact of Gender and Blood Pressure on Post-Stroke Cognitive Decline among Older Latinos 
Post-stroke cognitive decline (PSCD) is an important consequence of stroke that may be more severe in women than men. The existence of any gender differences in PSCD among Mexican Americans, and their potential mechanisms, such as blood pressure (BP), remain unknown. We assessed PSCD stratified on gender in older Mexican Americans and explored the influence of pre-stroke and post-stroke systolic BP on PSCD.
Among 1,576 non-demented, stroke-free adults 60 years or older when recruited in 1998–99 in the Sacramento Area Latino Study on Aging (SALSA) cohort, we examined pre-stroke and post-stroke longitudinal changes in Spanish English Verbal Learning test scores (WL), a verbal memory test, and errors on the Modified Mini Mental State Exam (3MSE) scores, a global cognition test, stratified by gender, adjusting for baseline and time-varying covariates with linear mixed-effects models.
We identified 151 adults (mean age, 72 ± 8 years) with incident first-ever stroke during ten years of follow-up. After adjustment for age, education and time-varying depressive symptoms, 3MSE errors increased by 22%/year (95% CI, 6.8%–36.7%) in men and 13.2%/year (95% CI, 3.5%–22.9%) in women over the post-stroke period. Post-stroke WL scores improved by 0.05 words/year (95% CI, −0.24–0.33) in men and by 0.09 words/year (95% CI, −0.16–0.34) in women. Results persisted after adjustment for time-varying systolic BP.
Among this population of older Mexican Americans, PSCD did not differ by gender. We found no evidence that systolic BP influenced PSCD in women or men.
PMCID: PMC4030756  PMID: 22748715
[MeSH] Cerebrovascular disease/stroke; Cognition; Hispanic Americans; Sex; Epidemiology
24.  Interleukin-6, Age, and Corpus Callosum Integrity 
PLoS ONE  2014;9(9):e106521.
The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.
PMCID: PMC4154691  PMID: 25188448
25.  Type 2 Diabetes and 10-Year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans 
Diabetes Care  2013;36(9):2600-2606.
Type 2 diabetes has been linked with increased risk of dementia and cognitive impairment among older adults and with premature mortality in young and middle-aged adults. No studies have evaluated the association between diabetes and dementia among Mexican Americans, a population with a high burden of diabetes. We evaluated the association of diabetes with incidence of dementia and cognitive impairment without dementia (CIND) among older Mexican Americans while accounting for competing risk from death.
This study included 1,617 participants 60–98 years of age from the Sacramento Area Latino Study on Aging followed up to 10 years from 1998. We evaluated the association between diabetes and dementia/CIND with competing risk regression models.
Participants free of dementia/CIND at baseline (n = 1,617) were followed annually up to 10 years. There were 677 (41.9%) participants with diabetes, 159 (9.8%) incident dementia/CIND cases, and 361 (22.3%) deaths. Treated and untreated diabetes (hazard ratio 2.12 [95% CI 1.65–2.73] and 2.15 [1.58–2.95]) and dementia/CIND (2.48 [1.75–3.51]) were associated with an increased risk of death. In models adjusted for competing risk of death, those with treated and untreated diabetes had an increased risk of dementia/CIND (2.05 [1.41–2.97] and 1.55 [0.93–2.58]) compared with those without diabetes.
These findings provide evidence that the association between type 2 diabetes and dementia/CIND among Mexican Americans remains strong after accounting for competing risk of mortality. Treatments that modify risk of death among those with diabetes may change future dementia risk.
PMCID: PMC3747945  PMID: 23514732

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