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Parkinsonism & related disorders  2013;19(12):10.1016/j.parkreldis.2013.07.018.
Whereas the motor dysfunction in Parkinson’s disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss.
High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences.
PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients.
Non-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized “frontal lobe” function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD.
PMCID: PMC3858507  PMID: 23932064
Parkinson’s disease; Cognition; MRI; Voxel-based morphometry; Gray Matter Volume
2.  Unveiling the Longitudinal Association between Short Sleep Duration and the Incidence of Obesity: the Penn State Cohort 
Several epidemiologic, longitudinal studies have reported that short sleep duration is a risk factor for the incidence of obesity. However, the vast majority of these studies used self-reported measures of sleep duration and did not examine the role of objective short sleep duration, subjective sleep disturbances, and emotional stress.
Longitudinal, population-based study.
We studied a random sample of 815 non-obese adults from the Penn State Cohort in the sleep laboratory for one night using polysomnography (PSG) and followed them up for a mean of 7.5 years. Subjective and objective measures of sleep as well as emotional stress were obtained at baseline. Obesity was defined as a body mass index (BMI) ≥ 30kg/m2.
The incidence of obesity was 15% and it was significantly higher in women and in individuals who reported sleep disturbances, shorter sleep duration, and higher emotional stress. Significant mediating effects showed that individuals with subjective sleep disturbances who developed obesity reported the shortest sleep duration and the highest emotional stress and that subjective sleep disturbances and emotional stress were independent predictors of incident obesity. Further analyses revealed that the association between short sleep duration, subjective sleep disturbances, and emotional stress with incident obesity was stronger in young and middle-age adults. Objective short sleep duration was not associated with a significantly increased risk of incident obesity.
Self-reported short sleep duration in non-obese individuals at risk of developing obesity is a surrogate marker of emotional stress and subjective sleep disturbances. Objective short sleep duration is not associated with a significant increased risk of incident obesity. The detection and treatment of sleep disturbances and emotional stress should become a target of our preventive strategies against obesity.
PMCID: PMC3954466  PMID: 24100421
Incidence; Obesity; Polysomnography; Poor sleep; Sleep duration; Stress
3.  Subjective and objective sleep and self-harm behaviors in young children: A general population study 
Psychiatry research  2013;209(3):549-553.
Significant association between sleep disturbances and suicidal ideation and/or attempts is reported in adults and adolescents. However, there is paucity of studies exploring the association between sleep and self-harm behaviors (SHB) in young children and are limited to only subjective sleep measures. We examined the association between SHB and both subjective and objective sleep in a population-based sample of 5–12 yr. old. Parents of every student in 3 local school (K-5) districts (n=7,312) was sent a screening questionnaire. Randomly selected children from this sample underwent a comprehensive history, physical examination, a 9-hour overnight polysomnogram and completed several questionnaires. Among the final sample (n=693), 27 children had SHB with adjusted prevalence of 3%. There was no difference in age, gender, obesity, or socioeconomic status in subjects with or without SHB. Significantly more children with SHB had subjective sleep difficulty and depression. Difficulty maintaining sleep and frequent nightmares were associated with SHB independent of depression or demographics. Polysomnographic %REM-sleep was significantly higher in the SHB group after adjusting for demographics and depression. These data indicate that parent reported sleep disturbances are independently associated with SHB. It is possible that higher REM-sleep is a non-invasive biomarker for risk of self-harm behaviors in young children.
PMCID: PMC3742723  PMID: 23623452
Sleep; Self-harm behaviors; Suicide; REM sleep; Nightmares; Sleep disturbances; Polysomnogram; Depression
4.  Analysis of Time-to-Event and Duration Outcomes in Neonatal Clinical Trials with Twin Births 
Contemporary clinical trials  2008;30(2):150-154.
When conducting neonatal trials in pre-term and/or low-birth-weight infants, twins may represent 10–20% of the study sample. Frailty models and proportional hazards regression with a robust sandwich variance estimate are common approaches for handling correlated time-to-event data or duration outcomes that are subject to censoring. However, the operating characteristics of these methods for mixes of correlated and independent time-to-event data are not well established. Simulation studies were conducted to compare frailty models and proportional hazards regression models with a robust sandwich variance estimate to standard proportional hazards regression models to estimate the treatment effect in two-armed clinical trials. While overall frailty models showed the best performance, caution must be exercised as the interpretation of the parameters differs from the marginal models. Data from the National Institute of Child Health & Human Development sponsored PROPHET trial are used for illustration.
PMCID: PMC3606884  PMID: 19027881
correlated data; frailty models; robust variance
5.  Relationships of Race and Socioeconomic Status to Postpartum Depressive Symptoms in Rural African American and Non-Hispanic White Women 
Maternal and child health journal  2013;17(7):1277-1287.
This study examines the potential racial disparity in postpartum depression (PPD) symptoms among a cohort of non-Hispanic white and African American women after taking into consideration the influence of socioeconomic status (SES). Participants (N = 299) were recruited from maternity clinics serving rural counties, with over-sampling of low SES and African Americans. The Edinburgh Postnatal Depression Scale (EPDS) was administered 1 and 6 months postpartum, and subjective SES scale at 6 months postpartum. Demographic information was collected during enrollment and 1 month postpartum, with updates at 6 months postpartum. Separate logistic regressions were conducted for 1 and 6 month time points for minor-major PPD (EPDS ≥ 10) and major PPD (EPDS > 12); with marital status, poverty, education, subjective SES, and race predictors entered in block sequence. After including all other predictors, race was not a significant predictor of minor-major or major PPD at 1 or 6 months postpartum. Subjective SES was the most consistent predictor of PPD, being significantly associated with minor-major PPD and major PPD at 6 months postpartum, with higher subjective SES indicating lower odds of PPD, even after accounting for all other predictors. This study shows that significant racial disparities were not observed for minor-major or major PPD criteria at 1 or 6 months postpartum. The most consistent and significant predictor of PPD was subjective SES. Implications of these findings for future research, as well as PPD screening and intervention are discussed.
PMCID: PMC3584227  PMID: 22961387
Postpartum depression; Race; Subjective socioeconomic status; Health disparity; Objective socioeconomic status
6.  Resilience and psychosocial outcomes in parents of children with cancer 
Pediatric blood & cancer  2013;61(3):552-557.
The psychosocial function of parents of children with cancer can impact the well-being of the entire family. Resilience resources are likely related to psychosocial outcomes and may be amenable to intervention. We hypothesized that parents with lower resources would report worse outcomes.
In the “Understanding Resilience in Parents of Children with Cancer” study, comprehensive surveys were mailed to consecutive, English-speaking parents of children with cancer who were treated at Seattle Children’s Hospital and completed therapy between 01/01/2009 and 12/31/2010. Resilience resources were measured by the Connor-Davidson Resilience Scale; outcome measures included psychological distress, health-related behaviors, social and family function, and perceived communication with the medical team.
96 parents (86% of contactable) completed the survey. Compared to population norms, enrolled parents had lower resilience resources, higher psychological distress, and more commonly reported binge drinking. Conversely, they reported higher social support and family adaptability (p<0.001–0.006). Lower resilience resources were associated with higher distress, lower social support, and lower family function (p<0.001–0.007). Parents in the lowest quartile of resilience resources had higher odds of frequent sleep difficulties (OR 5.19, 95% CI 1.74,15.45), lower health satisfaction (OR 5.71, 95% CI 2.05,15.92), and decreased ability to express worries to the medical team (OR 4.00, 95% CI 1.43,11.18).
Parents of children with cancer are at risk for poor psychosocial outcomes and those with low resilience resources may be at greater risk. Interventions directed at promoting resilience resources may provide a novel and complimentary approach towards improving outcomes for families facing pediatric cancer.
PMCID: PMC4066960  PMID: 24249426
resilience; psychosocial outcomes; parents; pediatric cancer; whole patient care
7.  Higher iron in the red nucleus marks Parkinson’s dyskinesia 
Neurobiology of aging  2012;34(5):1497-1503.
Dopamine cell loss and increased iron in the substantia nigra (SN) characterize Parkinson’s disease (PD), with cerebellar involvement increasingly recognized, particularly in motor compensation and levodopa-induced-dyskinesia (LID) development. Because the red nucleus (RN) mediates cerebellar circuitry, we hypothesized that RN iron changes may reflect cerebellum-related compensation, and/or the intrinsic capacity for LID development. We acquired high resolution MRI images from 23 Controls and 38 PD subjects [12 with (PD+DYS) and 26 without (PD−DYS) LID history]. Iron content was estimated from bilateral RN and SN transverse relaxation rates (R2*). PD subjects overall displayed higher R2* values in both the SN and RN. RN R2* values correlated with off-drug Unified Parkinson’s Disease Rating Scale-motor scores, but not disease duration or drug dosage. RN R2* values were significantly higher in PD+DYS subjects compared to Controls and PD−DYS; Controls and PD−DYS did not differ. The association of higher RN iron content with PD-related dyskinesia suggests increased iron content is involved in, or reflects, greater cerebellar compensatory capacity and thus increased likelihood of LID development.
PMCID: PMC3570638  PMID: 23177595
Parkinson’s disease (PD); red nucleus; transverse relaxation rate (R2*); magnetic resonance imaging (MRI)
8.  The Study of Pathogen Resistance and Antimicrobial Use in Dementia: Study Design and Methodology 
Advanced dementia is characterized by the onset of infections and antimicrobial use is extensive. The extent to which this antimicrobial use is appropriate and contributes to the emergence of antimicrobial resistant bacteria is not known. The object of this report is to present the methodology established in the Study of Pathogen Resistance and Exposure to Antimicrobials in Dementia (SPREAD), and describe how challenges specific to this research were met. SPREAD is an ongoing, federally-funded, 5-year prospective cohort study initiated in September 2009. Subjects include nursing home residents with advanced dementia and their proxies recruited from 31 Boston-area facilities. The recruitment and data collection protocols are described. Characteristics of participant facilities are presented and compared to those nationwide. To date, 295 resident/proxy dyads have been recruited. Baseline and selected follow-up data demonstrate successful recruitment of subjects and repeated collection of complex data documenting infections, decision-making for these infections, and antimicrobial bacteria resistance among the residents. SPREAD integrates methods in dementia, palliative care and infectious diseases research. Its successful implementation further establishes the feasibility of conducting rigorous, multi-site NH research in advanced dementia, and the described methodology serves as a detailed reference for subsequent publications emanating from the study.
PMCID: PMC3502703  PMID: 22925431
dementia; palliative care; infections; nursing home; methodology
9.  Women's Preconceptional Health and Use of Health Services: Implications for Preconception Care 
Health Services Research  2008;43(1 Pt 1):54-75.
To improve understanding of women's use of health care before pregnancy, by analyzing how the health status and health risks of pre- and interconceptional women are associated with health services use.
Data Source
Data are from a cross-sectional random-digit dial telephone survey of a representative sample of 2002 women ages 18–45 years from the Central Pennsylvania Women's Health Study (CePAWHS). A subsample of 1,325 respondents with current reproductive capacity, classified by reproductive life stage (preconceptional or interconceptional), was analyzed.
Study Design
Bivariate and multiple logistic regression analyses were conducted to determine how health needs (including indices of health status and health risks related to adverse pregnancy outcomes) are associated with five indicators of health services use (receipt of a regular physical exam, obstetrician–gynecologist [ob/gyn] visit, receipt of a set of recommended screening services, receipt of health counseling services on general health topics, and receipt of pregnancy-related counseling), controlling for predisposing and enabling variables.
Principal Findings
Only half of women at risk of pregnancy report receiving counseling about pregnancy planning in the past year. One-third of women surveyed did not receive routine physical examinations and screening services, and over half received little or no health counseling. Multivariate analyses showed that all the measures of health needs except for negative health behavior were related to some type of health services use. Psychosocial stress was associated with having a recent ob/gyn visit, with receiving general health counseling, and with receiving pregnancy planning counseling. Cardiovascular risk was positively associated with receiving general health counseling and a regular physical exam, but negatively associated with seeing an ob/gyn. Positive health behaviors were associated with receiving screening services and with receiving general health counseling. Preconceptional reproductive life stage was positively associated with receiving a regular physical exam and negatively associated with having an ob/gyn visit.
Pre- and interconceptional women with specific health care needs may not receive appropriate health care before pregnancy. Improving pregnancy experiences and outcomes requires more comprehensive preconception health care and more preventive care before the first pregnancy.
PMCID: PMC2323151  PMID: 18211518
Women's health; pregnancy; preconception health; health care utilization; surveys
10.  Imaging nigral pathology and clinical progression in Parkinson's disease 
The pattern of dopamine cell loss in Parkinson's disease is known to be prominent in the ventrolateral and caudal substantia nigra, but less severe in the dorsal and rostral region. Both diffusion tensor imaging and R2* relaxometry of the substantia nigra have been reported as potential markers for Parkinson's disease, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear.
High resolution T2-weigthed, R2*, and diffusion tensor imaging were obtained from 28 controls and 40 Parkinson's disease subjects [15 early-stage (disease duration≤1 year), 14 mid-stage (duration 2-5 years), and 11 late-stage (duration>5 years)]. Fractional anisotropy and R2* values in both rostral and caudal substantia nigra were obtained for all subjects, and clinical measures (disease duration; levodopa-equivalent daily dosage; “off”-drug Unified Parkinson's Disease Rating Scale motor score) were obtained for Parkinson's subjects.
There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal substantia nigra was significantly decreased in Parkinson's disease patients of all stages, whereas in rostral substantia nigra it was decreased significantly only in the late-stage group. R2* in both substantia nigra regions was significantly increased in the mid-stage and late-stage, but not early-stage, of Parkinson's disease subjects.
These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal substantia nigra, whereas the changes in R2* may more closely track Parkinson's disease's clinical progression after symptom onset.
PMCID: PMC3510346  PMID: 23008179
Parkinson's disease (PD); substantia nigra; diffusion tensor imaging (DTI); transverse relaxation rate (R2*); magnetic resonance imaging (MRI)
11.  Scales for the Evaluation of End-of-Life Care in Advanced Dementia: Sensitivity to Change 
The paucity of valid and reliable instruments designed to measure end-of-life experiences limits advanced dementia and palliative care research. Two end-of-life in dementia (EOLD) scales that evaluate the experiences of severely cognitively impaired persons and their health care proxies (HCP) have been developed: 1) symptom management (SM) and 2) satisfaction with care (SWC). The study objective was to examine the sensitivity of the EOLD scales to detect significant differences in clinically relevant outcomes in nursing home residents with advanced dementia. The SM-EOLD scale was sensitive to detecting changes in comfort among residents with pneumonia, pain, dyspnea, and receiving burdensome interventions. The SWC-EOLD scale was sensitive to detecting changes in HCP satisfaction with the care of residents when addressing whether the health care provider spent > 15 minutes discussing the resident’s advanced care planning, whether the physician counseled about the resident’s live expectancy, whether resident resided in a special care unit and whether the physician counseled possible resident health problems. This study extends the psychometric properties of the EOLD scales by showing the sensitivity to clinically meaningful change in these scales to specific outcomes related to end-of-life care and quality of life among residents with end-stage advanced dementia and their HCPs.
PMCID: PMC3424399  PMID: 22273800
Dementia; Nursing homes; End-of-life; Health care proxy; Sensitivity to change; Responsiveness
Hypertension  2012;60(4):929-935.
Insomnia with objective short sleep duration appears to be a biologically more severe phenotype of the disorder. No longitudinal study to date has examined the association of this type of insomnia with incident hypertension using polysomnography. From a random, general population sample of 1741 adults of the Penn State Cohort, 1395 were followed-up after 7.5 years and 786 did not have hypertension at baseline. Hypertension was determined by a self-report of receiving treatment for high blood pressure. Chronic insomnia was defined as a complaint of insomnia lasting ≥ 1 year, while poor sleep was defined as moderate-to-severe sleep difficulties. All subjects underwent 8-hour polysomnography. Sleep disordered breathing (SDB) was defined as an obstructive apnea/hypopnea index ≥ 5. We used the median polysomnographic percent of sleep time to define short sleep duration (i.e., < 6 hours). We controlled for gender, race, age, caffeine, cigarettes, alcohol consumption, depression, SDB, diabetes, obesity, and blood pressure in our analyses. Compared to normal sleepers who slept ≥ 6 hours, the highest risk for incident hypertension was in chronic insomniacs with short sleep duration (OR= 3.8, 95% CI=1.6–9.0). The risk for incident hypertension in poor sleepers with short sleep duration was significantly increased but became marginally significant after controlling for obesity (OR= 1.6, 95% CI=0.9–2.8). Chronic insomnia with short sleep duration is associated with an increased risk for incident hypertension in a degree comparable to SDB. Objective short sleep duration in insomnia may serve as a useful predictor of the biological severity of the disorder.
PMCID: PMC3679545  PMID: 22892811
Insomnia; Polysomnography; Hypertension; Incidence
13.  Health Knowledge Among the Millennial Generation 
The Millennial Generation, also known as Generation Y, is the demographic cohort following Generation X, and is generally regarded to be composed of those individuals born between 1980 and 2000. They are the first to grow up in an environment where health-related information is widely available by internet, TV and other electronic media, yet we know very little about the scope of their health knowledge. This study was undertaken to quantify two domains of clinically relevant health knowledge: factual content and ability to solve health related questions (application) in nine clinically related medical areas. Study subjects correctly answered, on average, 75% of health application questions but only 54% of health content questions. Since students were better able to correctly answer questions dealing with applications compared to those on factual content contemporary US high school students may not use traditional hierarchical learning models in acquisition of their health knowledge.
PMCID: PMC4140324  PMID: 25170479
health education; knowledge acquisition
14.  Parent Perception of Healthy Infant and Toddler Growth 
Clinical pediatrics  2009;49(4):343-349.
We hypothesized that parents of infants prefer growth at higher percentiles and are averse to growth at lower percentiles. Of 279 participating parents, only 10% desired their child’s weight to be in the lowest quartile. For children weighing in the lowest quartile, 57% of parents thought their child’s weight was “too low.” In contrast, 66% of parents whose child’s weight was in the top quartile preferred their child weigh that much. When viewing hypothetical infant growth trajectories, 47% ranked a growth chart demonstrating growth along the 10th percentile for weight as “least healthy” of 6 growth patterns, and 29% chose charts showing an infant at the 90th percentile for weight at age 1 as “healthiest.” In conclusion, parents are averse to growth at the bottom of the weight growth chart but are much less likely to feel negatively about growth at higher percentiles. This is troubling given the childhood obesity epidemic.
PMCID: PMC3623679  PMID: 19745095
infant; growth; growth chart; obesity
15.  Risk Factors for Incident Chronic Insomnia: A General Population Prospective Study 
Sleep Medicine  2012;13(4):346-353.
The few population-based, prospective studies that have examined risk factors of incident insomnia were limited by small sample size, short follow-up, and lack of data on medical disorders or polysomnography. We prospectively examined the associations between demographics, behavioral factors, psychiatric and medical disorders, and polysomnography with incident chronic insomnia.
From a random, general population sample of 1741 individuals of the adult Penn State Sleep Cohort, 1395 were followed-up after 7.5 years. Only subjects without chronic insomnia at baseline (n=1246) were included in this study. Structured medical and psychiatric history, personality testing, and 8-hour polysomnography were obtained at baseline. Structured sleep history was obtained at baseline and follow-up.
Incidence of chronic insomnia was 9.3%, with a higher incidence in women (12.9%) than in men (6.2%). Younger age (20–35 years), non-white ethnicity, and obesity increased the risk of chronic insomnia. Poor sleep and mental health were stronger predictors of incident chronic insomnia compared to physical health. Higher scores in MMPI-2, indicating maladaptive personality traits, and excessive use of coffee at baseline predicted incident chronic insomnia. Polysomnographic variables, such as short sleep duration or sleep apnea, did not predict incident chronic insomnia.
Mental health, poor sleep, and obesity, but not sleep apnea, are significant risk factors for incident chronic insomnia. Focusing on these more vulnerable groups and addressing the modifiable risk factors may help reduce the incident of chronic insomnia, a common and chronic sleep disorder associated with significant medical and psychiatric morbidity and mortality.
PMCID: PMC3319648  PMID: 22425576
chronic insomnia; incidence; physical health; mental health; general population
16.  Do Cortisol Concentrations Predict Short-Term Outcomes in Extremely Low Birth Weight Infants? 
Pediatrics  2008;122(4):775-781.
Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes.
Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile.
Median cortisol values were 16.0 μg/dL at baseline and 13.1 μg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or day 5 to 7 were not associated with increased morbidity or mortality rates and were not predictive of open-label hydrocortisone use. In fact, vasopressor use was lower for infants with lower cortisol values at baseline. Severe intraventricular hemorrhage was more frequent in infants with cortisol levels in the upper quartile at baseline, and values of >90th percentile were significantly associated with higher rates of death, severe intraventricular hemorrhage, periventricular leukomalacia, gastrointestinal perforation, and severe retinopathy of prematurity.
Low cortisol concentrations were not predictive of adverse short-term outcomes, but high cortisol concentrations were associated with severe intraventricular hemorrhage, and extremely elevated values were associated with morbidity and death. Low cortisol concentrations alone at these 2 time points did not identify the infants at highest risk for adverse outcomes. In contrast, high cortisol values were associated with increased morbidity and mortality rates.
PMCID: PMC3586215  PMID: 18829801
bronchopulmonary dysplasia; extremely preterm infants; hydrocortisone; outcomes of high-risk infants
17.  Premature Cardiac Contractions and Risk of Incident Ischemic Stroke 
The etiologies of ischemic stroke remain undetermined in 15% to 40% of patients. Apart from atrial fibrillation, other arrhythmias are less well-characterized as risk factors. Premature cardiac contractions are known to confer long-term cardiovascular risks, like myocardial infarction. Ischemic stroke as cardiovascular risk outcome remains a topic of interest. We examined the prospective relationships in the Atherosclerosis Risk in Communities (ARIC) study, to determine whether premature atrial (PAC) or ventricular (PVC) contractions are associated with increased risk for incident ischemic stroke.
Methods and Results
We analyzed 14 493 baseline stroke-free middle-aged individuals in the ARIC public-use data. The presence of PAC or PVC at baseline was assessed from 2-minute electrocardiogram. A physician-panel confirmed and classified all stroke cases. Average follow-up time was 13 years. Proportional hazards models assessed associations between premature contractions and incident stroke. PACs and PVCs were identified in 717 (4.9%) and 793 (5.5%) participants, respectively. In all, 509(3.5%) participants developed ischemic stroke. The hazard ratio (HR) (95% confidence interval [CI]) associated with PVC was 1.77 (1.30, 2.41), attenuated to 1.25 (0.91, 1.71) after adjusting for baseline stroke risk factors. The interaction between PVC and baseline hypertension was marginally significant (P=0.08). Among normotensives, having PVCs was associated with nearly 2-fold increase in the rate of incident ischemic stroke (HR 1.69; 95% CI 1.02, 2.78), adjusting for stroke risk factors. The adjusted risk of ischemic stroke associated with PACs was 1.30 (95% CI 0.92, 1.83).
Presence of PVCs may indicate an increased risk of ischemic stroke, especially in normotensives. This risk approximates risk of stroke from being black, male, or obese in normotensives from this cohort.
PMCID: PMC3541607  PMID: 23316293
brain ischemia; embolic stroke; premature atrial contraction; premature ventricular contraction; risk factors
18.  Combined R2* and diffusion tenser imaging changes in the substantia nigra in Parkinson disease 
Recent magnetic resonance imaging (MRI) studies suggest increased transverse relaxation rate (R2*) and reduced diffusion tensor imaging (DTI) fractional anisotropy (FA) values in the SN in PD. The R2* and FA changes may reflect different aspects of PD-related pathological processes (i.e., tissue iron deposition and microstructure disorganization). This study investigated the combined changes of R2* and FA in the SN in PD.
High resolution MRI (T2-weighted, T2*, and DTI) were obtained from 16 PD and 16 Controls. Bilateral SNs were delineated manually on T2-weighted images and co-registered to R2* and FA maps. The mean R2* and FA values in each SN then were calculated and compared between PD and Controls. Logistic regression, followed by ROC curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating PD subjects from Controls.
Compared to Controls, PD subjects demonstrated increased R2* (p<0.0001) and reduced FA (p=0.0365) in the SN. There was no significant correlation between R2* and FA values. Logistic regression analyses indicated that the combined use of R2* and FA values provides excellent discrimination between PD and Controls (c-statistic=0.996) compared to R2* (c-statistic=0.930) or FA (c-statistic=0.742) alone.
This study shows that the combined use of R2* and FA measures in the SN of PD enhances the sensitivity and specificity in differentiating PD from Controls. Further studies are warranted to evaluate the pathophysiological correlations of these MRI measurements, and their effectiveness in assisting in diagnosing PD and following its progression.
PMCID: PMC3154471  PMID: 21618607
Parkinson’s disease (PD); substantia nigra; diffusion tensor imaging (DTI); transverse relaxation rate (R2*); magnetic resonance imaging (MRI)
19.  Systemic inflammation and circadian rhythm of cardiac autonomic modulation 
Systemic inflammation (SI) is associated with impairment of cardiac autonomic modulation (CAM), which is associated with cardiac disease. However, there is limited data about SI on CAM circadian pattern, which this study is aimed to investigate in a middle-aged sample. C-reactive protein (CRP) was used as a SI marker. We performed HRV analysis on each 5-minute segment RRs from of a 24-hour 12-lead ECG to obtain time and frequency domain HRV indices as measures of CAM. The circadian pattern of CAM was analyzed by a two-stage modeling. Stage one, for each individual we fit a cosine periodic model based on the 288 segments of 5-minute HRV data to produce three individual-level cosine parameters that quantity the circadian pattern: mean (M), amplitude (Â), and acrophase time (θ), measure the overall average, the amplitude of the oscillation, and the timing of the highest oscillation, respectively. Stage two, we used random-effects-meta-analysis to summarize the effects of CRP on the three circadian parameters obtained in stage one. CRP was adversely associated with lower M of log-HF, log-LF, SDNN, and RMSSD [β (SE): −0.22 (0.07) ms2, −0.20 (0.06) ms2, −3.62 (0.99) ms, and −2.32 (0.73) ms, respectively, with all p-values<0.01]. More importantly, CRP was also adversely associated with lower  of SDNN and RMSSD [β (SE): −0.84 (0.44) ms and −0.86 (0.38) ms, respectively, both p-values<0.05]. SI is adversely associated with circadian pattern of CAM, suggesting that the cardiac risk associated with SI may be partially mediated via inflammation-related changes in CAM.
PMCID: PMC3111893  PMID: 21444250
C-reactive Protein; Inflammatory Marker; Heart Rate Variability; Periodic Regression; Random-effects Model; Meta-analysis; Community Population
20.  Grief among Family Members of Nursing Home Residents with Advanced Dementia 
To describe pre-loss and post-loss grief symptoms among family members of nursing home (NH) residents with advanced dementia, and to identify predictors of greater post-loss grief symptoms.
Prospective cohort study.
22 NHs in the greater Boston area.
123 family members of NH residents who died with advanced dementia.
Pre-loss grief was measured at baseline, and post-loss grief was measured 2 and 7 months post-loss using the Prolonged Grief Disorder scale. Independent variables included resident and family member sociodemographic characteristics, resident comfort, acute illness, acute care prior to death, family member depression, and family member understanding of dementia and of resident’s prognosis.
Levels of pre-loss and post-loss grief were relatively stable from baseline to 7 months post-loss. Feelings of separation and yearning were the most prominent grief symptoms. After multivariable adjustment, greater pre-loss grief and the family member having lived with the resident prior to NH admission were the only factors independently associated with greater post-loss grief 7 months after resident death.
The pattern of grieving for some family members of NH residents with advanced dementia is prolonged and begins before resident death. Identification of family members at risk for post-loss grief during the pre-loss period may help guide interventions aimed at lessening post-loss grief.
PMCID: PMC3101368  PMID: 21606897
dementia; grief; nursing homes
21.  Serum Cholesterol and Nigrostriatal R2* Values in Parkinson's Disease 
PLoS ONE  2012;7(4):e35397.
The occurrence of Parkinson's disease (PD) is known to be associated both with increased nigrostriatal iron content and with low serum cholesterol and PD, but there has been no study to determine a potential relationship between these two factors.
High-resolution MRI (T1-, T2, and multiple echo T2*-weighted imaging) and fasting lipid levels were obtained from 40 patients with PD and 29 healthy controls. Iron content was estimated from mean R2* values (R2* = 1/T2*) calculated for each nigrostriatal structure including substantia nigra, caudate, putamen, and globus pallidus. This was correlated with serum cholesterol levels after controlling for age, gender, and statin use.
In patients with PD, higher serum cholesterol levels were associated with lower iron content in the substantia nigra (R = −0.43, p = 0.011 for total-cholesterol, R = −0.31, p = 0.080 for low-density lipoprotein) and globus pallidus (R = −0.38, p = 0.028 for total-cholesterol, R = −0.27, p = 0.127 for low-density lipoprotein), but only a trend toward significant association of higher total-cholesterol with lower iron content in the striatum (R = −0.34, p = 0.052 for caudate; R = −0.32, p = 0.061 for putamen). After adjusting for clinical measures, the cholesterol-iron relationships held or became even stronger in the substantia nigra and globus pallidus, but weaker in the caudate and putamen. There was no significant association between serum cholesterol levels and nigrostriatal iron content for controls.
The data show that higher serum total-cholesterol concentration is associated with lower iron content in substantia nigra and globus pallidus in Parkinson's disease patients. Further studies should investigate whether this is mechanistic or epiphenomenological relationship.
PMCID: PMC3328461  PMID: 22530017
22.  Use of the Ages and Stages Questionnaire and Bayley Scales of Infant Development-II in Neurodevelopmental Follow-up of Extremely Low Birth Weight Infants 
For infants born extremely low birth weight (ELBW), we examined the 1) correlation between results on the Ages and Stages Questionnaire (ASQ), and the Bayley Scales of Infant Development II (BSID-II) at 18-22 months corrected age; 2) degree to which earlier ASQ assessments predict later BSID-II results; 3) impact of ASQ use on follow-up study return rates.
Study Design
ASQ data were collected at 4, 8, 12, and 18-22 months corrected age. The BSID-II was completed at 18-22 months corrected age. ASQ and BSID-II 18 – 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses.
ASQ sensitivity and specificity at 18-22 months were 73% and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results.
For ELBW infant assessment, the ASQ cannot substitute for the BSID-II, but appears to improve tracking success.
PMCID: PMC3139816  PMID: 21311498
Bayley Scales of Infant Development; Ages and Stages Questionnaire; neurodevelopment; developmental assessment; developmental screening; NICU
23.  Maturational and Aging Effects on Human Brain Apparent Transverse Relaxation 
PLoS ONE  2012;7(2):e31907.
The goal of this study was to address the need for comprehensive reference data regarding maturational and aging effects on regional transverse relaxation rates (R2) of the brain in normal humans. Regional R2s were measured in twenty-five brain structures from a sample of seventy-seven normal volunteers 9 to 85 years of age. The relationships between regional R2 and age were determined using generalized additive models, without the constraint of a specified a priori model. Data analysis demonstrated that the brain tissue R2-age correlations followed various time courses with both linear and non-linear characteristics depending on the particular brain structure. Most anatomical structures studied exhibited non-linear characteristics, including the amygdala, hippocampus, thalamus, globus pallidus, putamen, caudate nucleus, red nucleus, substantia nigra, orbitofrontal white matter and temporal white matter. Linear trends were detected in occipital white matter and in the genu of corpus callosum. These results indicate the complexity of age-related R2 changes in the brain while providing normative reference data that can be utilized in clinical examinations and studies utilizing quantitative transverse relaxation.
PMCID: PMC3283700  PMID: 22363767
24.  Hospice Utilization and Outcomes Among Nursing Home Residents with Advanced Dementia 
To identify characteristics of nursing home (NH) residents with advanced dementia and their health care proxies (HCPs) associated with hospice referral; and examine the association between hospice use and 1) the treatment of pain and dyspnea, and 2) unmet needs during the last 7 days of life.
Prospective cohort study.
Twenty-two Boston-area NHs.
323 NH residents with advanced dementia and their HCPs.
Data were collected at baseline and quarterly up to 18 months. Hospice referral, the frequency pain and dyspnea were experienced, and treatment of these symptoms was ascertained. HCPs reported unmet needs during the last 7 days of the residents' lives for the following domains: communication, information, emotional support, and help with personal care.
Twenty-two percent of residents were referred to hospice. After multivariable adjustment, factors associated with hospice referral included: non-White race, eating problems, HCP's perception the resident's prognosis was < 6 months, and better HCP mental health. Residents on hospice were more likely to receive scheduled opioids for pain (adjusted odds ratio (AOR), 3.16; 95% confidence interval (CI95%), 1.57-6.36), and oxygen, morphine, scopolamine or hyoscyamine for dyspnea (AOR, 3.28; CI95%, 1.37-7.86). HCPs of residents on hospice reported fewer unmet needs in all domains during the last 7 days of the residents' life.
A minority of NH residents with advanced dementia received hospice care. Hospice recipients were more likely to received scheduled opioids for pain and symptomatic treatment for dyspnea, and had fewer unmet needs at the end of life.
PMCID: PMC3057929  PMID: 21143437
Hospice; palliative care; Alzheimer's disease; dementia; nursing homes
25.  Prediction of 6-Month Survival of Nursing Home Residents With Advanced Dementia Using ADEPT vs Hospice Eligibility Guidelines 
Estimating life expectancy is challenging in advanced dementia, potentially limiting the use of hospice care in these patients.
To prospectively validate and compare the performance of the Advanced Dementia Prognostic Tool (ADEPT) and hospice eligibility guidelines to estimate 6-month survival in nursing home residents with advanced dementia.
Design, Setting, and Participants
A prospective cohort study conducted in 21 nursing homes in Boston, Massachusetts, of 606 residents with advanced dementia who were recruited between November 1, 2007, and July 30, 2009. Data were ascertained at baseline to determine the residents’ ADEPT score (range, 1.0-32.5; higher scores indicate worse prognosis) and whether they met Medicare hospice eligibility guidelines. Survival was followed up to 6 months.
Main Outcome Measures
Assessment and comparison of the performance of the ADEPT score and hospice guidelines to predict 6-month survival using sensitivity, specificity, and the area under the receiver operating characteristic (AUROC) curve.
At baseline, the residents’ mean (SD) ADEPT score was 10.1 (3.1) points and 65 residents (10.7%) met hospice eligibility guidelines. Over 6 months, 111 residents (18.3%) died. The AUROC for the ADEPT score’s prediction of 6-month mortality as a continuous variable was 0.67 (95% confidence interval [CI], 0.62-0.72). The AUROC for Medicare hospice eligibility guidelines was 0.55 (95% CI, 0.51-0.59), the specificity was 0.89 (95% CI, 0.86-0.92), and the sensitivity was 0.20 (95% CI, 0.13-0.28). Using a cutoff of 13.5 on the ADEPT score, which also had specificity of 0.89, the AUROC was 0.58 (95% CI, 0.54-0.63) and the sensitivity was 0.27 (95% CI, 0.19-0.36).
When prospectively validated at the bedside and used as a continuous measure, the ability of the ADEPT score to identify nursing home residents with advanced dementia at high risk of death within 6 months was modest, albeit better than hospice eligibility guidelines. Care provided to these residents should be guided by their goals of care rather than estimated life expectancy.
PMCID: PMC3017367  PMID: 21045099

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