Maria Vassilaki

Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia

IMPORTANCE To increase the opportunity to delay or prevent mild cognitive impairment (MCI) or Alzheimer disease (AD) dementia, markers of early detection are essential. Olfactory impairment may be an important clinical marker and predictor of these conditions and may help identify persons at increased risk. OBJECTIVE To examine associations of impaired olfaction with incident MCI subtypes and progression from MCI subtypes to AD dementia. DESIGN, SETTING, AND PARTICIPANTS Participants enrolled in the population-based, prospective Mayo Clinic Study of Aging between 2004 and 2010 were clinically evaluated at baseline and every 15 months through 2014. Participants (N = 1630) were classified as having normal cognition, MCI (amnestic MCI [aMCI] and nonamnestic MCI [naMCI]), and dementia. We administered the Brief Smell Identification Test (B-SIT) to assess olfactory function. MAIN OUTCOMES AND MEASURES Mild cognitive impairment, AD dementia, and longitudinal change in cognitive performance measures. RESULTS Of the 1630 participants who were cognitively normal at the time of the smell test, 33 died before follow-up and 167 were lost to follow-up. Among the 1430 cognitively normal participants included, the mean (SD) age was 79.5 (5.3) years, 49.4% were men, the mean duration of education was 14.3 years, and 25.4% were APOE ε4 carriers. Over a mean 3.5 years of follow-up, there were 250 incident cases of MCI among 1430 cognitively normal participants. We observed an association between decreasing olfactory identification, as measured by a decrease in the number of correct responses in B-SIT score, and an increased risk of aMCI. Compared with the upper B-SIT quartile (quartile [Q] 4, best scores), hazard ratios (HRs) (95% CI) were 1.12 (0.65-1.92) for Q3 (P = .68); 1.95 (1.25-3.03) for Q2 (P = .003); and 2.18 (1.36-3.51) for Q1 (P = .001) (worst scores; P for trend <.001) after adjustment for sex and education, with age as the time scale. There was no association with naMCI. There were 64 incident dementia cases among 221 prevalent MCI cases. The B-SIT score also predicted progression from aMCI to AD dementia, with a significant dose-response with worsening B-SIT quartiles. Compared with Q4, HR (95% CI) estimates were 3.02 (1.06-8.57) for Q3 (P = .04); 3.63 (1.19-11.10) for Q2 (P = .02); and 5.20 (1.90-14.20) for Q1 (P = .001). After adjusting for key predictors of MCI risk, B-SIT (as a continuous measure) remained a significant predictor of MCI (HR, 1.10 [95% CI, 1.04-1.16]; P < .001) and improved the model concordance. CONCLUSIONS AND RELEVANCE Olfactory impairment is associated with incident aMCI and progression from aMCI to AD dementia. These findings are consistent with previous studies that have reported associations of olfactory impairment with cognitive impairment in late life and suggest that olfactory tests have potential utility for screening for MCI and MCI that is likely to progress.

Early growth characteristics and the risk of reduced lung function and asthma : A meta-analysis of 25,000 children

BACKGROUND Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Association of early life exposure to bisphenol A with obesity and cardiometabolic traits in childhood

BACKGROUND Bisphenol A (BPA) is a chemical used extensively worldwide in the manufacture of plastic polymers. The environmental obesogen hypothesis suggests that early life exposure to endocrine disrupting chemicals such as BPA may increase the risk for wt gain later in childhood but few prospective epidemiological studies have investigated this relationship. OBJECTIVES We examined the association of early life BPA exposure with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the RHEA pregnancy cohort in Crete, Greece. METHODS BPA concentrations were measured in spot urine samples collected at the 1st trimester of pregnancy) and from children at 2.5 and 4 years of age. We measured birth wt, body mass index (BMI) from 6 months to 4 years of age, waist circumference, skinfold thickness, blood pressure, serum lipids, C-reactive protein, and adipokines at 4 years of age. BMI growth trajectories from birth to 4 years were estimated by mixed effects models with fractional polynomials of age. Adjusted associations were obtained via multivariable regression analyses. RESULTS The prevalence of overweight/obesity was 9% at 2, 13% at 3% and 17% at 4 years of age. Geometric mean BPA concentrations were 1.2μg/g creatinine±7.9 in 1st trimester, 5.1μg/g±13.3 in 2.5 years and 1.9μg/g±4.9 in 4 years. After confounder adjustment, each 10-fold increase in BPA at 4 years was associated with a higher BMI z-score (adj. β=0.2; 95% CI: 0.01, 0.4), waist circumference (adj. β=1.2; 95% CI: 0.1, 2.2) and sum of skinfold thickness (adj. β=3.7mm; 95% CI: 0.7, 6.7) at 4 years. Prenatal BPA was negatively associated with BMI and adiposity measures in girls and positively in boys. We found no associations of early life exposure to BPA with other offspring cardiometabolic risk factors. CONCLUSIONS Prenatal BPA exposure was not consistently associated with offspring growth and adiposity measures but higher early childhood BPA was associated with excess child adiposity.

Choice of Analytic Approach for Eye-Specific Outcomes: One Eye or Two?

PURPOSE To investigate the use of analytic approaches for eye-specific outcomes in ophthalmology publications. DESIGN A review of analytic approaches used in original research articles published in ophthalmology journals. METHODS All 161 research articles published in 5 ophthalmology journals in the first 2 months of 2008 were considered. Publications were categorized according to analytic approach: 1 eye selected, both eyes contribute, or per-individual outcome. Studies were considered suboptimal when criteria for eye selection were not provided or when measurements from both eyes were included without interocular correlation being considered. Visual impairment prevalence data were used to illustrate analytic approach choices. RESULTS Measurements from both eyes were included in 38% of the 112 studies that used statistical inferential techniques. In 31 (74%), there was no mention of possible correlation. Only 7% used statistical methods appropriate for correlated outcomes. In 35 studies (31%), measurements from 1 eye were selected; 31% of these did not provide selection criteria. In 67%, only univariate tests were used. A review of 47 articles published in 2011 produced similar findings. Characteristics of studies were not found to differ according whether the studies were suboptimal. Using a test appropriate for correlated outcomes resulted in a P value 3.5 times that obtained ignoring the correlation. CONCLUSIONS Between-eye correlation seems not to be assessed commonly in ophthalmology publications, although its knowledge aids the choice of analytic approach when eye-specific variables are of interest. Statistical methods appropriate for correlated ocular outcome data are not being applied widely.

Association of Prenatal Exposure to Persistent Organic Pollutants with Obesity and Cardiometabolic Traits in Early Childhood: The Rhea Mother-Child Cohort (Crete, Greece).

Background Prenatal exposure to endocrine-disrupting chemicals such as persistent organic pollutants (POPs) may increase risk of obesity later in life. Objective We examined the relation of in utero POPs exposure to offspring obesity and cardiometabolic risk factors at 4 years of age in the Rhea mother–child cohort in Crete, Greece (n = 689). Methods We determined concentrations of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) in first-trimester maternal serum. We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), blood levels of lipids, C-reactive protein, and adipokines at 4 years of age. Childhood obesity was defined using age- and sex-specific cut points for body mass index (BMI) as recommended by the International Obesity Task Force. Results On multivariable regression analyses, a 10-fold increase in HCB was associated with a higher BMI z-score (adjusted β = 0.49; 95% CI: 0.12, 0.86), obesity [relative risk (RR) = 8.14; 95% CI: 1.85, 35.81], abdominal obesity (RR = 3.49; 95% CI: 1.08, 11.28), greater sum of skinfold thickness (β = 7.71 mm; 95% CI: 2.04, 13.39), and higher systolic BP (β = 4.34 mmHg; 95% CI: 0.63, 8.05) at 4 years of age. Prenatal DDE exposure was associated with higher BMI z-score (β = 0.27; 95% CI: 0.04, 0.5), abdominal obesity (RR = 3.76; 95% CI: 1.70, 8.30), and higher diastolic BP (β = 1.79 mmHg; 95% CI: 0.13, 3.46). PCBs were not significantly associated with offspring obesity or cardiometabolic risk factors. Conclusions Prenatal exposure to DDE and HCB was associated with excess adiposity and higher blood pressure levels in early childhood. Citation Vafeiadi M, Georgiou V, Chalkiadaki G, Rantakokko P, Kiviranta H, Karachaliou M, Fthenou E, Venihaki M, Sarri K, Vassilaki M, Kyrtopoulos SA, Oken E, Kogevinas M, Chatzi L. 2015. Association of prenatal exposure to persistent organic pollutants with obesity and cardiometabolic traits in early childhood: the Rhea mother–child cohort (Crete, Greece). Environ Health Perspect 123:1015–1021; http://dx.doi.org/10.1289/ehp.1409062

Hepcidin is a key mediator of anemia of inflammation in Crohn's disease

UNLABELLED Anemia often complicates the course of Inflammatory Bowel Disease (IBD). Hepcidin, a liver-produced peptide hormone, is a key mediator of anemia of chronic disease (ACD). We hypothesized that hepcidin is significantly elevated in anemic CD patients and that hepcidin may cause iron restriction and, therefore, mediate ACD. METHODS We enrolled 17 patients with CD and ACD recruited from the Cedars-Sinai IBD Center. Routine blood tests included hemoglobin (Hgb), hematocrit, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Anemia was defined as hemoglobin <12g/dL and <13.5g/dL, in men and women, respectively. ACD was diagnosed on the basis of a combination of the following: a) normal or elevated ferritin b) lowered serum iron and total iron binding capacity and c) normal percent iron saturation. Serum and urine hepcidin, as well as IL-6 levels were also measured. Patients with documented iron-deficiency anemia were excluded. RESULTS There was an excellent correlation between urine (expressed as ng/mg of creatinine) and serum hepcidin levels expressed as ng/ml (r=0.853, p<0.001). We also found a strong positive correlation between serum hepcidin and ferritin levels (r=0.723, p=0.0015). There was a positive correlation between serum hepcidin and IL-6 levels (r=0.546, p=0.023). We found a strong negative correlation between serum hepcidin concentrations and Hgb levels (r=0.528, p=0.029). CONCLUSION We demonstrate that ACD in CD is characterized by high serum IL-6 and hepcidin levels, which negatively correlate with Hgb levels. Our data support the hypothesis that IL-6-driven hepcidin production mediates ACD in patients with CD.

The metabolic syndrome in early pregnancy and risk of gestational diabetes mellitus

AIM The objective of the present study was to determine whether or not maternal metabolic syndrome in early pregnancy in women without previous diabetes is associated with the development of gestational diabetes mellitus (GDM). METHODS A total of 508 women from the Rhea study-involving a pregnant cohort in Crete, Greece (2007-2009)-with singleton pregnancies were included in the present analysis. Maternal fasting serum samples were collected and blood pressure measured before gestational week 15. The metabolic syndrome in early pregnancy was defined according to NHLBI/AHA criteria. Pregnant women were screened for GDM between weeks 24 and 28 of gestation, as defined by Carpenter and Coustan criteria. Multivariable log-binomial regression models were used to estimate the effect of the metabolic syndrome in early pregnancy on the risk of GDM, after adjusting for confounding factors. RESULTS Women with the metabolic syndrome were at high risk of GDM (RR=3.17; 95% CI: 1.06-9.50). Among the components of the metabolic syndrome, the most significant risk factors were impaired fasting glucose (RR=4.92; 95% CI: 1.41-17.23) and pre-pregnancy obesity (RR=2.65; 95% CI: 1.23-5.70). A 10-mmHg rise in systolic and diastolic blood pressure increased the relative risk of GDM by 49% (RR=1.49; 95% CI: 1.10-2.02) and 34% (RR=1.34; 95% CI: 1.04-1.73), respectively, whereas a 1-unit increase in pre-pregnancy BMI increased the relative risk of GDM by 6% (RR=1.06; 95% CI: 1.01-1.12). CONCLUSION These findings suggest that women with the metabolic syndrome in early pregnancy have a greater risk of developing GDM.

Multimorbidity and Risk of Mild Cognitive Impairment

To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment (MCI) and dementia.

Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals

Importance While amyloid and neurodegeneration are viewed together as Alzheimer disease pathophysiology (ADP), the factors that influence amyloid and AD-pattern neurodegeneration may be considerably different. Protection from these ADP factors may be important for aging without significant ADP. Objective To identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration in a population-based sample and to test the hypothesis that “exceptional agers” with advanced ages do not have significant ADP because they have protective factors for amyloid and neurodegeneration. Design, Setting, and Participants This cohort study conducted a prospective analysis of 942 elderly individuals (70-≥90 years) with magnetic resonance imaging and Pittsburgh compound B–positron emission tomography scans enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We operationalized “exceptional aging” without ADP by considering individuals 85 years or older to be without significant evidence of ADP. Main Outcomes and Measures We evaluated predictors including demographics, APOE, intellectual enrichment, midlife risk factors (physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia), and the total number of late-life cardiac and metabolic conditions. We used multivariate linear regression models to identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration. Using a subsample of the cohort 85 years of age or older, we computed Cohen d–based effect size estimations to compare the quantitative strength of each predictor variable in their contribution with exceptional aging without ADP. Results The study participants included 423 (45%) women and the average age of participants was 79.7 (5.9) years. Apart from demographics and the APOE genotype, only midlife dyslipidemia was associated with amyloid deposition. Obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. In the 85 years or older cohort, the Cohen d results showed small to moderate effects (effect sizes > 0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without ADP. Conclusions and Relevance The protective factors that influence amyloid and AD-pattern neurodegeneration are different. “Exceptional aging” without ADP may be possible with a greater number of protective factors across the lifespan but warrants further investigation.

Colorectal cancer screening and surveillance in Crohn's colitis

AIMS To assess colonoscopic screening and surveillance for detecting neoplasia in patients with long-standing colonic Crohns disease (CD). PATIENTS AND METHODS Colonoscopy and biopsy records from patients with colonic CD were evaluated at the Cedars-Sinai Inflammatory Bowel Disease Center during a 17-year period (1992-2009). RESULTS Overall, 904 screening and surveillance examinations were performed on 411 patients with Crohns colitis (mean 2.2 examinations per patient). The screening and surveillance examinations detected neoplasia in 5.6% of the patient population; 2.7% had low-grade dysplasia (LGD) (n=11), 0.7% had high-grade dysplasia (HGD) (n=3), and 2.2% had carcinoma (anal carcinoma n=3; rectal carcinoma n=6). Mean age of CD diagnosis was 25.6±0.8 years in those with normal examinations, compared to 17.7±2.7 years (p<0.001) in those with HGD, 36.85±1.43 in those with LGD (p=0.021) and 28.32±3.24 years in those with any dysplasia/cancer (p=0.034). Disease duration in patients with normal examinations was 19.1±0.5 years, compared to 36.8±4.4 years (p<0.001) in HGD, 16.88±2.59 in those with LGD (p=0.253) and 30.68±4.03 years in those with any dysplasia/cancer (p=0.152). The mean interval between examinations was higher in HGD (31.5±9.4 months) compared to those with normal colonoscopies (12.92±1.250 months; p=0.002). CONCLUSIONS We detected cancer or dysplasia in 5.6% of patients with long-standing Crohns colitis enrolled in a screening and surveillance program. Younger age at diagnosis of CD, longer disease course, and greater interval between exams were risk factors for the development of dysplasia.