Philip J. Lupo

Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores: A Texas Alzheimer's Research Consortium Study

BACKGROUND The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established. OBJECTIVE To investigate the effectiveness of CDR-SOB scores in staging dementia severity compared with the global CDR score. DESIGN Retrospective study. SETTING Texas Alzheimers Research Consortium minimum data set cohort. PARTICIPANTS A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis. MAIN OUTCOME MEASURES Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample. RESULTS Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.0, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, kappa scores ranged from 0.86 to 0.94 (P < .001 for all), with 93.0% of the participants falling within the new staging categories. CONCLUSIONS The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.

Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis.

Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207(+) dendritic cells with an inflammatory infiltrate. BRAFV600E remains the only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro. Single cases of somatic mutations of the mitogen-activated protein kinase (MAPK) pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal end point in LCH arising from pathological activation of upstream signaling proteins.

BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups

The Rockefeller University Press

Differences in exposure assignment between conception and delivery: the impact of maternal mobility.

30.00 J. Exp. Med. 2014 Vol. 211 No. 4 669-683 www.jem.org/cgi/doi/10.1084/jem.20130977 669 Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions that include pathological langerin+ DCs. LCH has pleotropic clinical presentations ranging from single lesions cured by curettage to potentially fatal multisystem disease. The first descriptions of LCH, including Hand-Schüller-Christian disease and Letter-Siwe disease, were based on anatomical location and extent of the lesions (Arceci, 1999). The diagnosis of high-risk LCH, defined by involvement of “risk organs” which include BM, liver, and spleen, conferred mortality rates >20%, where patients with disease limited to non-risk organs (low-risk LCH) had nearly 100% survival, CORRESPONDENCE Carl Allen: ceallen@txch.org OR Miriam Merad: miriam.merad@mssm.edu

Maternal Exposure to Ambient Levels of Benzene and Neural Tube Defects among Offspring: Texas, 1999–2004

In studies of reproductive outcomes, maternal residence at delivery is often the only information available to characterise environmental exposures during pregnancy. The goal of this investigation was to describe residential mobility during pregnancy and to assess the extent to which change of residence may result in exposure misclassification when exposure is based on the address at delivery. Maternal residential mobility was compared between neural tube defect cases and unaffected controls from Texas participants in the National Birth Defects Prevention Study (NBDPS). Maternal residential information was obtained from the NBDPS interview. Data from the U.S. EPA National Air Toxics Assessment [Assessment System for Population Exposure Nationwide (ASPEN)], modelled at the census tract level, were used to estimate benzene exposure based on address at conception and address at delivery. Quartiles of exposure were assigned based on these estimates and the quartile assignments based on address at conception and address at delivery were compared using traditional methods (kappa statistics) and a novel application of mixed-effects ordinal logistic regression. Overall, 30% of case mothers and 24% of control mothers moved during pregnancy. Differences in maternal residential mobility were not significant between cases and controls, other than case mothers who moved did so earlier during pregnancy than control mothers (P = 0.01). There was good agreement between quartiles of estimated benzene exposure at both addresses (kappa = 0.78, P < 0.0001). Based on the mixed-effects regression model, address at delivery was not significantly different from using address at conception when assigning quartile of benzene exposure based on estimates from ASPEN (odds ratio 1.03, 95% confidence interval 0.85, 1.25). Our results indicate that, in this Texas population, maternal residential movement is generally within short distances, is typically not different between cases and controls, and does not significantly influence benzene exposure assessment.

Comparative Assessment of Air Pollution-Related Health Risks in Houston

Background Previous studies have reported positive associations between maternal exposure to air pollutants and several adverse birth outcomes. However, there have been no studies assessing the association between environmental levels of hazardous air pollutants, such as benzene, and neural tube defects (NTDs), a common and serious group of congenital malformations. Objective Our goal was to conduct a case–control study assessing the association between ambient air levels of benzene, toluene, ethylbenzene, and xylene (BTEX) and the prevalence of NTDs among offspring. Methods The Texas Birth Defects Registry provided data on NTD cases (spina bifida and anencephaly) delivered between 1999 and 2004. The control group was a random sample of unaffected live births, frequency matched to cases on year of birth. Census tract–level estimates of annual BTEX levels were obtained from the U.S. Environmental Protection Agency 1999 Assessment System for Population Exposure Nationwide. Restricted cubic splines were used in mixed-effects logistic regression models to determine associations between each pollutant and NTD phenotype. Results Mothers living in census tracts with the highest benzene levels were more likely to have offspring with spina bifida than were women living in census tracts with the lowest levels (odds ratio = 2.30; 95% confidence interval, 1.22–4.33). No significant associations were observed between anencephaly and benzene or between any of the NTD phenotypes and toluene, ethylbenzene, or xylene. Conclusion In the first study to assess the relationship between environmental levels of BTEX and NTDs, we found an association between benzene and spina bifida. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes.

Variants of folate metabolism genes and the risk of conotruncal cardiac defects.

Background Airborne emissions from numerous point, area, and mobile sources, along with stagnant meteorologic conditions, contribute to frequent episodes of elevated air pollution in Houston, Texas. To address this problem, decision makers must set priorities among thousands of individual air pollutants as they formulate effective and efficient mitigation strategies. Objectives Our aim was to compare and rank relative health risks of 179 air pollutants in Houston using an evidence-based approach supplemented by the expert judgment of a panel of academic scientists. Methods Annual-average ambient concentrations by census tract were estimated from the U.S. Environmental Protection Agency’s National-scale Air Toxics Assessment and augmented with measured levels from the Houston monitoring network. Each substance was assigned to one of five risk categories (definite, probable, possible, unlikely, uncertain) based on how measured or monitored concentrations translated into comparative risk estimates. We used established unit risk estimates for carcinogens and/or chronic reference values for noncarcinogens to set thresholds for each category. Assignment to an initial risk category was adjusted, as necessary, based on expert judgment about the quality and quantity of information available. Results Of the 179 substances examined, 12 (6.7%) were deemed definite risks, 9 (5.0%) probable risks, 24 (13.4%) possible risks, 16 (8.9%) unlikely risks, and 118 (65.9%) uncertain risks. Conclusions Risk-based priority setting is an important step in the development of cost-effective solutions to Houston’s air pollution problem.

Childhood Brain Tumor Epidemiology: A Brain Tumor Epidemiology Consortium Review

Background—Although congenital heart defects (CHD) are the most common and serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well as genetic variants in folate-related genes. However, efforts to establish the relationships between these factors and CHD risk have been hampered by a number of factors including small study sample sizes and phenotypic heterogeneity. Methods and Results—The present study examined the relationships between variation in 9 folate-related genes and a subset of CHD phenotypes (ie, conotruncal defects, perimembranous and malalignment type ventricular septal defects, and isolated aortic arch anomalies) in a cohort of >700 case-parent triads. Further, both maternal and embryonic genetic effects were considered. Analyses of the study data confirmed an earlier reported association between embryonic genotype for MTHFR A1298C and disease risk (unadjusted P=0.002). Conclusions—These results represent the most comprehensive and powerful analysis of the relationship between CHD and folate-related genes reported to date, and provide additional evidence that, similar to neural tube defects, this subset of CHD is folate related.

Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly

Childhood brain tumors are the most common pediatric solid tumor and include several histologic subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors. Cancer Epidemiol Biomarkers Prev; 23(12); 2716–36. ©2014 AACR.

Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment : Prognosis and conversion to dementia

The cyclopic and laterality phenotypes in model organisms linked to disturbances in the generation or propagation of Nodal-like signals are potential examples of similar impairments resulting in birth defects in humans. However, the types of gene mutation(s) and their pathogenetic combinations in humans are poorly understood. Here we describe a mutational analysis of the human NODAL gene in a large panel of patients with phenotypes compatible with diminished NODAL ligand function. Significant reductions in the biological activity of NODAL alleles are detected among patients with congenital heart defects (CHD), laterality anomalies (e.g. left-right mis-specification phenotypes), and only rarely holoprosencephaly (HPE). While many of these NODAL variants are typical for family-specific mutations, we also report the presence of alleles with significantly reduced activity among common population variants. We propose that some of these common variants act as modifiers and contribute to the ultimate phenotypic outcome in these patients; furthermore, we draw parallels with strain-specific modifiers in model organisms to bolster this interpretation.