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author:("erbe, Gary")
1.  FMR1 Gray Zone Alleles: Association with Parkinson Disease in Women? 
Carriers of fragile X mental retardation 1 (FMR1) repeat expansions in the premutation range (55–200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism.1–2 These neurological signs are believed to be due to elevated levels of expanded CGG repeat FMR1 mRNA. The purpose of this study was to determine the prevalence of FMR1 repeat expansions in a movement disorder population, comprised of all types of tremor, ataxia or parkinsonism subjects.
We screened 335 consecutive movement disorders patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders.
There was no difference in FMR1 premutation size expansions in the cases compared to controls. Eleven percent of the women with Parkinson disease (PD) had FMR1 gray zone expansions compared to 4.4% of female controls, odds ratio of 3.2 (95% CI 1.2–8.7). Gray zone expansions in patients with other phenotypes were not overrepresented in comparison with controls.
FMR1 premutation range expansions are not more common in a mixed movement disorder population compared to controls. Our results, however, suggest that FMR1 gray zone alleles may be associated with PD in women.
PMCID: PMC3934001  PMID: 21567456
Parkinson disease; FMR1; FXTAS; genetics; parkinsonism
2.  Acculturation, maternal cortisol and birth outcomes in women of Mexican descent 
Psychosomatic medicine  2012;74(3):296-304.
This study investigated the effects of acculturation on cortisol, a biological correlate of maternal psychological distress, and perinatal infant outcomes, specifically gestational age at birth and birth weight.
Fifty-five pregnant women of Mexican descent were recruited from a community hospital and collected saliva samples at home over 3 days during pregnancy at 15–18 (early), 26–2 (mid), and 32+ (late) weeks gestation and once in the postpartum period (4–12 weeks). These values were used to determine the diurnal cortisol slope at each phase of pregnancy. Mothers also completed an acculturation survey and gave permission for a medical chart review to obtain neonate information.
Multiple regression analyses determined that greater acculturation levels significantly predicted earlier infant gestational age at birth (R2=0.09, p=0.03). T-tests revealed that mothers of low birth weight infants weight (<2500g) had significantly higher acculturation scores than mothers of infants with birth weight >2500g (t=−2.95, p=0.005). A blunted maternal cortisol slope during pregnancy was also correlated with low birth weight (r=−0.29, p=0.05), but not gestational age (r=−0.08, p=0.59). In addition, more acculturated women had a flatter diurnal cortisol slope late in pregnancy (R2=0.21, p=0.01). Finally diurnal maternal cortisol rhythms were identified as a potential mediator between increased acculturation and birth weight.
This study associated increased acculturation with perinatal outcomes in the US Mexican population. This relationship may be mediated by prenatal maternal diurnal cortisol, which can program the health of the fetus leading to several adverse perinatal outcomes.
PMCID: PMC3751979  PMID: 22366584
perinatal; hypothalamic-pituitary-adrenal axis; mother; immigrant; gestational age; birth weight
3.  Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia 
The American journal of psychiatry  2008;165(8):1040-1047.
Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of α7-nicotinic receptors. Patients’ heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial α7-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.
Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.
There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.
DMXB-A, a nicotinic agonist that activates α7-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.
PMCID: PMC3746983  PMID: 18381905
4.  Solutions for Determining the Significance Region Using the Johnson-Neyman Type Procedure in Generalized Linear (Mixed) Models 
Researchers often compare the relationship between an outcome and covariate for two or more groups by evaluating whether the fitted regression curves differ significantly. When they do, researchers need to determine the “significance region,” or the values of the covariate where the curves significantly differ. In analysis of covariance (ANCOVA), the Johnson-Neyman procedure can be used to determine the significance region; for the hierarchical linear model (HLM), the Miyazaki and Maier (M-M) procedure has been suggested. However, neither procedure can assume nonnormally distributed data. Furthermore, the M-M procedure produces biased (downward) results because it uses the Wald test, does not control the inflated Type I error rate due to multiple testing, and requires implementing multiple software packages to determine the significance region. In this article, we address these limitations by proposing solutions for determining the significance region suitable for generalized linear (mixed) model (GLM or GLMM). These proposed solutions incorporate test statistics that resolve the biased results, control the Type I error rate using Scheffé’s method, and uses a single statistical software package to determine the significance region.
PMCID: PMC3682820  PMID: 23772174
generalized estimating equations; hierarchical linear models; longitudinal analysis; multiple testing; simultaneous testing
5.  Antidepressants May Mitigate the Effects of Prenatal Maternal Anxiety on Infant Auditory Sensory Gating 
The American journal of psychiatry  2012;169(6):616-624.
Prenatal maternal anxiety has detrimental effects on the resulting offspring’s neurocognitive development, including impaired attentional function. Antidepressants are commonly utilized during pregnancy, yet their impact on offspring attention and their interaction with maternal anxiety has not been assessed. Using P50 auditory sensory gating, a putative marker of early attentional processes measurable in young infants, the impact of maternal anxiety and antidepressant use are explored.
Two hundred forty-two mother-infant dyads were classified relative to maternal history of anxiety and maternal prenatal antidepressant use. Infant P50 auditory sensory gating was recorded during active sleep at a mean± standard deviation of 76 ± 38 days of age.
In the absence of prenatal antidepressant exposure, infants with mothers with a history of anxiety diagnoses had diminished P50 sensory gating (p<.001). Prenatal antidepressants mitigated the effect of anxiety (uncorrected p=.041). The effect of maternal anxiety was limited to amplitude of response to the second stimulus while antidepressants impacted the amplitude or response to both the first and second stimulus.
Maternal anxiety disorders are associated less inhibition during infant sensory gating, a performance deficit mitigated by prenatal antidepressant use. This effect may be important in considering the risks and benefits of prenatal antidepressant treatment. Cholinergic mechanisms are hypothesized for both anxiety and antidepressant effects; however the cholinergic receptors involved are likely different for anxiety and antidepressant effects. Additional work focused on understanding how treatment impacts the relationship between maternal prenatal illness and offspring neurocognitive development is indicated.
PMCID: PMC3640273  PMID: 22581104
6.  Influence of Age and Nature of Primary Infection on Varicella-Zoster Virus—Specific Cell-Mediated Immune Responses 
The Journal of infectious diseases  2010;201(7):1024-1030.
Varicella-zoster virus (VZV)-specific cell-mediated immunity is important for protection against VZV disease. We studied the relationship between VZV cell-mediated immunity and age after varicella or VZV vaccination in healthy and human immunodeficiency virus (HIV)–infected individuals.
VZV responder cell frequency (RCF) determinations from 752 healthy and 200 HIV-infected subjects were used to identify group-specific regression curves on age.
In healthy individuals with past varicella, VZV RCF peaked at 34 years of age. Similarly, VZV-RCF after varicella vaccine increased with age in subjects aged <1 to 43 years. In subjects aged 61–90 years, VZV RCF after zoster vaccine decreased with age. HIV-infected children had lower VZV RCF estimates than HIV-infected adults. In both groups, VZV RCF results were low and constant over age. Varicella vaccination of HIV-infected children with CD4 levels ≥20% generated VZV RCF values higher than wild-type infection and comparable to vaccine-induced responses of healthy children.
In immunocompetent individuals with prior varicella, VZV RCF peaked in early adulthood. Administration of varicella vaccine to HIV-infected or uninfected individuals aged >5 years generated VZV RCF values similar to those of immunocompetent individuals with immunity induced by wild-type infection. A zoster vaccine increased the VZV RCF of elderly adults aged <75 years to values higher than peak values induced by wild-type infection.
PMCID: PMC3136368  PMID: 20170376
7.  Ventral Striatal Blood Flow is Altered by Acute Nicotine but Not Withdrawal from Nicotine 
Neural mechanisms underlying the reinforcing effects of nicotine and other drugs have been widely studied and are known to involve the ventral striatum, which is part of the mesocorticolimbic dopamine system. In contrast, mechanisms of nicotine withdrawal have received less attention although subjective withdrawal likely contributes to the difficulty of quitting. The goal of this study was to determine if nicotine withdrawal was associated with alterations of cerebral blood flow (CBF) in ventral striatum. Twelve smokers, moderately dependent on nicotine, underwent MR dynamic susceptibility contrast (DSC) imaging at baseline, after overnight withdrawal from nicotine, and after nicotine replacement. DSC images were used to calculate CBF in three regions of interest: ventral striatum, thalamus, and medial frontal cortex. Subjective withdrawal symptoms were measured at each time point. In spite of significant subjective withdrawal symptoms, there was no main effect of withdrawal on CBF in the three regions. However, there was a significant correlation between the increase in withdrawal symptoms and a reduction in thalamic CBF. In contrast to withdrawal, nicotine replacement significantly increased CBF in ventral striatum. Our findings are consistent with the known role of ventral striatum in drug reward. The lack of a main effect on withdrawal, but correlation of thalamic blood flow with withdrawal symptoms suggests that more complex mechanisms mediate the subjective features of the withdrawal state.
PMCID: PMC2856639  PMID: 17460613
nicotine; subjective withdrawal; cerebral blood flow; ventral striatum
8.  Perinatal and early childhood risk factors associated with rheumatoid factor positivity in a healthy paediatric population 
Annals of the Rheumatic Diseases  2007;66(2):179-183.
To examine perinatal and childhood risk factors for the presence of rheumatoid factor in healthy children.
The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal study of children at increased risk of type 1 diabetes, based on possession of human leucocyte antigen (HLA)‐DR4 and DR3 alleles or a family history of diabetes. 651 children who participated in DAISY, with an average age of 6.4 (range 1–15) years, were tested for the presence of rheumatoid factor in their most recent serum sample. 23 children were positive for rheumatoid factor. Exposure data were collected prospectively by interview. HLA‐DR4 alleles were identified using polymerase chain reaction‐based Class II genotyping.
While exploring risk factors for rheumatoid factor positivity in a multivariate model, several important interaction terms involving HLA‐DR4 status suggested the need to evaluate risk factors in HLA‐DR4‐positive and HLA‐DR4‐negative children separately. In HLA‐DR4‐negative children, rheumatoid factor‐positive infants were less likely to have been breast fed for >3 months (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04 to 0.99), more likely to have been exposed to non‐parental tobacco smoke (OR 5.38; 95% CI 0.93 to 31.27) and more likely to be a race/ethnicity other than non‐Hispanic white (OR 6.94; 95% CI 1.10 to 43.88) compared with rheumatoid factor‐negative children, after adjusting for age, sex and maternal education. In HLA‐DR4‐positive children, there were no significantly associated risk factors for rheumatoid factor positivity.
Risk factors for rheumatoid factor positivity in children vary by HLA‐DR4 genotype. In HLA‐DR4‐negative children, breast feeding may decrease the risk, and environmental tobacco smoke may increase the risk, of autoimmunity.
PMCID: PMC1798519  PMID: 17242018
9.  The Stability of Inhibitory and Working Memory Deficits in Children and Adolescents Who are Children of Parents With Schizophrenia 
Schizophrenia Bulletin  2007;34(1):47-51.
Cognitive deficits are a central feature of schizophrenia and occur in first-degree relatives of schizophrenic probands, even in the absence of psychotic symptoms. A number of cognitive domains have been implicated including measures of response inhibition and working memory. While the stability of cognitive deficits has been demonstrated in individuals with schizophrenia, stability of deficits has not been explored in first-degree relatives. This report focuses on 25 children (ages 6–15 years), all with at least one schizophrenic parent. The children were assessed twice, utilizing inhibitory and working memory tasks, with a mean 2.6 years between visits. Stop reaction time (a measure of motor inhibition) and performance on a counting span task (a measure of verbal working memory) were borderline to mildly impaired (compared with a typically developing comparison group) at both visits with similar effect sizes (stopping task time 1, effect size = 0.46, time 2 effect size = 0.50; counting span time 1 effect size = 0.53, time 2 effect size = 0.42). For these 2 tasks, individual age-adjusted scores also correlated across both time points (r = 0.41–0.76) suggesting that individual children maintained deficits across time. As etiologically driven strategies are developed for the cognitive deficits of schizophrenia, expansion of these treatments to relatives who share the cognitive but not the psychotic symptoms may be worth exploring.
PMCID: PMC2632372  PMID: 17873150
schizophrenia; inhibition; working memory
10.  Permutation-Based Adjustments for the Significance of Partial Regression Coefficients in Microarray Data Analysis 
Genetic epidemiology  2008;32(1):1-8.
The aim of this paper is to generalize permutation methods for multiple testing adjustment of significant partial regression coefficients in a linear regression model used for microarray data. Using a permutation method outlined by Anderson and Legendre [1999] and the permutation P-value adjustment from Simon et al. [2004], the significance of disease related gene expression will be determined and adjusted after accounting for the effects of covariates, which are not restricted to be categorical. We apply these methods to a microarray dataset containing confounders and illustrate the comparisons between the permutation-based adjustments and the normal theory adjustments. The application of a linear model is emphasized for data containing confounders and the permutation-based approaches are shown to be better suited for microarray data.
PMCID: PMC2592303  PMID: 17630650
multiple comparisons; gene expression; permutation; linear regression; adjusted P-values
11.  Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study 
BMC Genetics  2003;4(Suppl 1):S83.
The relationship between elevated blood pressure and cardiovascular and cerebrovascular disease risk is well accepted. Both systolic and diastolic hypertension are associated with this risk increase, but systolic blood pressure appears to be a more important determinant of cardiovascular risk than diastolic blood pressure. Subjects for this study are derived from the Framingham Heart Study data set. Each subject had five records of clinical data of which systolic blood pressure, age, height, gender, weight, and hypertension treatment were selected to characterize the phenotype in this analysis.
We modeled systolic blood pressure as a function of age using a mixed modeling methodology that enabled us to characterize the phenotype for each individual as the individual's deviation from the population average rate of change in systolic blood pressure for each year of age while controlling for gender, body mass index, and hypertension treatment. Significant (p = 0.00002) evidence for linkage was found between this normalized phenotype and a region on chromosome 1. Similar linkage results were obtained when we estimated the phenotype while excluding values obtained during hypertension treatment. The use of linear mixed models to define phenotypes is a methodology that allows for the adjustment of the main factor by covariates. Future work should be done in the area of combining this phenotype estimation directly with the linkage analysis so that the error in estimating the phenotype can be properly incorporated into the genetic analysis, which, at present, assumes that the phenotype is measured (or estimated) without error.
PMCID: PMC1866523  PMID: 14975151

Results 1-11 (11)