Christina N. Lessov-Schlaggar

Prediction of Individual Brain Maturity Using fMRI

Connectivity Map of the Brain The growing appreciation that clinically abnormal behaviors in children and adolescents may be influenced or perhaps even initiated by developmental miscues has stoked an interest in mapping normal human brain maturation. Several groups have documented changes in gray and white matter using structural and functional magnetic resonance imaging (fMRI) in cross-sectional and longitudinal studies. Dosenbach et al. (p. 1358) developed an index of resting-state functional connectivity (that is, how tightly neuronal activities in distinct brain regions are correlated while the subject is at rest or even asleep) from analyses of three independent data sets (each based on fMRI scans of 150 to 200 individuals from ages 6 to 35 years old). Long-range connections increased with age and short-range connections decreased, indicating that networks become sparser and sharper with brain maturation. Multivariate pattern analysis of 5-minute brain scans provides a measure of brain maturity. Group functional connectivity magnetic resonance imaging (fcMRI) studies have documented reliable changes in human functional brain maturity over development. Here we show that support vector machine-based multivariate pattern analysis extracts sufficient information from fcMRI data to make accurate predictions about individuals’ brain maturity across development. The use of only 5 minutes of resting-state fcMRI data from 238 scans of typically developing volunteers (ages 7 to 30 years) allowed prediction of individual brain maturity as a functional connectivity maturation index. The resultant functional maturation curve accounted for 55% of the sample variance and followed a nonlinear asymptotic growth curve shape. The greatest relative contribution to predicting individual brain maturity was made by the weakening of short-range functional connections between the adult brain’s major functional networks.

The Effects of Tobacco Smoke and Nicotine on Cognition and the Brain

Tobacco smoke consists of thousands of compounds including nicotine. Many constituents have known toxicity to the brain, cardiovascular, and pulmonary systems. Nicotine, on the other hand, by virtue of its short-term actions on the cholinergic system, has positive effects on certain cognitive domains including working memory and executive function and may be, under certain conditions, neuroprotective. In this paper, we review recent literature, laboratory and epidemiologic, that describes the components of mainstream and sidestream tobacco smoke, including heavy metals and their toxicity, the effect of medicinal nicotine on the brain, and studies of the relationship between smoking and (1) preclinical brain changes including silent brain infarcts; white matter hyperintensities, and atrophy; (2) single measures of cognition; (3) cognitive decline over repeated measures; and (4) dementia. In most studies, exposure to smoke is associated with increased risk for negative preclinical and cognitive outcomes in younger people as well as in older adults. Potential mechanisms for smoke’s harmful effects include oxidative stress, inflammation, and atherosclerotic processes. Recent evidence implicates medicinal nicotine as potentially harmful to both neurodevelopment in children and to catalyzing processes underlying neuropathology in Alzheimer’s Disease. The reviewed evidence suggests caution with the use of medicinal nicotine in pregnant mothers and older adults at risk for certain neurological disease. Directions for future research in this area include the assessment of comorbidities (alcohol consumption, depression) that could confound the association between smoking and neurocognitive outcomes, the use of more specific measures of smoking behavior and cognition, the use of biomarkers to index exposure to smoke, and the assessment of cognition-related genotypes to better understand the role of interactions between smoking/nicotine and variation in genotype in determining susceptibility to the neurotoxic effects of smoking and the putative beneficial effects of medicinal nicotine.

A genome-wide screen for nicotine dependence susceptibility loci

Genome‐wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter‐marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Identification of Novel CYP2A6*1B Variants : The CYP2A6*1B Allele is Associated With Faster In Vivo Nicotine Metabolism

Cytochrome P450 2A6 (CYP2A6) is the human enzyme responsible for the majority of nicotines metabolism. CYP2A6 genetic variants contribute to the interindividual and interethnic variation in nicotine metabolism. We examined the association between the CYP2A6*1B variant and nicotines in vivo metabolism. Intravenous infusions of deuterium‐labeled nicotine were administered to 292 volunteers, 163 of whom were White and did not have common CYP2A6 variants, other than CYP2A6*1B. We discovered three novel CYP2A6*1B variants in the 3′‐flanking region of the gene that can confound genotyping assays. We found significant differences between CYP2A6*1A/*1A, CYP2A6*1A/*1B, and CYP2A6*1B/*1B groups in total nicotine clearance (17.2±5.2, 19.0±6.4, and 20.4±5.9, P<0.02), non‐renal nicotine clearance (16.4±5.0, 18.5±6.2, and 19.8±5.7, P<0.01), and the plasma trans‐3′‐hydroxycotinine/cotinine ratio (0.26±0.1, 0.26±0.1, and 0.34±0.1, P<0.001). There were also differences in total nicotine (29.4±12.9, 25.8±0.12.9, and 22.4±12.4, P<0.01), cotinine (29.2±8.1, 32.2±9.1, and 33.0±6.6, P<0.01) and trans‐3′‐hydroxycotinine (32.4±9.1, 34.2±12.3, and 41.3±11.3, P<0.001) excreted in the urine. We report evidence that CYP2A6*1B genotype is associated with faster nicotine clearance in vivo, which will be important to future CYP2A6 genotype association studies.

Association of sex steroid hormones with brain morphology and cognition in healthy elderly men

Background: There is inconsistent evidence of the presence and direction of the relationship between sex hormone concentrations and cognitive function in older men, and there is little published literature on the relationship of sex hormone concentrations and brain volume as measured by MRI. Objective: To examine the hypothesis that midlife total serum concentrations of testosterone (T), estradiol, estrone, and sex hormone binding globulin (SHBG) predict cognitive task performance and regional brain volumes at 10- to 16-year follow-up, in a longitudinal sample of World War II veteran twin men. Methods: Treating twins as individuals, linear regression models were used, adjusting analyses for age, education, depressive symptomatology, blood pressure, alcohol consumption, years of cigarette smoking, and APOE ε4 allele status. Results: There were no significant associations between sex hormone or SHBG concentrations and performance on a series of cognitive tasks measuring global and executive function, visual and verbal learning and memory. Higher midlife T concentrations were associated with larger hemispheric, frontal, and parietal regional brain volumes and with smaller left occipital brain volume. Higher estradiol and estrone concentrations were also associated with smaller right (estradiol) and both right and left (estrone) occipital volumes, but with no other brain regions. Owing to the multiple comparisons conducted, some significant associations may have occurred by chance. Conclusions: Overall, the pattern of results suggests a role for sex hormones in brain volume that predates potentially observable associations between sex hormones and cognitive task performance.

Gender Differences in Determinants of Smoking Initiation and Persistence in California Twins

Objective: To determine the effects of genetic versus environmental influences on smoking initiation (SI) and smoking persistence (SP). Methods: Native California twins (32,359 pairs), who completed a questionnaire in 1992 or 1998 to 2001, were studied. Standard epidemiologic and genetic analyses were conducted using multiple logistic regression and biometric models to determine factors related to smoking phenotype. Results: The strongest influence on SI was having a co-twin who ever smoked; the adjusted odds ratio was 9.7 [95% confidence limits (CL), 8.8-10.6] among monozygotic twins and 5.7 (95% CL, 5.2-6.2) among dizygotic like-sex pairs. The risk of SP was also increased if the co-twin currently smoked [adjusted odds ratios, 3.5 (95% CL, 3.0-4.1) for monozygotic twins and 2.3 (95% CL, 2.0-2.7) for like-sex dizygotic pairs]. The proportions of variance due to genetic effects, shared environment, and individual environment for SI were 31.6% (24.2-39.1), 47.5% (41.1-53.7), and 20.9% (18.8-23.1) for females, and 71.2% (66.7-75.4), 12.0% (8.7-15.7), and 16.7% (15.0-18.7) for males. For SP, estimates were identical by gender: 54.6% (43.6-65.5), 8.6% (0-17.1), and 36.8% (32.9-40.9). Modification of SI by closeness between twins was found, but little difference was seen for SP by closeness, birth cohort, or age. Conclusions: Gender differences in the pattern of genetic and environmental determinants of SI indicate that gender-specific approaches may be needed for smoking prevention efforts. Modification of genetic effects by closeness between twins and birth cohort suggests that environmental interventions could reduce a heritable propensity to smoke. However, the apparently heritable tendency to continue smoking is unaffected by gender, age, birth cohort, or closeness between twins. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1189–97)

Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study

AIMSnThe gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide.nnnDESIGNnUsing data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABA(A) receptor system as well as GABBR2 (a GABA(B) gene).nnnFINDINGSnWe found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence.nnnCONCLUSIONSnGiven the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.

Apolipoprotein E ε4 and Change in Cognitive Functioning in Community-Dwelling Older Adults

The relationship between apolipoprotein E (APOE) ε4 and change in cognition was examined in older men (n = 247; age = 75.0 ± 3.5 years) and women (n = 79; age = 70.8 ± 4.9 years) free of history of stroke. Participants were examined again 4.0 ± 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4genotype. Men with ε4showed greater decline in some measures of executive function and verbal memory compared to those without ε4; women with ε4showed greater decline in Trail Making test performance relative to women without the allele. A significant gender × APOEε4interaction was seen for change in performance on short delay cued recall. These results suggest that APOEε4is associated with cognitive decline differently in older adult men and women.

Validity of Recall of Tobacco Use in Two Prospective Cohorts

This project studied the convergent validity of current recall of tobacco-related health behaviors, compared with prospective self-report collected earlier at two sites. Cohorts were from the Oregon Research Institute at Eugene (N = 346, collected 19.5 years earlier) and the University of Pittsburgh, Pennsylvania (N = 294, collected 3.9 years earlier). Current recall was examined through computer-assisted interviews with the Lifetime Tobacco Use Questionnaire from 2005 through 2008. Convergent validity estimates demonstrated variability. Validity estimates of some tobacco use measures were significant for Oregon subjects (age at first cigarette, number of cigarettes/day, quit attempts yes/no and number of attempts, and abstinence symptoms at quitting; all P < 0.03). Validity estimates of Pittsburgh subjects’ self-reports of tobacco use and abstinence symptoms were significant (P < 0.001) for all tobacco use and abstinence symptoms and for responses to initial use of tobacco. These findings support the utility of collecting recalled self-report information for reconstructing salient lifetime health behaviors and underscore the need for careful interpretation.

Initial response to cigarettes predicts rate of progression to regular smoking: findings from an offspring-of-twins design.

The aim of this study was to examine the association between initial subjective effects from cigarettes and the rate of progression from first cigarette to regular smoking. Latent class analysis (LCA) was applied to subjective effects data from 573 offspring of twins ranging in age from 14 to 32 years. LCA revealed four classes: 1) High on both pleasurable and physiological responses, 2) Cough only response, 3) High on physiological, low on pleasurable responses, and 4) High on pleasurable, low on physiological responses. Classes of responses were then used to predict time from first cigarette to the onset of regular smoking in a Cox proportional hazards model. Time-varying covariates representing relevant psychiatric and psychosocial factors as well as dummy variables representing the offspring-of-twins design were included in the model. Members of classes 1 and 4 transitioned more rapidly to regular smoking than the classes characterized as low on the pleasurable response dimension. Our findings provide evidence that previously reported associations between pleasurable initial experiences and progression to regular smoking hold true as well for the rate at which that transition occurs. Furthermore, the fact that profiles of responses did not fall into global categories of exclusively pleasurable vs. exclusively negative (physiological) responses suggests the importance of considering both dimensions in combination to characterize risk for smoking-related outcomes.