Terrie Vasilopoulos

Genetic Architecture of the Delis-Kaplan Executive Function System Trail Making Test: Evidence for Distinct Genetic Influences on Executive Function

OBJECTIVE To examine how genes and environments contribute to relationships among Trail Making Test (TMT) conditions and the extent to which these conditions have unique genetic and environmental influences. METHOD Participants included 1,237 middle-aged male twins from the Vietnam Era Twin Study of Aging. The Delis-Kaplan Executive Function System TMT included visual searching, number and letter sequencing, and set-shifting components. RESULTS Phenotypic correlations among TMT conditions ranged from 0.29 to 0.60, and genes accounted for the majority (58-84%) of each correlation. Overall heritability ranged from 0.34 to 0.62 across conditions. Phenotypic factor analysis suggested a single factor. In contrast, genetic models revealed a single common genetic factor but also unique genetic influences separate from the common factor. Genetic variance (i.e., heritability) of number and letter sequencing was completely explained by the common genetic factor while unique genetic influences separate from the common factor accounted for 57% and 21% of the heritabilities of visual search and set shifting, respectively. After accounting for general cognitive ability, unique genetic influences accounted for 64% and 31% of those heritabilities. CONCLUSION A common genetic factor, most likely representing a combination of speed and sequencing, accounted for most of the correlation among TMT 1-4. Distinct genetic factors, however, accounted for a portion of variance in visual scanning and set shifting. Thus, although traditional phenotypic shared variance analysis techniques suggest only one general factor underlying different neuropsychological functions in nonpatient populations, examining the genetic underpinnings of cognitive processes with twin analysis can uncover more complex etiological processes.

Early identification and heritability of mild cognitive impairment

BACKGROUND Identifying mild cognitive impairment (MCI) in midlife could improve early identification of Alzheimers disease (AD). Also, AD is highly heritable, but the heritability of MCI has not been established. We estimated prevalence rates, association with premorbid general cognitive ability (GCA) and heritability for different definitions of neuropsychologically defined MCI in adults in their 50s. METHOD We examined 1126 twins aged 51-59 years when recruited into the Vietnam Era Twin Study of Aging (VETSA). Six neurocognitive domains were assessed using tests designed to avoid ceiling effects. To differentiate MCI from low overall ability, criteria included adjustment for GCA measured at approximately age 20 years. RESULTS As in older adults, prevalence rates varied widely. Among the lower prevalence rates were some definitions of multiple-domain MCI and single-domain amnestic MCI, which may be less likely than other MCI categories to revert to normal on follow-up. Low prevalence rates in middle-aged adults are also more likely to be valid. MCI was also associated with lower premorbid GCA. Heritability estimates for any MCI and amnestic MCI averaged .40-.48. CONCLUSIONS By testing multiple cognitive domains and avoiding ceiling effects, MCI can be identified before age 60 years. Premorbid GCA is a risk/protective factor, but deficits after adjusting for early adult GCA suggest additional processes leading to declining trajectories. Heritabilities were comparable to AD, suggesting MCI as an appropriate phenotype for genetic association studies. Full validation will require follow-up assessments (currently under way). Community-based studies are important for this early identification because adults of this age are unlikely to present in clinics.

Anesthesia with sevoflurane in neonatal rats: Developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl(-) importer antagonists.

BACKGROUND 1.5 million children under 12 months of age are exposed to general anesthesia annually in the United States alone. Human and especially animal studies provide evidence that exposure to general anesthesia during the early postnatal period may lead to long-term neurocognitive abnormalities via poorly understood mechanisms. We investigated whether an immature stress response system and γ-aminobutyric acid (GABA) type A receptor activities are involved in mediating these abnormalities. METHODS Sprague-Dawley rats at postnatal days 4, 5 or 6 were anesthetized with 2.1% sevoflurane for 6h; maternally separated and house reared rats served as controls. RESULTS Sevoflurane anesthesia markedly increased corticosterone levels in rat pups of both genders. In adulthood, these rats responded to stress with heightened secretion of corticosterone and a greater increase in corticosterone levels in males versus females. Only male rats, previously exposed to neonatal sevoflurane, had a higher frequency of miniature inhibitory postsynaptic currents in CA1 neurons, spent a shorter time in open arms of the elevated plus maze (EPM) and exhibited impaired prepulse inhibition (PPI) of startle. Pretreatment of male rats prior to sevoflurane with the Na(+)-K(+)-2Cl(-) cotransporter inhibitor, bumetanide, or the mineralocorticoid receptor antagonist, RU28318, normalized endocrine responses to stress and the EPM behavior in adulthood, while only those pretreated with bumetanide exhibited normalized PPI of startle responses. Neither bumetanide nor RU28318 altered the effect of sevoflurane on synaptic activity. CONCLUSIONS Sevoflurane-enhanced neuronal excitation and elevated corticosteroid levels at the time of anesthesia contribute to the mechanisms initiating neonatal sevoflurane-induced long-term endocrine and neurobehavioral abnormalities.

Limitations of Significance Testing in Clinical Research: A Review of Multiple Comparison Corrections and Effect Size Calculations with Correlated Measures.

Modern clinical research commonly uses complex designs with multiple related outcomes, including repeated-measures designs. While multiple comparison corrections and effect size calculations are needed to more accurately assess an intervention’s significance and impact, understanding the limitations of these methods in the case of dependency and correlation is important. In this review, we outline methods for multiple comparison corrections and effect size calculations and considerations in cases of correlation and summarize relevant simulation studies to illustrate these concepts.

Prior Podcast Experience Moderates Improvement in Electroencephalography Evaluation After Educational Podcast Module.

BACKGROUND:There is continued interest in using technology to enhance medical education and the variables that may affect its success. METHODS:Anesthesiology residents and fourth-year medical students participated in an electroencephalography (EEG) educational video podcast module. A 25-item evaluation tool was administered before any EEG education was provided (baseline), and the podcast was then viewed. Another 25-item evaluation tool was administered after podcast viewing (after podcast). Ten EEG interpretations were completed with a neurophysiologist with an additional 25-item evaluation tool administered after the interpretations (after 10 EEG interpretations). Participants were surveyed concerning technology and podcasting experience before the educational module and their responses to the podcast educational model. Multiple analyses were performed (1) to evaluate differences in improvement in EEG evaluation scores between the podcast module and the standard didactics (control group); and (2) to evaluate potential moderation by technology and the podcast experience on the change in mean EEG evaluation scores from after the podcast module to after 10 EEG interpretations. RESULTS:A total of 21 anesthesiology residents and 12 fourth-year medical students participated. Scores on the 25-item evaluation tool increased with each evaluation time (P ⩽ 0.001). Moderation analyses revealed that individuals with more podcast experience (≥4 previous podcasts) had greater increases in scores after a podcast and 10 EEG interpretations compared with individuals with less experience (⩽3 previous podcasts) (P = 0.027). Furthermore, compared with a control group with similar baseline characteristics that received only standard didactics without a podcast, those in the podcast group had greater increases in mean EEG evaluation scores between baseline and after 10 EEG interpretations. CONCLUSIONS:In reviewing the improvement in EEG evaluation after a podcast education module, those with more podcast experience achieved greater gains in EEG evaluation scores. For EEG education, those receiving the podcast education module showed greater increases in scores compared with those receiving didactic teaching without podcasting, as measured by change in a mean EEG evaluation scores.

Interaction of APOE genotype and testosterone on episodic memory in middle-aged men

Age-related changes in testosterone are believed to be a key component of the processes that contribute to cognitive aging in men. The APOE-ε4 allele may interact with testosterone and moderate the hormones association with cognition. The goals of the present study were to examine the degree to which free testosterone is associated with episodic memory in a community-based sample of middle-aged men, and examine the potential interaction between free testosterone and the APOE-ε4 allele. Data were used from 717 participants in the Vietnam Era Twin Study of Aging. Average age was 55.4 years (standard deviation = 2.5). Significant positive associations were observed between free testosterone level and verbal episodic memory, as well as a significant interaction between free testosterone and APOE-ε4 status. In ε4 carriers free testosterone was positively associated with verbal episodic memory performance (story recall), whereas no association was observed in ε4 noncarriers. Results support the hypothesis that APOE-ε4 status increases susceptibility to other risk factors, such as low testosterone, which may ultimately contribute to cognitive decline or dementia.

Blood pressure and heart rate QTL in mice of the B6/D2 lineage sex differences and environmental influences

A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F(2) adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F(2) data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F(2) mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.

Lower Extremity Stiffness Changes after Concussion in Collegiate Football Players.

Purpose Recent research indicates that a concussion increases the risk of musculoskeletal injury. Neuromuscular changes after concussion might contribute to the increased risk of injury. Many studies have examined gait postconcussion, but few studies have examined more demanding tasks. This study compared changes in stiffness across the lower extremity, a measure of neuromuscular function, during a jump-landing task in athletes with a concussion (CONC) to uninjured athletes (UNINJ). Methods Division I football players (13 CONC and 26 UNINJ) were tested pre- and postseason. A motion capture system recorded subjects jumping on one limb from a 25.4-cm step onto a force plate. Hip, knee, and ankle joint stiffness were calculated from initial contact to peak joint flexion using the regression line slopes of the joint moment versus the joint angle plots. Leg stiffness was (peak vertical ground reaction force [PVGRF]/lower extremity vertical displacement) from initial contact to peak vertical ground reaction force. All stiffness values were normalized to body weight. Values from both limbs were averaged. General linear models compared group (CONC, UNINJ) differences in the changes of pre- and postseason stiffness values. Results Average time from concussion to postseason testing was 49.9 d. The CONC group showed an increase in hip stiffness (P = 0.03), a decrease in knee (P = 0.03) and leg stiffness (P = 0.03), but no change in ankle stiffness (P = 0.65) from pre- to postseason. Conclusion Lower extremity stiffness is altered after concussion, which could contribute to an increased risk of lower extremity injury. These data provide further evidence of altered neuromuscular function after concussion.

The absence of the CD163 receptor has distinct temporal influences on intracerebral hemorrhage outcomes

Hemoglobin (Hb) toxicity precipitates secondary brain damage following intracerebral hemorrhage (ICH). CD163 is an anti-inflammatory Hb scavenger receptor and CD163-positive macrophages/microglia locally accumulate post-bleed, yet no studies have investigated the role of CD163 after ICH. ICH was induced in wildtype and CD163−/− mice and various anatomical and functional outcomes were assessed. At 3 d, CD163−/− mice have 43.4 ± 5.0% (p = 0.0002) and 34.8 ± 3.4% (p = 0.0003) less hematoma volume and tissue injury, respectively. Whereas, at 10 d, CD163−/− mice have 49.2 ± 15.0% larger lesions (p = 0.0385). An inflection point was identified, where CD163−/− mice perform better on neurobehavioral testing and have less mortality before 4 d, but increased mortality and worse function after 4 d (p = 0.0389). At 3 d, CD163−/− mice have less Hb, iron, and blood–brain barrier dysfunction, increased astrogliosis and neovascularization, and no change in heme oxygenase 1 (HO1) expression. At 10 d, CD163−/− mice have increased iron and VEGF immunoreactivity, but no significant change in HO1 or astrogliosis. These novel findings reveal that CD163 deficiency has distinct temporal influences following ICH, with early beneficial properties but delayed injurious effects. While it is unclear why CD163 deficiency is initially beneficial, the late injurious effects are consistent with the key anti-inflammatory role of CD163 in the recovery phase of tissue damage.

Imputing observed blood pressure for antihypertensive treatment: impact on population and genetic analyses.

BACKGROUND Elevated blood pressure (BP), a heritable risk factor for many age-related disorders, is commonly investigated in population and genetic studies, but antihypertensive use can confound study results. Routine methods to adjust for antihypertensives may not sufficiently account for newer treatment protocols (i.e., combination or multiple drug therapy) found in contemporary cohorts. METHODS We refined an existing method to impute unmedicated BP in individuals on antihypertensives by incorporating new treatment trends. We assessed BP and antihypertensive use in male twins (n = 1,237) from the Vietnam Era Twin Study of Aging: 36% reported antihypertensive use; 52% of those treated were on multiple drugs. RESULTS Estimated heritability was 0.43 (95% confidence interval (CI) = 0.20-0.50) and 0.44 (95% CI = 0.22-0.61) for measured systolic BP (SBP) and diastolic BP (DBP), respectively. We imputed BP for antihypertensives by 3 approaches: (i) addition of a fixed value of 10/5mm Hg to measured SBP/DBP; (ii) incremented addition of mm Hg to BP based on number of medications; and (iii) a refined approach adding mm Hg based on antihypertensive drug class and ethnicity. The imputations did not significantly affect estimated heritability of BP. However, use of our most refined imputation method and other methods resulted in significantly increased phenotypic correlations between BP and body mass index, a trait known to be correlated with BP. CONCLUSIONS This study highlights the potential usefulness of applying a representative adjustment for medication use, such as by considering drug class, ethnicity, and the combination of drugs when assessing the relationship between BP and risk factors.