2 results
1 The Impact of APOzA and BDNF val66met on Executive Function in Older Veterans with Post-traumatic Stress Disorder
- Julie E Gretler, Madeline D.W. Noland, Laura Lazzeroni, Arthur Noda, Jerome A Yesavage, Lisa M Kinoshita
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 521-522
-
- Article
-
- You have access Access
- Export citation
-
Objective:
Both Apolipoprotein z4 (APOz4) and Brain-Derived Neurotropic Factor val66met (BDNF-met) have been implicated as cognitive risk polymorphisms and may signal a more rapid trajectory of cognitive decline (Boots et al., 2017; Lim et al., 2015). The presence of both risk alleles may additively result in greater cognitive difficulties (Cechova et al., 2020), specifically executive functioning (Sapkota et al., 2017). As executive functioning difficulties can be associated with Posttraumatic Stress Disorder (PTSD; Woon et al., 2017), individuals with PTSD who carry these polymorphisms may be at higher risk for decline in executive functioning. In this study, we examined the cross-sectional and longitudinal impact of these alleles on executive functioning performance in Veterans with PTSD.
Participants and Methods:Seventy community-dwelling male Veterans were enrolled as part of a larger study at VAPAHCS and consented to genetic analysis. A current or lifetime history of PTSD (score > 40 on the CAPS-IV; Blake et al., 1995) was required for study participation. Trail Making Test B (TMT-B; Army Individual Test Battery, 1994) was used to assess executive functioning. TMT-B was part of a comprehensive neuropsychological battery administered at baseline and yearly over the following three years. Mean age and education were 61 years old (SD = 4.5; range = 55-78) and 14 years (SD = 2.3; range = 8-20), respectively.
The majority of the sample was White (71%) and were from the Korean and Vietnam War eras.
Results:APOz4 and BDNF-met were present in 29% and 27% of the sample, respectively; both were present in six participants. Regression models were fitted separately for TMT-B raw time-to-complete and number of errors, both cross-sectionally at screening and then longitudinally. The presence of BDNF-met was a significant predictor of TMT-B time and number of errors in both models (Time: ß = 0.09, p = 0.03 and ß = 0.11, p < 0.01; Errors: IRR = 2.4, p = 0.01 and IRR = 1.9, p = 0.01), while APOz4 only predicted errors longitudinally (IRR = 1.8, p = 0.03). There was no significant allelic interaction; however, the presence of both alleles additively multiplied TMT-B errors by approximately 3.7 times at screening (IRR = 3.7; p = 0.01) and 3.3 times longitudinally (IRR = 3.3; p < 0.01).
Conclusions:Altogether, these results are suggestive of an adverse, additive, effect of the APOz4 and BDNF-met polymorphisms on executive functioning, in particular error-proneness, with their combined presence tripling the errors made on TMT-B cross-sectionally and longitudinally. Consistent with previous research, the TMT-B error analysis increases detection of cognitive impairment, similar to other clinical samples (Varjacic et al., 2018). While TMT-B errors are typically interpreted qualitatively, the strong effect of these established risk alleles on error rates further support this metric as a clinically useful indicator of executive dysfunction in a PTSD population. In keeping with the Boston Process approach, these findings support the importance of error analysis in clinical interpretation of neuropsychological performance.
Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability
- Martin S. Angst, Nicholas G. Phillips, David R. Drover, Martha Tingle, Jeffrey L. Galinkin, Uwe Christians, Gary E. Swan, Laura C. Lazzeroni, J. David Clark
-
- Journal:
- Twin Research and Human Genetics / Volume 13 / Issue 5 / 01 October 2010
- Published online by Cambridge University Press:
- 21 February 2012, pp. 412-425
-
- Article
-
- You have access Access
- Export citation
-
Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.