Women with mutations in BRCA1 or BRCA2 (BRCA1/2) susceptibility genes are at increased risk for developing breast and ovarian cancers.1 Although risk-reducing salpingo-oophorectomy (RRSO) may lower the risk of breast and ovarian cancer by 37% to 64% and 69% to 85%,1,2 respectively, there are several important health consequences of being hypogonadal at such an early age.
Given that ovarian hormones such as estradiol (E2) and progesterone have numerous neuromodulatory and neuroprotective effects,3 recent studies have examined RRSO as a potential risk for central nervous system impairment and overall decline in quality of life. Large cohort studies have shown women who undergo oophorectomy before natural menopause are at increased risk of dementia4 and cognitive dysfunction during and after the seventh decade of life.4,5 More specifically, the largest declines in cognitive performance after oophorectomy occur in executive functioning domains.6 Previous research has also shown that adverse childhood experiences (ACE) are associated with executive dysfunction in naturally menopausal women in the absence, but not presence, of exogenous E2.7,8 Together, these studies suggest that premature, abrupt loss of E2 with RRSO induces executive function difficulties in many, but not all, hypogonadal women. They also suggest ACE may be one factor contributing to risk versus resilience for executive dysfunction after oophorectomy. However, no studies examining the effect of ACE on executive function after RRSO have been reported.
It is well established that ACE are associated with greater incidence of anxiety and depressive symptoms,9-13 particularly during the menopause transition.14 Previous research has demonstrated that anxiety and depressive symptoms mediate the negative impact of ACE on health-related quality of life,15 smoking status,16 substance dependence,9 and chronic pain disorders.12 Importantly, anxiety and depressive symptoms have been independently associated with executive dysfunction.17 Several studies have shown that mood symptoms negatively impact subjective18,19 and objective20 measures of cognitive function in breast cancer survivors. However, whether ACE is associated with executive dysfunction after RRSO and to what extent ACE effects on executive function in hypogonadal women are mediated by mood symptoms is not clear and has not been reported. That childhood adversity and current mood can be easily assessed with patient questionnaires in the clinical gynecology setting supports the significance of this line of investigation.
We examined the association between ACE and subjective and objective measures of executive function while rigorously controlling for multiple possible confounding variables in 552 women who underwent RRSO. We hypothesized that high levels of childhood adversity would be associated with greater self-reported symptoms of executive dysfunction and poorer performance on executive function tasks. Furthermore, we hypothesized that mood symptoms would partially mediate the relationship between ACE and executive function.
Participants were recruited through mailings from the Cancer Risk Evaluation Program at the University of Pennsylvania, local advertising, and an advocacy group for women with genetic risk for breast and ovarian cancer (Facing Our Risk of Cancer Empowered). Women considered for inclusion were over the age of 30, had BRCA1 or BRCA2 germline mutations, and had undergone RRSO to reduce the risk of primary or recurrent breast and ovarian cancers given their genetic predisposition. Exclusion criteria included inability to provide informed consent. This study was approved by the institutional review board; all participants provided informed consent.
Participants completed online surveys through Qualtrics.21 Surveys assessed mood, cognition, menopausal symptoms, childhood adversity, and medication use. To date, ≈55% of participants have repeated these surveys as part of an ongoing, longitudinal study. In this report, we consider the sample of participants from this cohort that completed one or more outcomes of interest at least once. Although the impact of ACE on changes in cognitive function over time after RRSO would be of interest, given the short duration of time between testing sessions (≈1 y) and the limited portion of the sample that completed both sessions (≈55%), we focused on the associations between ACE and cognition rather than the associations between ACE and change in cognition between sessions.
Assessment of subjective executive function
Subjective executive dysfunction was evaluated using a modified Brown Attention Deficit Disorder Scale (BADDS) adapted for online use. The BADDS is a validated22 subjective measure of five domains of executive dysfunction: (1) organization and activating for work; (2) sustaining attention and concentration; (3) alertness, effort, and processing speed; (4) managing affective interference; and (5) working memory and accessing recall. Higher scores indicate greater dysfunction. Total BADDS score was the primary measure of subjective executive function whereas BADDS subscales were secondary outcomes. Given the limited number of items per subscale, participants who skipped a question were excluded from analyses related to that BADDS subscale but not from analyses of other subscales or total score.
Assessment of objective executive function
As part of a comprehensive computerized cognitive battery,23 participants completed two neuropsychological tasks probing executive function domains. In this report, we specifically focused on measures related to executive functions given our hypothesis regarding the association between childhood adversity and executive functioning post-RRSO as well as the converging evidence for the effects of E2 and early life stress on this domain.3,24 The Pennsylvania continuous performance task (CPT) number and letter version25 was used to assess sustained attention. During the task, participants were instructed to respond when the image was a complete letter or number. The primary measure of sustained attention was d’, a signal detection metric that limits the influence of response bias.26
A letter version of the n-back task27 was used to probe working memory function across four conditions: 0-back, 1-back, 2-back, and 3-back. In the 0-back condition, participants responded to a prespecified target stimulus whereas participants responded to a stimulus “n” number of stimuli before it in other conditions. Because the 3-back condition places the greatest demands on working memory, 3-back d’ served as the primary measure of working memory.
Assessment of childhood adversity
The ACE questionnaire28 was used to assess history of childhood abuse, neglect, and household dysfunction. The ACE questionnaire has been widely used to examine the association between overall early adversity and health-related outcomes in adult life.29 The number of exposures was summed to create the ACE score (range: 0-10). Based on evidence from prior studies indicating increased risk of depressive disorders in later life in those with two or more ACEs,14,30 we considered participants with an ACE score ≥2 “high ACE” and participants with an ACE score of <2 “low ACE.”
Assessment of mood symptoms
Depressive and anxiety symptoms were assessed using the 14-item Hospital Anxiety and Depression Scale. This scale contains a seven-item depression subscale that assesses changes in mood, loss of interest, and psychomotor slowing and a seven-item anxiety subscale that assesses mental agitation and psychological distress. In line with prior studies of executive functions that have represented anxiety and depressive symptoms as a composite “mood” score,17 total scores on the depression and anxiety subscales were summed to create a composite measure of mood symptoms.
Generalized estimating equations implemented using the geepack package31 in R32 were used to evaluate associations between ACE and executive function outcomes. This method accommodates multiple survey assessments per woman and adjusts for nonindependence of these repeated measures. Age, time since oophorectomy, and age at oophorectomy were assessed as covariates. However, at baseline, age was highly correlated with both age at oophorectomy (r = 0.85, P < 0.0001) and time since oophorectomy (r = 0.49, P < 0.0001). To fully account for the effects of age on cognitive outcomes, generalized estimating equations with cognitive measures as the outcomes and age as the predictor were used to obtain age-residualized scores for each outcome: BADDS, CPT, and n-back. Subsequent analyses were performed on these residualized outcomes rather than raw values. Time without hormones (calculated by subtracting the duration of hormone therapy use post-RRSO, if any from the duration of time since oophorectomy), education level, and history of chemotherapy use were included as covariates in all models. Results reported are multivariable adjusted. Bivariable associations, t tests, Wilcoxon rank sum tests, and Pearson chi-square tests were used as appropriate to assess whether sociodemographic information differed between ACE groups. Two-sided hypotheses were evaluated with statistical significance defined as P ≤ 0.05. Given that all three outcomes are designed to assess the cognitive domain of executive function and adjusting for multiple comparisons may be overly conservative, P values reported are uncorrected.
Mediation models were used to examine whether ACE associations with executive dysfunction after RRSO were mediated by increased mood symptoms. The three primary outcome measures served as the dependent variable in three separate analyses. Total ACE served as the independent variable, whereas the composite mood score served as the mediator. Similar to models described above, adjusted models were developed to estimate the following components of the mediation model: associations between (1) ACE and executive function (which is the total effect of ACE), (2) ACE and mood, and (3) mood and executive function after accounting for ACE. When these associations were significant, the statistical significance of mood as a mediator was evaluated by estimating the indirect effect of ACE on executive function through mood using the product of coefficients approach. Significance testing of the indirect effect estimates was conducted using standard error estimates estimated via a bootstrap resampling approach implemented with the boot package33 using ordinary nonparametric bootstrapping and 2,000 iterations. The percent mediated was computed as the ratio of the indirect effect to the total effect, with 95% CI estimated using bootstrap estimates.
Psychotropic medication use served as an additional covariate in supplementary analyses of primary outcome variables. Supplementary analyses also examined the effects of ACE in the subset of women who underwent oophorectomy before the age 47.4, 2 standard deviations (1 SD = 2.26 y) below the average age (51.9 y) of postmenopause onset.34 To evaluate whether timing of childhood adversity was driving results, we also separately examined the effects of prepubertal ACE and postpubertal ACE on primary outcome measures. Prepuberty was defined as the period between birth and 2 years before menstrual cycle onset. Given that history of cancer could be an important potential confounder, we repeated our primary analyses of ACE associations with executive function with this covariate rather than history of chemotherapy given collinearity.
Eight hundred participants completed cognitive testing at baseline and were eligible for inclusion in this report. Of these 800 participants, 453 completed a second cognitive testing session, yielding a total of 1,253 sessions that were eligible for inclusion. Sessions included in analyses must have completed at least one outcome of interest (n = 1,058). Sessions missing information regarding age at testing (n = 16), hormone therapy use post-RRSO (n = 165), ACE (n = 12), education level (n = 8), and mood symptoms (n = 30) were excluded. As part of data quality assurance, participants who performed below chance (<50% true positives) on the CPT or 0-back control condition were excluded from analyses of the CPT (n = 20) and n-back (n = 13), respectively. The final sample included in analyses was 552 participants (Table 1; Fig. 1).
ACE associations with executive function
ACE was associated with higher age-residualized total BADDS score (n = 493, adjusted mean difference (aMD) = 7.1, P = 0.0005) (Fig. 2A) as well as each BADDS subscale (organization/activation for work, aMD = 1.7, P = 0.002; attention/concentration, aMD = 1.8, P = 0.001; alertness/effort/processing speed, aMD = 1.4, P = 0.004; managing affective interference, aMD = 1.3, P = 0.0007; working memory/accessing recall, aMD = 0.8 P = 0.03) (Fig. 2B). The high ACE group also performed worse on both the n-back (n = 479, aMD = –0.17, P = 0.007) (Fig. 3A) and CPT (n = 500, aMD = –0.1, P = 0.03) (Fig. 3B) in comparison to the low ACE group. Chemotherapy use was negatively associated with sustained attention (aMD = −0.17, P = 0.006) (Fig. 4) but was not associated with subjective symptoms or working memory.
Mood symptoms mediate ACE associations with executive function
We next examined whether mood symptoms mediated ACE associations with executive function (Fig. 5A). ACE was significantly associated with greater mood symptoms (aMD = 2.1, P = 0.0003) and mood symptoms were significantly associated with age-residualized total BADDS scores (coefficient = 2.1, P < 0.0001). After adjusting for mood symptoms, the direct effect of ACE on total BADDS scores was lower (aMD = 2.8, P = 0.08). The estimated indirect effect of ACE on total BADDS through mood was also statistically significant (aMD = 4.48, P = 0.0004), an indication that mood symptoms partially mediate the association between ACE and total BADDS score (62.8% mediated; 95% CI: 42.3%-100%).
Similarly, we evaluated the extent to which mood symptoms mediated the association between ACE and sustained attention (Fig. 5B). ACE was significantly associated with greater mood symptoms (aMD = 2.1, P = 0.0002) and mood symptoms were significantly negatively associated with age-residualized CPT d’ (coefficient = –0.01, P = 0.001). After adjusting for mood symptoms, the direct effect of ACE on CPT d’ was diminished (aMD = –0.09, P = 0.08). The estimated indirect effect of ACE on sustained attention through mood was also statistically significant (aMD = –0.024, P = 0.03), an indication that mood symptoms partially mediated ACE associations with sustained attention (21.3% mediated; 95% CI: 9.3%-100%).
In contrast, mood symptoms did not mediate a major proportion of the relationship between ACE and working memory performance (6.5% mediated, 95% CI: –1.4% to 50%; Fig. 5C). Given that mood symptoms were not significantly associated with n-back d’ (coefficient = –0.006, P = 0.20) after accounting for mood symptoms, the direct effect of ACE on n-back d’ was practically unchanged (aMD = –0.16, P = 0.01).
ACE associations with subjective executive function (aMD = 6.1, P = 0.002), sustained attention (aMD = –0.11, P = 0.03), and working memory (aMD = –0.16, P = 0.01) were similar when controlling for use of psychoactive medications. Results were also similar in the subset of women who underwent oophorectomy before the age 47.4 (total BADDS, n = 353, aMD = 8.4, P = 0.0008; CPT d’, n = 350, aMD = −0.12, P = 0.06; n-back d’, n = 382, aMD = −0.16, P = 0.06). While prepubertal ACE was associated with significantly more subjective executive function difficulties (aMD = 5.6, P = 0.03), postpubertal ACE was not. In contrast, postpubertal ACE was associated with worse sustained attention (aMD = −0.24, P = 0.006), whereas prepubertal ACE was not. Prepubertal ACE (aMD = −0.13, P = 0.08) and postpubertal ACE (aMD = −0.22, P = 0.07) were both associated with poorer working memory. Given that history of cancer could be an important potential confounder, we repeated our primary analyses of ACE associations with executive function with this covariate rather than history of chemotherapy given collinearity. ACE association with subjective executive function (aMD = 8.4, P = 0.01) and working memory (aMD = −0.18, P = 0.02) was similar, but ACE association with sustained attention was no longer significant (aMD = −0.08, P = 0.18).
In this large study of cognitive function in BRCA1/2 mutation carriers who underwent RRSO, we examined the association between childhood adversity and executive function as well as the mediating role of mood. Women with higher levels of childhood adversity reported more symptoms of dysfunction across executive function domains. High ACE women also performed worse on executive function tasks probing sustained attention and working memory. Although mood symptoms partially mediated ACE associations with sustained attention and subjective report of executive dysfunction, the negative associations between ACE and these measures remained present after accounting for the effects of anxiety and depression symptoms. Taken together, these data emphasize that childhood adversity is associated with increased risk of executive dysfunction after RRSO.
Evidence for ACE associations with executive function
As predicted, we found that ACE was associated with a greater subjective report of executive dysfunction and poorer performance on neuropsychological tasks of executive function. Childhood adversity has been shown to adversely impact cognitive performance in a general population.35-38 Several studies have demonstrated that early life adversity is associated with poorer executive function during childhood and adolescence39-41 and that this negative effect persists into adulthood.38 However, ACE associations with subjective and objective measures of executive function have not been studied in women who have undergone RRSO, a specific surgical procedure that leads to hypogonadism and is associated with a number of psychological issues related to concerns about cancer risk or recurrence. We have recently shown that ACE has negative impacts on executive function in naturally menopausal women7,8 and that the negative impact of ACE is heightened in the absence of exogenous E2.7 This literature suggests childhood adversity likely alters the developmental trajectory of the executive system24 and that abrupt loss of E2 regulation of executive system function after RRSO is a potential mechanism underlying the observed differences in executive function between high and low ACE groups.3
Evidence for mood as a mediator of ACE associations with executive function
ACE associations with subjective report of executive dysfunction and sustained attention after RRSO were partially mediated by anxiety and depressive symptoms. Our prior studies focusing on naturally menopausal women have shown that healthy women experience onset of executive function difficulties during menopause concurrent with loss of E2.7,8,42-44 There is also an increased risk for affective disturbances, including major depressive disorder with the transition to menopause45 and among high ACE women in particular.14 Further, loss of E2 has been shown to impact brain neurochemistry, structure, and function.3 Our more recent studies have provided preliminary evidence that childhood adversity may be a risk factor for both executive function difficulties3 and mood changes14 during periods of waning E2. Mood symptoms are also associated with executive system dysfunction in both youths17 and adults,46 though this has not specifically been studied in postmenopause. Further, our previous work has suggested that ACE-associated vulnerability for executive function difficulties with loss of E2 during menopause involves alterations in serotonergic neurotransmission,7 highlighting the importance of jointly considering the role of early adversity and mood changes on executive functions after RRSO as we do in this report. Notably, the mediating role of mood and timing of prepubertal versus postpubertal adversity varied across domains, suggesting future studies of ACE effects on executive function would benefit from further dissociation between sustained attention, working memory, and subjective executive dysfunction symptoms as well as timing of adversity onset in relation to puberty. Our result demonstrating a major impact of mood on CPT but not n-back performance is consistent with a recent study examining correlations between depressive symptoms and performance on several executive functioning tasks in a mixed sample of older male and female adults. Similar to our findings, depressive symptoms in that study were associated with poorer scores on an attention task but not with a working memory task.47 That negative affect did not mediate the ACE effect on working memory is particularly important given a growing neuroimaging literature showing that ACEs impacts neural7 and network8 outcomes during working memory tasks in postmenopausal women.
No studies to our knowledge have pulled ACE and mood into one study to address the complexity of their contribution to executive dysfunction after RRSO with or without history of chemotherapy. By doing so in a large sample of well-characterized women post-RRSO, we were able to determine the relative impact of ACE and ACE related negative affect on our outcomes of interest. Our results highlight that addressing concurrent mood changes is a critical step in treating surgical menopause-induced executive function difficulties. Importantly, we found that ACE associations were mediated by anxiety and depressive symptoms, which may not translate to a full diagnosis of generalized anxiety disorder, major depressive disorder, or other mood disorder. The mediating role of mood was significant even though the average anxiety and depression subscale scores in this sample (Table 1) were below those corresponding to full categorical diagnoses of anxiety (8+) or depressive disorders (8+),48 further emphasizing the importance of screening for subthreshold mood symptoms in this population.
Although this study had a large sample size and controlled for multiple possible confounds, certain limitations should be acknowledged. First, participants completed cognitive testing at home rather than in a controlled environment under supervision of research staff, potentially reducing validity of these neuropsychological tests due to lack of consistency across testing settings. However, excluding participants who performed below chance on control conditions allowed us to limit this effect. Additionally, such a study design enabled us to examine the effects of early adversity on cognition post-RRSO at a scale that would have been much less feasible with in-office visits. Although we detected statistically and clinically significant differences in subjective symptoms, the absolute difference in cognitive task performance between groups was small and may not be clinically significant. Second, all participants in this study were surveyed after undergoing RRSO, so it is not possible to ascertain whether ACE has similar associations before RRSO. However, we have previously shown that treatment with E2 attenuates the negative impact of ACE on executive function in naturally menopausal women,7 suggesting that ACE associations, whether present before RRSO or not, may be magnified by the abrupt loss of E2. The relative risks of hormone therapy use in the current study population present an inherent limitation to examining the moderating impact of E2, so longitudinal studies that evaluate participants before and after RRSO would be necessary to support or refute this hypothesis.
In summary, these data provide novel evidence regarding the impact of childhood adversity on executive function after RRSO. These results emphasize that mood symptoms, in part, mediate the negative associations between early adversity and executive function, underscoring the importance of assessing anxiety and depressive symptoms in women who have undergone RRSO.
Pending future longitudinal studies, questionnaires assessing childhood adversity and mood symptoms may play a role in identifying at-risk women, providing greater context for the discussion of cognitive effects of premature menopause when counseling women who would benefit from RRSO. The largest study (n = 846) on quality of life in women who underwent RRSO to date noted that a portion of women in their sample who underwent RRSO experienced anxiety that affected their mood (≈30%) and everyday functioning (≈10%).49 Given that executive dysfunction is also associated with poorer quality of life,50,51 assessment of childhood adversity may help identify women who are more likely to experience executive function difficulties and mood symptoms after surgery, with the goal of treating these difficulties before symptoms negatively impact quality of life. Our results also suggest that current anxiety and depression symptoms should be evaluated in women who report cognitive complaints after RRSO. Assessment of mood symptoms would also be beneficial in selecting a nonhormone treatment for women who experience vasomotor symptoms, a major complaint affecting quality of life in women who have undergone RRSO. Selective serotonin and serotonin–norepinephrine reuptake inhibitors are effective treatments for both conditions.52
We thank Korrina Duffy, PhD, for her help with editing and submitting the manuscript.
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