Abstract
Background
Posttraumatic stress disorder (PTSD) has been linked to cognitive decline, but research in women is generally lacking. We examined whether trauma and elevated PTSD symptoms were associated with worse cognitive function in middle-aged civilian women. A secondary objective was to investigate the possible role of depression in the relation of PTSD symptoms to cognitive function.
Methods
The sample comprised 14,029 middle-aged women in the Nurses’ Health Study II. Lifetime trauma exposure, lifetime PTSD symptoms, and past-week depressive symptoms were measured in 2008. Cognitive function was measured in 2014–2016 using the Cogstate Brief Battery, a self-administered online cognitive battery that assesses psychomotor speed, attention, learning, and working memory. We used linear regression models to estimate mean differences in cognition across PTSD symptom levels.
Results
Compared to no trauma, elevated PTSD symptoms consistent with probable PTSD (i.e., 4+ symptoms on a screening questionnaire) were associated with worse performance on psychomotor speed/attention (b=−0.08 standard units, p=.001) and learning/working memory (b=−0.09, p<.001) composites, after adjusting for socio-demographics. Although attenuated, associations remained significant when adjusted for depressive symptoms and other cognitive risk factors. We found the strongest associations among women with comorbid probable PTSD and depression.
Conclusions
PTSD symptoms were negatively related to measures of psychomotor speed/attention and learning/working memory in middle-aged women. Our study adds to a growing literature that suggests that mental disorders are associated with worse cognitive function over the life course.
Keywords: posttraumatic stress disorder, depression, cognitive function, women
Introduction
Posttraumatic stress disorder (PTSD) is associated with increased risk for cardiometabolic and other diseases of aging.[1] With a growing aging population in the United States (U.S.), cognitive decline is a significant public health issue.[2] Furthermore, mounting evidence suggests that brain aging and cognitive decline begin in midlife, long before clinical signs of cognitive decline typically manifest.[3–5] Therefore, identifying potentially modifiable early risk factors for cognitive decline is critical.
PTSD has been linked to decrements in multiple cognitive systems, including processing speed, learning, memory, and executive function.[6–9] Most of this research has been cross-sectional, with many samples comprising male veterans and/or patients with PTSD recruited from healthcare clinics.[9] Neural structural differences that may contribute to poor cognitive function have also been observed in individuals with PTSD compared to those without the disorder, including smaller hippocampal, frontal lobe, and total brain volumes.[10–13] Evidence suggests that the association between PTSD and impaired cognitive function is bidirectional. For example, research indicates that low intelligence and poor pre-trauma cognitive function increase risk of developing PTSD.[14–16] Indeed, prospective analyses indicated that poor pre-deployment visual immediate memory was associated with greater post-deployment PTSD symptom severity in a predominantly male sample of war-deployed soldiers.[17] In addition, research suggests that PTSD is associated with acquired cognitive deficits. In a male Vietnam veteran sample, PTSD severity was negatively correlated with cognitive performance, even when cognitive measures were adjusted for estimated premilitary intelligence.[18] Additionally, among young adults exposed to a natural disaster, higher PTSD symptom levels (particularly re-experiencing symptoms) were associated with lower levels of verbal memory improvement from pre- to post-trauma, although those who developed PTSD had worse pre-trauma cognitive function than those without post-disaster PTSD.[16] These findings highlight the bidirectional nature of the PTSD-cognitive function relation. In another longitudinal sample of predominantly male, war-deployed soldiers, higher PTSD symptom levels were associated with worse attention one year after returning from deployment, over and above pre-deployment attention.[19] Furthermore, initial research in predominantly male samples of treatment-seeking older veterans has found that PTSD is associated with an approximately two-fold increased risk of incident dementia.[20–22] Notably, associations of PTSD with cognitive function have been largely independent of depression. Depression is frequently comorbid with PTSD,[23] and has been linked to cognitive decline.[24–26]
Although studies suggest an association between PTSD and poor cognitive function, further research is needed to examine the generalizability of these findings. In particular, work in civilians, non-treatment-seeking individuals, and women will address key limitations of prior research. Studying non-treatment-seeking samples is especially important because ascertainment bias might inflate associations between PTSD and cognitive decline in treatment-seeking samples (i.e., if greater PTSD severity and cognitive difficulties both independently motivate greater engagement with healthcare providers). Furthermore, it is important to examine the relation between PTSD and cognitive function in women in particular. PTSD is twice as common in women than in men,[23] and cognitive decline is more common in women because they live longer. Additionally, women are less likely than men to experience certain traumas, such as combat and accidents,[27] that may result in severe head injury—a risk factor for dementia.[28] However, studies of PTSD and cognitive function in civilian women exposed to a wide range of traumatic experiences are generally lacking.
We investigated associations among trauma exposure, PTSD symptoms, and cognitive function in a large cohort of middle-aged women participating in the Nurses’ Health Study II (NHS II). We hypothesized that, compared to no trauma, elevated PTSD symptoms would be associated with worse performance on measures of psychomotor speed/attention and learning/working memory. Consistent with previous research, we predicted that the PTSD symptom-cognitive function relation would be independent of depression, although we hypothesized that comorbid elevated PTSD and depressive symptoms would have the strongest associations with cognition.
Materials and Methods
Participants
The NHS II cohort comprises 116,429 female nurses in the U.S., aged 25–42 years at enrollment in 1989. Women complete questionnaires biennially; follow-up is ongoing. In 2008, a supplemental questionnaire on trauma exposure and PTSD[29] was mailed to 60,804 women selected according to their prior NHS II participation; 54,224 women returned this questionnaire (89% response rate). From 2014–2016, 40,082 women with information on trauma/PTSD, and with known email addresses, were invited to complete the Cogstate Brief Battery, a self-administered online cognitive battery; 14,151 women completed this assessment (35% response rate). This study was approved by the Partners Healthcare Human Research Committee and conducted in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Return of questionnaires and Cogstate completion constituted consent.
Trauma and PTSD Symptom Assessment
Trauma exposure was measured with a 16-item modified version of the Brief Trauma Questionnaire,[29,30] a reliable and valid trauma exposure measure that parallels interview measures.[30] Lifetime exposure to 15 traumatic events (e.g., physical assault, natural disaster exposure), in addition to “a seriously traumatic event not already covered,” was assessed. Respondents reported whether events occurred, and identified the first event and the worst/most distressing event. The Short Screening Scale for DSM-IV PTSD[31] was used to assess whether women ever experienced any of seven PTSD symptoms subsequent to their worst trauma. Women provided information on the following symptoms of PTSD only if they reported a history of trauma exposure: 1) avoided places/people/activities associated with the trauma; 2) lost interest in important/enjoyable activities; 3) felt isolated/distant from others; 4) found it hard to have love/affection for others; 5) had a sense of foreshortened future; 6) had sleep difficulties; 7) became jumpy/easily startled. Reliability of self-reported age-of-onset of trauma and PTSD has been excellent in this sample (intraclass correlation coefficient=.95).
Women were classified into four groups indicating lifetime trauma/PTSD symptom status: 1) no trauma exposure, 2) trauma-exposed with no PTSD symptoms, 3) trauma-exposed with 1–3 symptoms, and 4) trauma-exposed with 4–7 symptoms. This classification was based on previous research with this screening questionnaire recommending a score of 4+ as a clinical cutoff for PTSD.[31] This cutoff defined positive PTSD cases in other community-based samples with a sensitivity of 85% and specificity of 93%.[31]
Depression Assessment
The 10-item Center for Epidemiologic Studies Depression (CES-D) scale was administered in the 2008 trauma/PTSD supplemental questionnaire. This CES-D short form has excellent psychometric properties and performs similarly to the 20-item version.[32] Responses were summed to indicate past-week depressive symptom severity (possible range=0–30). The 10-item CES-D was also administered with the 2013 NHS II biennial questionnaire and examined in a sensitivity analysis. Reported history of depression diagnosis at trauma/PTSD assessment (i.e., reporting physician-diagnosed depression on any of the 2003–2009 NHS II biennial questionnaires) was considered in secondary analyses.
Cognitive Assessment
Cognitive function was measured using the Cogstate Brief Battery,[33] a self-administered online battery. The Cogstate Brief Battery has four tasks: Detection, Identification, One Card Learning, and One Back (see Supplemental Methods for details).[33,34] The validity of Cogstate has been well-established,[33,35,36] with evidence of good criterion[37,38] and construct validity.[35,37] Moreover, Cogstate has been shown to be a sensitive indicator of early cognitive deficits.[35] Cogstate performance has been found to be similar in supervised and unsupervised settings,[39] and the feasibility and utility of an unsupervised, online administration of the brief battery has been demonstrated in a large population-based sample.[34] Internet speed does not affect Cogstate performance data because the Cogstate tasks are first loaded via the Internet and then run locally on a participant’s computer.
As in previous research,[34] scores on the Detection, Identification, and One Back tasks were calculated by log10 transforming mean response times for correct trials; scores on the One Card Learning task were calculated by arcsine transforming the square root of the proportion of correct responses. Some research suggests that composites formed from scores on the Cogstate tasks may be more sensitive measures of cognitive function than individual task scores;[40,41] this approach is consistent with neuropsychological models that highlight the benefit of using composite scores in clinical research.[42,43] We created two composite scores based on within-sample z-scores for the individual tasks (task scores were standardized before being combined in composites). A psychomotor speed/attention composite averaged the Detection and Identification task z-scores, and a learning/working memory composite averaged the One Card Learning and One Back task z-scores (see Supplemental Methods for details).[34] These two composites have had high test-retest reliability and clinical utility in identifying cognitive impairment.[40]
Covariates
Potential confounders included age at cognitive assessment, race/ethnicity (African American, Latina, Asian, Caucasian, other), parental education at participant’s birth (high school or less, some college, 4+ years of college), husband’s education (high school or less, 2- or 4-year college, graduate school), subjective social standing in the U.S., and subjective social standing in the community. Subjective social standing was rated on a 1–10 scale; lower scores indicated higher social standing. Adult body mass index (BMI, kg/m2) was computed from height and weight self-reported in 2009.[44] Physical activity (<3,3–<9,9–<18,18–<27,27+ metabolic equivalent hours/week), cigarette smoking (nonsmoker, former smoker, current smoker of 1–14, 15–24, or 25+ cigarettes/day), parity (nulliparous, 1, 2–3, 4+ children), oral contraceptive use (never used, current user, former user), and menopausal status (pre-menopausal, post-menopausal) were also measured in 2009. Diet quality based on the Alternative Healthy Eating Index[45] (divided into quintiles) and alcohol consumption (0,1–<5,5–<10,10–<20,20+ grams/day) were assessed in 2011. Variables indicating lifetime history of physician-diagnosed hypertension, myocardial infarction, and type 2 diabetes were computed from women’s reports on the 1989–2009 questionnaires.
Statistical Analysis
Using established thresholds,[33,34] we excluded the small number of participants (n=122, 0.9% of Cogstate completers) who failed integrity checks on all four tasks, which suggests that participants did not understand Cogstate instructions. We examined whether lifetime trauma and PTSD symptoms were associated with cognitive function using multivariable linear regression. Separate models were conducted for each cognitive composite; mean differences and 95% confidence intervals (CIs) were estimated. In one model, we adjusted for age at cognitive assessment. In a second model, we further adjusted for race/ethnicity; parental education, husband’s education, and subjective social standing were also included as proxies for participants’ socioeconomic status. In a third model, we additionally adjusted for depression. In a fourth model, we further adjusted for health behaviors and medical conditions.
To investigate how comorbidity of PTSD and depression might be associated with cognitive function, we categorized women into six groups: 1) no trauma/no depression, 2) no trauma/depression, 3) trauma only (reporting no PTSD symptoms)/no depression, 4) trauma only/depression, 5) PTSD (reporting 4+ symptoms)[31]/no depression, and 6) PTSD/depression. We classified women as having depression if they had a CES-D score≥10[32] in 2008. In a secondary analysis, we classified women with a history of physician-diagnosed depression as having depression. In these analyses, we focused on differences associated with trauma alone and probable psychiatric conditions (PTSD and depression) for clarity of presentation.
In supplemental analyses, we repeated the primary analyses for the individual Cogstate tasks. Additionally, since we were concerned about depressive symptoms near the cognitive assessment, we conducted a sensitivity analysis adjusting for depressive symptom severity from the 2013 questionnaire, along with Model 3 covariates. Analyses were conducted with SAS 9.4; a 2-tailed p-value of .05 was considered statistically significant.
Results
Participant Characteristics
Responders to the invitation to complete the Cogstate battery were highly similar to non-responders (Table 1). Women in these two groups were comparable on socio-demographics, trauma/PTSD symptom status, depression, health behaviors, and medical conditions relevant to cognitive function.
Table 1.
Characteristics of non-responders and responders to Cogstate invitation.
| Non-responders (n=25,931) |
Responders (n=14,151) |
|
|---|---|---|
| Mean (SD) or % (n) | Mean (SD) or % (n) | |
| Age at Cogstate invitation, years | 60.3 (4.6) | 61.2 (4.6) |
| Parents’ education at birth, ≥college, % | 23.4 (6,072) | 24.5 (3,473) |
| Husband’s education, ≥college, % | 72.3 (18,744) | 72.4 (10,242) |
| Subjective social standing in the USa | 3.9 (1.3) | 3.8 (1.3) |
| Subjective social standing in the communitya | 4.0 (1.6) | 4.0 (1.6) |
| Caucasian race, % | 93.8 (24,311) | 94.9 (13,435) |
| Body mass index, kg/m2 | 27.2 (6.2) | 27.3 (6.3) |
| Cigarette smoking, % | ||
| Never | 65.9 (17,093) | 65.8 (9,317) |
| Former smoker | 29.1 (7,557) | 30.3 (4,280) |
| Current smoker | 4.7 (1,223) | 3.8 (530) |
| Alcohol intake, grams/day | 6.9 (10.9) | 7.0 (11.0) |
| Physical activity, MET hrs/wk | 24.7 (29.6) | 25.0 (29.0) |
| Mean diet quality on the Alternate Healthy Eating Indexb |
61.2 (12.7) | 61.7 (12.8) |
| Oral contraceptive use, % | ||
| Never | 11.3 (2,927) | 10.6 (1,502) |
| Former user | 85.6 (22,208) | 86.9 (12,301) |
| Current user | 2.3 (605) | 2.1 (298) |
| Menopausal status, % | ||
| Pre-menopausal | 22.7 (5,883) | 22.3 (3,154) |
| Post-menopausal | 68.9 (17,865) | 70.0 (9,907) |
| Unknown menopausal status | 5.6 (1,444) | 5.7 (806) |
| Parity, % | ||
| Nulliparous | 17.7 (4,576) | 20.3 (2,877) |
| 1 child | 13.8 (3,569) | 13.4 (1,894) |
| 2–3 children | 61.2 (15,873) | 59.8 (8,458) |
| 4+ children | 7.4 (1,913) | 6.5 (922) |
| Lifetime trauma/PTSD symptom status, %c | ||
| No trauma | 19.9 (5,168) | 18.4 (2,601) |
| Trauma/no symptoms | 47.2 (12,243) | 47.5 (6,727) |
| Trauma/1–3 symptoms | 16.3 (4,225) | 17.4 (2,459) |
| Trauma/4–7 symptoms | 16.6 (4,295) | 16.7 (2,364) |
| Depressive symptom severityd | 5.9 (4.9) | 5.7 (4.8) |
| History of physician-diagnosed depression, %e | 26.1 (6,761) | 27.2 (3,855) |
| History of hypertension, % | 36.2 (9,392) | 35.1 (4,971) |
| History of myocardial infarction, % | 1.3 (333) | 1.1 (161) |
| History of type 2 diabetes, % | 6.9 (1,787) | 6.0 (848) |
Note. All health behaviors and medical conditions in the table were collected in the 2009 or 2011 Nurses’ Health Study II questionnaires, except depressive symptoms, which were assessed in 2008. History of hypertension, myocardial infarction, or type 2 diabetes was based on data from study baseline through the 2009 questionnaire. MET=metabolic equivalent.
Subjective social standing was rated on a scale from 1–10, with lower scores indicating higher social standing.
Higher scores on the Alternate Healthy Eating Index reflect better diet quality (possible range=0–110).
Lifetime history of trauma exposure and PTSD symptoms based on the Short Screening Scale for DSM-IV PTSD administered in 2008.
Total score on the Center for Epidemiologic Studies Depression (CES-D) scale, short form (possible range=0–30).
History of physician-diagnosed depression reported at the 2003–2009 questionnaires.
Characteristics for women in the analytic sample (n=14,029) by trauma/PTSD symptom status are presented in Table 2. The vast majority of women (81.6%) reported lifetime trauma exposure. Compared to women without trauma or with trauma and fewer than 4 PTSD symptoms, women with elevated PTSD symptoms (i.e., 4+ symptoms) had slightly worse subjective social standing and their husbands had lower educational attainment. Additionally, these women were more likely to be current or former cigarette smokers, and had higher BMI, lower physical activity, and higher prevalence of medical comorbidities. Women with elevated PTSD symptoms also had higher depressive symptom severity at trauma/PTSD assessment and higher prevalence of history of physician-diagnosed depression.
Table 2.
Participant characteristics according to trauma exposure and PTSD symptoms (N=14,029).
| Trauma-exposed (n=11,450) | ||||
|---|---|---|---|---|
| No trauma (n=2,579) |
No symptoms (n=6,662) |
1–3 symptoms (n=2,442) |
4–7 symptoms (n=2,346) |
|
| Mean (SD) or % (n) |
Mean (SD) or % (n) |
Mean (SD) or % (n) |
Mean (SD) or % (n) |
|
| Age at Cogstate assessment, years | 61.1 (4.7) | 61.2 (4.6) | 61.3 (4.5) | 61.2 (4.5) |
| Parents’ education at birth, ≥college, % | 25.3 (652) | 24.1 (1,604) | 24.4 (596) | 25.4 (595) |
| Husband’s education, ≥college, % | 72.4 (1,868) | 73.5 (4,895) | 72.6 (1,773) | 69.0 (1,619) |
| Subjective social standing in the USa | 3.8 (1.2) | 3.8 (1.3) | 3.8 (1.3) | 4.0 (1.4) |
| Subjective social standing in the communitya |
4.0 (1.5) | 3.9 (1.5) | 4.0 (1.5) | 4.2 (1.7) |
| Caucasian race, % | 94.8 (2,446) | 94.8 (6,317) | 95.3 (2,328) | 95.0 (2,229) |
| Body mass index, kg/m2 | 27.0 (6.2) | 27.3 (6.2) | 27.2 (6.0) | 28.0 (6.8) |
| Cigarette smoking, % | ||||
| Never | 69.3 (1,786) | 66.9 (4,455) | 64.2 (1,567) | 61.4 (1,441) |
| Former smoker | 26.5 (683) | 29.0 (1,933) | 31.5 (770) | 33.1 (777) |
| Current smoker | 4.1 (106) | 4.0 (267) | 4.3 (105) | 5.3 (124) |
| Alcohol intake, grams/day | 7.3 (10.7) | 7.0 (11.0) | 7.4 (11.4) | 6.5 (11.0) |
| Physical activity, MET hrs/wk | 24.4 (28.1) | 25.9 (30.1) | 25.3 (29.7) | 22.6 (24.8) |
| Mean diet quality on the Alternate Healthy Eating Indexb % |
65.2 (13.2) | 65.2 (13.0) | 65.8 (12.9) | 65.9 (13.5) |
| Oral contraceptive use, % | ||||
| Never | 12.7 (327) | 10.6 (709) | 9.6 (235) | 9.3 (218) |
| Former user | 84.4 (2,176) | 87.0 (5,794) | 88.0 (2,149) | 88.5 (2,077) |
| Current user | 2.5 (65) | 2.0 (134) | 2.1 (50) | 1.9 (45) |
| Menopausal status, % | ||||
| Pre-menopausal | 25.4 (654) | 23.0 (1,530) | 19.5 (477) | 20.2 (473) |
| Post-menopausal | 67.9 (1,752) | 69.2 (4,609) | 72.2 (1,762) | 72.0 (1,690) |
| Unknown menopausal status | 4.9 (125) | 5.7 (382) | 6.3 (153) | 6.0 (141) |
| Parity, % | ||||
| Nulliparous | 22.9 (591) | 19.0 (1,268) | 20.0 (488) | 21.6 (507) |
| 1 child | 11.1 (286) | 13.5 (900) | 12.7 (310) | 15.7 (368) |
| 2–3 children | 61.2 (1,579) | 60.6 (4,035) | 60.2 (1,470) | 56.0 (1,313) |
| 4+ children | 4.8 (123) | 6.9 (459) | 7.1 (174) | 6.7 (158) |
| Depressive symptom severityc | 4.5 (3.9) | 4.9 (4.1) | 6.2 (4.6) | 9.0 (6.0) |
| History of physician-diagnosed depression, %d |
16.8 (433) | 18.2 (1,214) | 29.1 (711) | 50.3 (1,181) |
| History of hypertension, % | 29.9 (771) | 31.2 (2,081) | 32.8 (802) | 35.2 (825) |
| History of myocardial infarction, % | 0.3 (8) | 0.8 (56) | 1.4 (35) | 1.8 (43) |
| History of type 2 diabetes, % | 3.8 (97) | 5.1 (340) | 5.3 (129) | 5.6 (132) |
Note. All health behaviors and medical conditions in the table were collected in the 2009 or 2011 Nurses’ Health Study II questionnaires, except depressive symptoms, which were assessed in 2008. History of hypertension, myocardial infarction, or type 2 diabetes was based on data from study baseline through the 2009 questionnaire. MET=metabolic equivalent.
Subjective social standing was rated on a scale from 1–10, with lower scores indicating higher social standing.
Higher scores on the Alternate Healthy Eating Index reflect better diet quality (possible range=0–110).
Total score on the Center for Epidemiologic Studies Depression (CES-D) scale, short form (possible range=0–30).
History of physician-diagnosed depression reported at the 2003–2009 questionnaires.
Trauma, PTSD Symptoms, and Cognitive Function
Distributions of the Cogstate composites are shown in Figure 1. The composites were relatively normally distributed, with a slight negative skew for psychomotor speed/attention. As expected, each increasing year of age was associated with significantly worse cognitive performance: mean difference (b)=−0.037 (95% CI, −0.040, −0.033) for psychomotor speed/attention; b=−0.027 (95% CI, −0.030, −0.024) for learning/working memory, ps<.001.
Figure 1.
Distributions of Cogstate composite scores: (a) psychomotor speed/attention and (b) learning/working memory.
Compared to no trauma, elevated PTSD symptoms were associated with significantly worse cognitive performance on both composites (Table 3). In age-adjusted models, we found a mean difference of −0.08 (95% CI, −0.13, −0.03) for psychomotor speed/attention for women with 4–7 PTSD symptoms vs. women without trauma. Additionally, among women with 4–7 PTSD symptoms, we found a mean difference of −0.10 (95% CI, −0.14, −0.06) for learning/working memory, compared to women without trauma. The larger mean difference—that for learning/working memory—was equivalent to the mean difference associated with nearly 4 years of aging. Results of models adjusted for age and also socio-demographics (Models 1 and 2, Table 3) were nearly identical. Tests for linear trends of trauma/PTSD symptoms in these models were significant, ps<.01. Although attenuated, associations remained significant when adjusting for depressive symptoms and other cognitive risk factors (Models 3 and 4, Table 3). Trauma exposure alone and subclinical PTSD symptoms were associated with significantly worse cognitive function on the learning/working memory composite compared with no trauma in models adjusting for socio-demographics (Models 1 and 2, Table 3). However, effect sizes were smaller than for elevated PTSD symptoms (mean differences ranged from −0.04 to −0.05, compared to women without trauma). Furthermore, only the association between trauma exposure alone (vs. no trauma) and learning/working memory remained significant when adjusting for depressive symptoms and other potential confounders. Results were similar when we operationalized depression as a history of physician-diagnosed depression (Supplemental Table 1). Results of the models for the primary analyses for the individual Cogstate tasks are presented in Supplemental Table 2.
Table 3.
Associations between trauma, PTSD symptoms, and Cogstate composite scores.
| No trauma | Trauma/no symptoms | Trauma/1–3 PTSD symptoms | Trauma/4–7 PTSD symptoms | |||||
|---|---|---|---|---|---|---|---|---|
| Psychomotor Speed/Attention (n=13,766) | ||||||||
| b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | p-linear trend | ||
| Model 1a | Ref | −0.02 (−0.06, 0.02) | .32 | −0.03 (−0.07, 0.02) | .31 | −0.08 (−0.13, −0.03) | .001 | .001 |
| Model 2b | Ref | −0.02 (−0.06, 0.02) | .35 | −0.03 (−0.07, 0.02) | .32 | −0.08 (−0.13, −0.03) | .001 | .001 |
| Model 3c | Ref | −0.02 (−0.06, 0.02) | .41 | −0.01 (−0.06, 0.04) | .58 | −0.05 (−0.10, −0.001) | .04 | .07 |
| Model 4d | Ref | −0.02 (−0.06, 0.02) | .38 | −0.02 (−0.07, 0.03) | .49 | −0.05 (−0.11, −0.002) | .04 | .06 |
| Learning/Working Memory (n=13,786) | ||||||||
| b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | p-linear trend | ||
| Model 1a | Ref | −0.04 (−0.08, −0.01) | .01 | −0.05 (−0.09, −0.01) | .01 | −0.10 (−0.14, −0.06) | <.001 | <.001 |
| Model 2b | Ref | −0.04 (−0.07, −0.01) | .01 | −0.05 (−0.09, −0.01) | .01 | −0.09 (−0.13, −0.05) | <.001 | <.001 |
| Model 3c | Ref | −0.04 (−0.07, −0.01) | .02 | −0.04 (−0.07, 0.004) | .08 | −0.05 (−0.09, −0.01) | .02 | .03 |
| Model 4d | Ref | −0.04 (−0.07, −0.005) | .02 | −0.04 (−0.08, 0.003) | .07 | −0.05 (−0.09, −0.01) | .02 | .04 |
Note. Higher scores indicate better cognitive performance.
Adjusted for age at cognitive assessment.
Adjusted for Model 1 covariates plus race/ethnicity, parental education, husband’s education, subjective social standing in the U.S., subjective social standing in the community.
Adjusted for Model 2 covariates plus depressive symptom severity in 2008.
Adjusted for Model 3 covariates plus body mass index, physical activity, diet quality, smoking, alcohol use, parity, menopausal status, oral contraceptive use, history of hypertension, history of myocardial infarction, history of type 2 diabetes.
Findings on comorbidity of probable PTSD and depression and cognitive function are shown in Table 4. In analyses of women with both elevated PTSD and depressive symptoms (consistent with probable PTSD and depression), we found strongest associations with cognitive function, compared to women with neither trauma nor depression (mean differences ranged from −0.12 to −0.15 in age-adjusted models). Additionally, among women with trauma (but not PTSD) and with depression, we found a mean difference of −0.17 (95% CI, −0.23, −0.11) for learning/working memory in age-adjusted models, compared to women without trauma or depression. Women with probable PTSD and without depression also performed worse on all outcomes vs. women without trauma or depression (mean difference of −0.06 for both composites). Results were highly similar when we considered comorbidity of probable PTSD and depression based on a history of physician-diagnosed depression (Supplemental Table 3). Results of the models for the primary analyses for the individual Cogstate tasks are presented in Supplemental Table 4.
Table 4.
Comorbidity of PTSD and depression in relation to performance on Cogstate composite scores.
| No trauma/No depression (n=2,276) |
No trauma/Depression (n=281) |
Trauma/No depression (n=5,799) |
Trauma/Depression (n=839) |
PTSD/No depression (n=1,381) |
PTSD/Depression (n=960) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Psychomotor Speed/Attention (n=11,364) | |||||||||||||
| b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | b (95% CI)) | p | ||||
| Model 1a | Ref | −0.01 (−0.12, 0.10) | .80 | −0.01 (−0.06, 0.03) | .53 | −0.08 (−0.15, −0.01) | .03 | −0.06 (−0.12, −0.002) | .04 | −0.12 (−0.18, −0.05) | .001 | ||
| Model 2b | Ref | −0.02 (−0.13, 0.09) | .78 | −0.01 (−0.05, 0.03) | .60 | −0.08 (−0.15, −0.01) | .03 | −0.06 (−0.12, −0.002) | .04 | −0.12 (−0.18, −0.05) | .001 | ||
| Model 3c | Ref | −0.01 (−0.12, 0.10) | .85 | −0.01 (−0.06, 0.03) | .58 | −0.07 (−0.14, −0.003) | .04 | −0.06 (−0.12, −0.001) | .05 | −0.11 (−0.18, −0.04) | .001 | ||
| Learning/Working Memory (n=11,383) | |||||||||||||
| b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | b (95% CI) | p | ||||
| Model 1a | Ref | −0.03 (−0.12, 0.06) | .53 | −0.03 (−0.06, 0.004) | .09 | −0.17 (−0.23, −0.11) | <.001 | −0.06 (−0.11, −0.02) | .01 | −0.15 (−0.21, −0.10) | <.001 | ||
| Model 2b | Ref | −0.03 (−0.12, 0.06) | .50 | −0.03 (−0.06, 0.01) | .14 | −0.17 (−0.22, −0.11) | <.001 | −0.06 (−0.11, −0.01) | .01 | −0.15 (−0.20, −0.09) | <.001 | ||
| Model 3c | Ref | −0.02 (−0.11, 0.07) | .65 | −0.02 (−0.06, 0.01) | .16 | −0.16 (−0.21, −0.10) | <.001 | −0.06 (−0.11, −0.01) | .02 | −0.14 (−0.19, −0.08) | <.001 | ||
Note. Higher scores indicate better cognitive performance. Probable PTSD=4+ symptoms on the Short Screening Scale for DSM-IV PTSD. Probable depression=10+ symptoms on the Center for Epidemiologic Studies Depression (CES-D) scale, short form.
Adjusted for age at cognitive assessment.
Adjusted for Model 1 covariates plus race/ethnicity, parental education, husband’s education, subjective social standing in the U.S., subjective social standing in the community.
Adjusted for Model 2 covariates plus body mass index, physical activity, diet quality, smoking, alcohol use, parity, menopausal status, oral contraceptive use, history of hypertension, history of myocardial infarction, history of type 2 diabetes.
In analyses adjusting for depressive symptom severity assessed in 2013 in addition to Model 3 covariates, elevated PTSD symptoms remained significantly associated with worse performance on the learning/working memory composite [b=−0.05 (95% CI, −0.09, −0.01), p=.02], and with nominally worse performance on the psychomotor speed/attention composite [b=−0.05 (95% CI, −0.10, 0.002), p=.06].
Discussion
To our knowledge, this is the first study to demonstrate that elevated lifetime PTSD symptoms are associated with worse cognitive function in a large civilian sample of middle-aged women. Traditionally, cognitive function research has focused on older persons; however, it is increasingly clear that cognitive decline starts in mid-life.[3–5] In these middle-aged women, we found that elevated PTSD symptoms falling above the recommended clinical cutoff were associated with worse performance on measures of psychomotor speed/attention and learning/working memory. Even after adjustment for depression, health behaviors, and medical conditions associated with cognitive risk, the association between elevated PTSD symptoms and cognitive function remained significant.
Moreover, strongest associations were observed among women with both elevated PTSD and depressive symptoms. PTSD and depression frequently co-occur,[23] and women with comorbid PTSD and depression may be particularly likely to exhibit impaired cognitive function. However, it is worth noting that women with elevated PTSD and depressive symptoms in our study might have had more severe PTSD manifestations, as co-occurring depression is often observed in individuals with higher PTSD symptom levels.[46,47] Thus, findings from this group could reflect worse cognitive performance in women with particularly severe PTSD rather than comorbidity per se. Future research with diagnostic interview assessments of PTSD and depression is needed to better understand this issue. Women with trauma and probable depression, as well as those with probable PTSD without depression, also had worse cognitive performance on the different composites compared to women without trauma or probable depression. This latter finding indicates that PTSD alone may be related to poor cognition. These results add to growing evidence that mental health is not just associated with psychological experience but also long-term brain health.[48,49]
Our findings build on prior studies of treatment-seeking, predominantly older, male veterans linking PTSD to worse cognitive function.[20–22] We examined a large sample of middle-aged community-dwelling women who were exposed to a wide range of traumas. By demonstrating an association between PTSD symptoms and cognitive function in women from the general population, our results suggest that the findings of these previous studies were not solely due to ascertainment bias related to use of treatment-seeking samples. We also accounted for a wide range of potential confounders, including socio-demographics, depression, health behaviors, and medical conditions relevant to cognitive function. Notably, associations between elevated PTSD symptoms with cognitive function were almost identical in models adjusted for age and socio-demographics. Although this may reflect the relatively homogeneous sample (participants were predominantly white professionals), it also suggests that confounding by socio-demographics was unlikely.
Several behavioral and biological mechanisms may underlie relations between elevated PTSD symptoms and cognitive function. For example, PTSD is associated with numerous behavior-related disturbances and conditions (e.g., physical inactivity,[50] obesity,[51] sleep disturbances[52]) that may contribute to poor cognition.[53] PTSD is also characterized by increased oxidative stress[54] and dysregulation of the hypothalamic-pituitary-adrenal axis, neuroendocrine system, and inflammatory response,[55,56] which could lead to cognitive decline (e.g., via increased neuronal death).[54,57] Animal research indicates that glucocorticoid exposure (like that resulting from chronic stress) can result in hippocampal damage,[58] and it is possible that these psychiatric disorders may inflict damage on the brain,[59] although we note that our study does not address these causal relations directly. However, neural structural deficits may also be risk factors for PTSD that predate trauma.[60] Research that distinguishes between pre-existing and acquired brain deficits is critical to establishing mechanisms and, eventually, interventions.
Several limitations of the current study merit consideration. First, lifetime PTSD symptoms were measured with a DSM-IV PTSD screening questionnaire, and research using gold-standard diagnostic interviews updated for DSM-5 is needed. However, our less rigorous measures would likely lead to misclassification and bias results toward the null rather than create spurious associations. Additionally, further research examining how PTSD duration and remission influence associations with cognition is needed in order to develop a more nuanced understanding of the PTSD-cognitive function relation. Second, similar to many studies of PTSD and cognitive function,[6,9,21] we lacked measures of pre-trauma cognitive function. It is possible that lower cognition preceded, rather than resulted from, trauma/PTSD symptoms. Our findings require confirmation in research with pre-trauma measures of cognitive function. Third, the Cogstate battery was administered several years after the PTSD and depression measures. Accordingly, we were able to include a slight lag between our hypothesized risk factors and cognition to reduce the possibility of reverse causation,[34] but were unable to capture current PTSD or depression status at cognitive assessment. This aspect of our study would likely bias results toward the null. Fourth, although likely minimal, variability in hardware and situational factors could have contributed to increased noise in the Cogstate data, which would also be expected to bias results toward the null. Fifth, although we assessed several domains of cognition using the Cogstate battery, further research with more comprehensive neuropsychological batteries is needed to understand the full extent of associations between elevated PTSD symptoms and cognitive function. Sixth, women needed to remain in the NHS II until 2008 to provide trauma/PTSD data. Survivor bias is thus a potential concern, although only 1.6% of the cohort (n=1,826) was deceased by trauma/PTSD assessment. Selection bias is also a potential concern. Only a subset of the NHS II cohort was eligible to complete Cogstate, and 35% of those invited to participate did so. Nevertheless, Cogstate responders and non-responders were highly similar on numerous characteristics.
Conclusions
Risk factors in mid-life play a role in later cognition.[3] Thus, it is essential to identify determinants of early cognitive decline in middle-aged individuals. Our findings suggest that elevated PTSD symptoms (with and without comorbid depression) are associated with worse cognitive function in middle-aged women. Future research is needed to examine how PTSD symptoms in civilian women relate to trajectories of cognitive decline over time and if they predict faster onset of disorders like dementia. Ultimately, results that elevated symptoms of PTSD (and depression) are negatively associated with cognitive function in middle-aged women from the general population emphasize that mental health has significant implications for other major health outcomes as women age.
Supplementary Material
Acknowledgments
We acknowledge the Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School for managing the NHS II.
This study was supported by the National Institutes of Health grants R21MH102570 (to KCK, FG), R01MH078928 (to KCK), R01MH101269 (to KCK), UM1CA176726 (for NHS II infrastructure), and K01HL130650 (to JAS). When this research was conducted, Dr. Harel was a full time employee of Cogstate, a cognitive test company that provided the cognitive tests used in this study.
Footnotes
Conflicts of Interest Disclosure: The authors do not have any additional personal or financial conflicts of interest to report.
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