Abstract
Aims/Introduction
This study was carried out to investigate the relationship of stressful life events (SLEs) with the risk of cognitive impairment in patients with type 2 diabetes mellitus.
Materials and Methods
A total of 316 patients with type 2 diabetes mellitus aged >45 years were recruited in this study, and data on demographics, medical history, lifestyle characteristics and SLEs were collected. The cognitive status of patients was evaluated with a battery of cognitive function scales. Logistic regression analyses were carried out to evaluate the risk and protective factors for mild cognitive impairment (MCI).
Results
Participants, including 217 type 2 diabetes mellitus patients with MCI and 99 patients without MCI, were enrolled in the current study. Among the SLEs, the death of an offspring or parent (odds ratio [OR] 1.994, 95% confidence interval [CI] 1.017–3.908) was a risk factor for MCI after adjustment for age and education level. In the subgroup of participants aged <60 years, the death of an offspring or parent (OR 2.731, 95% CI 1.119–6.665) and financial difficulty (OR 22.205, 95% CI 4.365–112.966) were risk factors for the development of MCI, whereas high working pressure (OR 0.154, 95% CI 0.048–0.495) and career changes (OR 0.324, 95% CI 0.124–0.847) were protective factors for MCI.
Conclusions
These data suggested that SLEs were associated with cognitive function in patients with type 2 diabetes mellitus. Adverse life events, such as the death of an offspring or parent, were risk factors for cognitive impairment, whereas high work pressure in middle‐aged people was a protective factor against cognitive impairment.
Keywords: Mild cognitive impairment, Stressful life events, Type 2 diabetes mellitus
Our study found that stressful life events were related to cognitive function in middle‐aged and elderly patients with type 2 diabetes mellitus. The death of an offspring or parent were risk factors for cognitive impairment, whereas high work pressure in middle‐aged people was a protective factor against cognitive impairment. Our findings would contribute to a better understanding of the association of stressful life events with cognitive impairment in patients with type 2 diabetes mellitus.
INTRODUCTION
In China, the prevalence of cognitive impairment and even dementia has been increasing because of increases in lifespan as a result of the progress in medical technology 1 . Cognitive impairment is an important dysfunction affecting elderly individuals; it not only reduces quality of life, but also imposes a heavy burden on the family because of the need for home care 2 , 3 . Due to the lack of effective treatment for dementia, researchers began to focus on the diagnosis and intervention of mild cognitive impairment (MCI). MCI is an intermediate state between normal aging and dementia; compared with elderly people with normal cognition, patients with MCI have a 4–10‐fold higher risk of dementia 4 , 5 .
It is well recognized that diabetes mellitus is one of the risk factors for dementia, previous epidemiological studies have reported a 1.5–3‐fold higher incidence of dementia in patients with diabetes than in those without diabetes 6 , 7 , 8 . Numerous studies have explored the mechanism of the association between diabetes mellitus and cognitive impairment. Glycated hemoglobin is an index reflecting the average level of blood glucose over 3 months, and some cohort studies have shown that an increase in glycated hemoglobin is associated with cognitive decline in type 2 diabetes mellitus patients 9 , 10 . Several studies have shown a link between diabetes mellitus and brain atrophy, especially in the hippocampus, which plays a key role in memory function. This relationship was interpreted as microvascular damage in diabetes mellitus patients 11 . In addition, patients with diabetes mellitus often suffer from hypoglycemia during treatment, and frequent severe hypoglycemia could lead to necrosis of neuronal cells, particularly in vulnerable areas, such as the hippocampus 12 , 13 . Recently, a growing number of studies reported that insulin resistance and insulin deficiency in the brains of patients with type 2 diabetes mellitus could promote the progression of dementia by leading to the accumulation of amyloid beta and phosphorylation of tau protein, which are considered pathological characteristics of Alzheimer's disease 14 , 15 .
In addition to diabetes, multiple factors, such as heredity 16 , environment 17 , metabolism 18 and intestinal flora imbalance 19 , have been suggested to play a role in the onset of dementia. Much evidence suggests that stress exposure and stress reactivity might be associated with an increased risk of dementia in older people 20 . Some studies found that stressful life events (SLEs), such as financial crisis, divorce and the death of spouse, were associated with the risk of cognitive impairment 21 , 22 . Researchers considered that stress exposure could trigger the activity of the hypothalamic–pituitary–adrenal axis and then induce the release of glucocorticoids 23 . Long‐term abnormal glucocorticoid secretion provokes damage to the hippocampus and leads to a decline in cognitive function 24 , 25 . Increased cortisol levels and activation of the hypothalamic–pituitary–adrenal axis were also found in individuals with glucose intolerance 26 . To our knowledge, the association of SLEs with the risk of cognitive impairment in patients with type 2 diabetes mellitus has not been explored until now. Therefore, the present study was carried out to investigate the relationship between SLEs and the risk of MCI in midlife and elderly type 2 diabetes mellitus patients.
MATERIALS AND METHODS
Study participants
We recruited inpatients and outpatients with type 2 diabetes mellitus aged >45 years at the First Hospital of Hebei Medical University, Shijiazhuang, China, from May 2021 to July 2022. Potential participants were excluded if they: (i) had thyroid dysfunction, parathyroid gland or other endocrine‐related diseases, or autoimmune diseases; (ii) had medical records of severe anemia, malignant tumors, serious heart disease, or liver or kidney dysfunction; (iii) had a serious history of neuropsychology, mental illness, alcohol and drug abuse; (iv) had severe nervous system diseases (Parkinson's disease, cerebrovascular disease, brain tumor, brain trauma etc.); (v) were suffering from acute infection or acute complications of diabetes; or (vi) were unable to complete the neuropsychological evaluation. This study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the First Hospital of Hebei Medical University. Written informed consent was obtained from all the participants before induction.
Demographic characteristics and clinical history
Demographic data, including age, sex, educational background, smoking and alcohol consumption, were collected through questionnaires. Medical history information of hypertension, dyslipidemia, stroke, and cardiovascular and cerebrovascular diseases was collected and confirmed according to the medical records of participants.
The blood pressure of participants was measured on the day of interview, and body mass index was calculated according to the height and weight of each participant. A 10‐mL venous blood sample was collected after at least 8 h of fasting for biochemical examination. Physical examination of the nervous system was carried out by well‐trained research neurologists.
Stressful life events
Participants were asked “Have you undergone any of the following events (including social relationships, finances, work and health, which seriously affected subjects and required adjustment or personal lifestyle changes) in your life”? (response: Yes or No). These events were based on the top eight adverse life events affecting the elderly population in China according to Deng's 21 life event scale. Two work‐related events were added for our research needs. The final list was as follows: the death of a spouse, the death of an offspring or parent, onset of a serious illness, financial difficulty, marital separation, unemployed or laid‐off, the theft or loss of an item of personal value, onset of a serious accident (encounter flood, earthquake, fire and traffic accident), career changes and high working pressure.
Assessment of cognition and diagnosis
The Mini‐Mental State Examination (MMSE) 27 and Montreal Cognitive Assessment (Beijing version) 28 were used to evaluate global cognitive function by well‐trained researchers in the present study. The boundary scores of the MMSE were defined as 17 (illiterate), 20 (≤6 years of education), and 24 (>6 years of education) 29 . Patients with MMSE scores below the boundary were excluded. The cut‐off value of normal cognition was Montreal Cognitive Assessment >24 points 30 , and 1 point was added for those with education ≤6 years 31 . The clinical diagnosis of MCI was carried out according to the established Petersen criteria 32 , including: (i) complaints of memory impairment; (ii) objective abnormal memory functioning adjusted for age and education; (iii) absence of dementia according to the Clinical Dementia Rating scale 33 (<1.0); and (iv) normal activities of daily living. The Auditory Verb Learning Test 34 was carried out to assess memory function. Language function was assessed with the Animal Fluency Test and Boston Naming Test 35 . The digit span test, including digit span forward and digit span backwards, was carried out to evaluate the attention domain 36 . Visuospatial function was evaluated with the clock‐drawing test 37 . The Trail‐Making Test, which included A and B 38 , was carried out to assess executive function.
The Zung Self‐rating Depression Scale 39 was carried out to evaluate whether participants experienced depressive symptoms in the past week. Depressive symptoms were identified if the Zung Self‐rating Depression Scale index score was ≥53 40 .
Statistical analysis
Data analysis was carried out with SPSS (version 25.0; IBM Corporation, Armonk, NY, USA) software. Continuous variables were tested for normality and are presented as the mean ± standard deviation (SD) or the median (interquartile range). Categorical variables are presented as percentages (%). Comparison of continuous data was carried out with Student's t‐test or Wilcoxon Mann–Whitney analysis. The χ2‐test was carried out for comparison of categorical data. Binary logistic regression analysis was carried out to screen the risk and protective factors for MCI. The results were considered to be statistically significant at a P‐value <0.05, and all P‐values and 95% confidence intervals (CIs) were two‐tailed.
RESULTS
Clinical characteristics and cognitive function in global and different domains of the participants
A total of 316 patients with type 2 diabetes mellitus who participated in the present study were divided into two groups according to the diagnostic criteria: 217 patients with MCI and 99 patients without MCI. The demographic and physical characteristics of the participants are shown in Table 1. There were no differences in sex, smoking, alcohol consumption, medical history, medication history, depression, duration of diabetes, biochemical examination or treatment type of diabetes between the groups with and without MCI. The patients with MCI tended to be older, had fewer years of education and had higher systolic blood pressure. Table 2 shows the results of the global cognitive function and different domains of cognition. Patients with MCI had a lower performance on the MMSE, Montreal Cognitive Assessment and all cognitive tasks than patients without MCI.
Table 1.
Demographic and physical characteristics of participants with and without mild cognitive impairment
| Demographic character | Total (n = 316) | T2DM without MCI (n = 99) | T2DM with MCI (n = 217) | Z/χ2 | P‐value |
|---|---|---|---|---|---|
| Age (years) | 62.00 (13.00) | 59.00 (14.00) | 62.94 ± 7.81 | −3.96 | 0.000* |
| Female, (%) | 45.25 | 40.40 | 47.47 | 1.368 | 0.242 |
| Education ≤6 years (%) | 12.97 | 4.04 | 17.05 | 10.192 | 0.001* |
| Smoking (%) | 39.87 | 42.42 | 38.71 | 0.391 | 0.532 |
| Drinking (%) | 47.47 | 52.53 | 45.16 | 1.478 | 0.224 |
| Hypertension (%) | 51.58 | 43.43 | 55.30 | 3.832 | 0.050 |
| Hypercholesterolemia (%) | 62.34 | 62.63 | 62.21 | 0.005 | 0.944 |
| Depression (%) | 41.14 | 35.35 | 43.78 | 1.993 | 0.158 |
| Median duration of diabetes, years (IQR) | 10.00 (14.00) | 8.00 (13.00) | 10.00 (14.00) | −1.893 | 0.058 |
| Medication history | |||||
| Aspirin (%) | 23.73 | 22.22 | 24.42 | 0.182 | 0.670 |
| Statins (%) | 35.44 | 37.37 | 34.56 | 0.235 | 0.628 |
| ACEIs or ARBs (%) | 46.20 | 39.39 | 49.31 | 2.689 | 0.101 |
| Treatment type | |||||
| No treatment (%) | 12.03 | 17.17 | 9.68 | 3.609 | 0.057 |
| Insulin (%) | 36.71 | 32.32 | 38.71 | 1.193 | 0.275 |
| Metformin (%) | 63.92 | 58.59 | 66.36 | 1.781 | 0.182 |
| Insulin secretagogues (%) | 22.47 | 18.18 | 24.42 | 1.521 | 0.218 |
| Alpha‐glucosidase inhibitor (%) | 41.14 | 33.33 | 44.70 | 3.628 | 0.057 |
| DPP4i (%) | 6.65 | 8.08 | 5.99 | 0.561 | 0.454 |
| SGLT2i (%) | 5.38 | 8.08 | 4.15 | 2.066 | 0.151 |
| GLP‐1(%) | 7.28 | 7.07 | 7.37 | 2.459 | 0.117 |
| Physical examination | |||||
| BMI (kg/ m2) | 25.70 (4.16) | 25.95 (4.50) | 25.65 (4.30) | −1.104 | 0.269 |
| SBP (mmHg) | 130.00 (19.00) | 130.00 (17.00) | 132.00 (20.00) | −2.187 | 0.029* |
| DBP (mmHg) | 80.00 (11.00) | 80.00 (11.00) | 79.00 (10.00) | −0.906 | 0.365 |
| Biochemical examination | |||||
| FBG (mmol/L) | 8.08 (3.46) | 7.90 (3.49) | 8.25 (3.40) | −0.143 | 0.886 |
| HbA1c (%) | 8.25 (2.40) | 8.00 (2.70) | 8.30 (2.30) | −0.963 | 0.336 |
| TG (mmol/L) | 1.45 (1.11) | 1.49 (1.20) | 1.42 (1.13) | −0.866 | 0.386 |
| TC (mmol/L) | 4.71 (1.64) | 4.87 ± 1.15 | 4.61 (1.58) | −0.255 | 0.799 |
| LDL‐C (mmol/L) | 3.00 ± 0.85 | 2.97 ± 0.86 | 3.02 ± 0.85 | −0.459 | 0.646 |
| HDL‐C (mmol/L) | 1.17 (0.36) | 1.18 (0.32) | 1.17 (0.39) | −0.283 | 0.777 |
Comparison between the group with cognitive impairment and the group without cognitive impairment. *P < 0.05. BMI, body mass index; DBP, diastolic blood pressure; DPP4i, dipeptidyl peptidase‐4 inhibitor; FBG, fasting blood glucose; GLP‐1, glucagon like peptide‐1; HbA1c, glycated hemoglobin; HDL‐C, high‐density lipoprotein cholesterol; IQR, interquartile range; LDL‐C, low‐density lipoprotein cholesterol; SBP, systolic blood pressure; SGLT2i, sodium–glucose transporter 2 inhibitor; TC, total cholesterol; TG, triglyceride.
Table 2.
Cognitive function of subjects with and without mild cognitive impairment
| Total (n = 316) | T2DM without MCI (n = 99) | T2DM with MCI (n = 217) | Z | P‐value | |
|---|---|---|---|---|---|
| MMSE | 27.00 (3.00) | 28.00 (2.00) | 27.00 (3.00) | −6.515 | 0.000* |
| MoCA | 23.00 (5.00) | 26.00 (2.00) | 22.00 (3.00) | −13.787 | 0.000* |
| Immediate recall | 21.54 ± 6.04 | 23.61 ± 6.28 | 20.60 ± 5.70 | 4.214 | 0.000; |
| Long delay free recall | 7.00 (5.00) | 9.00 (4.00) | 7.00 (4.00) | −5.669 | 0.000* |
| Long delay cued recall | 9.00 (4.00) | 11.00 (3.00) | 9.00 (4.00) | −4.732 | 0.000* |
| Long delay recognition | 12.00 (4.00) | 13.00 (2.00) | 12.00 (3.00) | −5.356 | 0.000* |
| AFT | 17.00 (6.00) | 18.00 (6.00) | 16.00 (6.00) | −4.260 | 0.000* |
| BNT | 24.00 (5.00) | 26.00 (4.00) | 24.00 (6.00) | −5.611 | 0.000* |
| DSF | 7.00 (2.00) | 8.00 (2.00) | 7.00 (2.00) | −5.574 | 0.000* |
| DSB | 4.00 (2.00) | 5.00 (1.00) | 4.00 (2.00) | −6.536 | 0.000* |
| CDT | 2.00 (1.00) | 3.00 (1.00) | 2.00 (1.00) | −5.625 | 0.000* |
| TMT‐A | 46.41 (29.19) | 37.41 (16.00) | 52.27 (31.20) | −5.492 | 0.000* |
| TMT‐B | 82.39 (241.70) | 62.49 (57.42) | 99.58 (235.87) | −5.148 | 0.000 |
Comparison between the group with cognitive impairment and the group without cognitive impairment. *P < 0.05. AFT, Animal Fluency Test; BNT, Boston Naming Test; CDT, Clock‐Drawing Test; DSB, Digit Span Backward; DSF, Digit Span Forward; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; TMT‐A, Trail Making Test‐A; TMT‐B, Trail Making Test‐B.
Incidence of SLEs in all participants and groups
As shown in Table 3, among all the stressful life events, the death of an offspring or parent (81.96%), career changes (30.70%), onset of a serious illness (23.73%), onset of a serious accident (22.78%) and financial difficulty (18.99%) were the top five events. There were significant differences in the death of an offspring or parent, financial difficulty, career changes and high working pressure between the groups with and without MCI (all P < 0.05).
Table 3.
Stressful life events category in subjects with and without mild cognitive impairment
| Stressful life events | Total (n = 316) | T2DM without MCI (n = 99) | T2DM with MCI (n = 217) | χ2 | P‐value |
|---|---|---|---|---|---|
| The death of a spouse (%) | 8.54 | 5.05 | 10.14 | 2.252 | 0.133 |
| The death of an offspring or parent (%) | 81.96 | 70.71 | 87.10 | 12.352 | 0.000* |
| Career change (%) | 30.70 | 41.41 | 25.81 | 7.785 | 0.005* |
| Onset of a serious illness (%) | 23.73 | 22.22 | 24.42 | 0.182 | 0.670 |
| Financial difficulty (%) | 18.99 | 11.11 | 22.58 | 5.814 | 0.016* |
| Marital separation (%) | 6.01 | 7.07 | 5.53 | 0.286 | 0.593 |
| Onset of a serious accident (%) | 22.78 | 25.25 | 21.66 | 0.499 | 0.480 |
| The theft or loss of an item of personal value (%) | 5.70 | 6.06 | 5.53 | 0.036 | 0.850 |
| Unemployment or laid‐off (%) | 8.54 | 8.08 | 8.76 | 0.040 | 0.842 |
| High working pressure (%) | 15.82 | 22.22 | 12.90 | 4.433 | 0.035* |
Comparison between the group with cognitive impairment and the group without cognitive impairment. *P < 0.05.
Association between SLEs and cognitive impairment tendency
We included the variables with significant differences between the two groups into a binary regression equation, and the results showed that the death of an offspring or parent (OR 2.843, 95% CI 1.549–5.215) and financial difficulty (OR 3.108, 95% CI 1.282–7.535) were associated with a high risk of MCI, whereas participants who experienced high working pressure (OR 0.440, 95% CI 0.223–0.870) had a lower risk for the development of MCI (as shown in Table 4). When age and education level were included as the independent variables, the results showed that only the death of an offspring or parent (OR 1.994, 95% CI 1.017–3.908) was a risk factor for MCI.
Table 4.
Logistic regression analysis of stressful life events and mild cognitive impairment tendency in all participants
| Stressful life events | B | SE | Wald | P‐value | OR | 95% CI |
|---|---|---|---|---|---|---|
| Death of an offspring or parent | 1.045 | 0.310 | 11.385 | 0.001* | 2.843 | 1.549–5.215 |
| Career change | −0.509 | 0.292 | 3.025 | 0.082 | 0.601 | 0.339–1.067 |
| Financial difficulty | 1.134 | 0.452 | 6.300 | 0.012* | 3.108 | 1.282–7.535 |
| High working pressure | −0.820 | 0.347 | 5.581 | 0.018* | 0.440 | 0.223–0.870 |
*P < 0.05.
Considering that participants of different ages experienced different SLEs at different times, we divided participants into two subgroups according to whether they were aged ≥60 years. The results showed that in the subgroup of participants aged ≤60 years, the death of an offspring or parent (OR 2.731, 95% CI 1.119–6.665) and financial difficulty (OR 22.205, 95% CI 4.365–112.966) were risk factors for the development of MCI, whereas high working pressure (OR 0.154, 95% CI 0.048–0.495) and career changes (OR 0.324, 95% CI 0.124–0.847) were protective factors against MCI (as shown in Table 5), and the results were maintained even after we adjusted for education level. However, for participants aged >60 years, the risk factor for the development of MCI was still the death of an offspring or parent (OR 3.550, 95% CI 1.160–10.867), and we found that no SLEs were protective factors for cognitive decline.
Table 5.
Logistic regression analysis of stressful life events and mild cognitive impairment tendency in the midlife participants
| Stressful life events | B | SE | Wald | P‐value | OR | 95% CI |
|---|---|---|---|---|---|---|
| Death of an offspring or parent | 0.947 | 0.469 | 4.081 | 0.043* | 2.579 | 1.029‐6.466 |
| Financial difficulty | 3.204 | 0.867 | 13.647 | 0.000* | 24.627 | 4.500–134.778 |
| Career change | −1.177 | 0.501 | 5.526 | 0.019* | 0.308 | 0.115–0.822 |
| High working pressure | −1.640 | 0.617 | 7.060 | 0.008* | 0.194 | 0.058–0.650 |
| Education level | −0.714 | 0.242 | 8.719 | 0.003* | 0.490 | 0.305–0.787 |
*P < 0.05.
Effect of SLEs on different cognitive domains
We analyzed the impact of these significant life events on different cognitive domains. The results showed that participants who experienced the death of an offspring or parent had lower scores in language, attention and executive function, whereas those who experienced high working pressure had higher scores in memory, language, attention and executive function (Table 6).
Table 6.
Comparison of each cognitive domain between experienced stressful life events or not
| High working pressure (n = 50) | Without‐high working pressure (n = 266) | Z | P‐value | The death of an offspring or parent (n = 259) | Without‐death of an offspring or parent (n = 57) | Z | P‐value | |
|---|---|---|---|---|---|---|---|---|
| Immediate recall | 23.00 (8.00) | 20.91 ± 5.77 | −3.578 | 0.000* | 21.30 ± 5.99 | 22.00 (8.00) | −1.080 | 0.280 |
| Long delay free recall | 8.00 (5.00) | 7.00 (4.00) | −2.098 | 0.036* | 7.00 (5.00) | 8.00 (4.00) | −1.152 | 0.249 |
| Long delay cued recall | 9.94 ± 2.97 | 9.00 (4.00) | −2.110 | 0.035* | 9.00 (4.00) | 10.00 (4.00) | −1.473 | 0.141 |
| AFT | 20.28 ± 6.23 | 16.00 (6.00) | −4.413 | 0.000* | 17.00 (6.00) | 17.00 (6.00) | −1.518 | 0.129 |
| BNT | 25.00 (4.00) | 24.00 (5.00) | −4.425 | 0.001* | 24.00 (5.00) | 25.00 (4.00) | −2.548 | 0.011* |
| DSF | 8.00 (2.00) | 7.00 (2.00) | −2.215 | 0.027* | 7.00 (2.00) | 8.00 (3.00) | −2.473 | 0.013* |
| DSB | 5.00 (1.00) | 4.00 (2.00) | −2.490 | 0.013* | 4.00 (2.00) | 4.00 (1.00) | −2.136 | 0.033*> |
| TMT‐A | 42.00 (28.26) | 47.84 (32.43) | −2.318 | 0.020* | 49.00 (31.90) | 38.86 (24.78) | −3.418 | 0.001* |
| TMT‐B | 63.70 (251.55) | 86.50 (239.57) | −2.531 | 0.011* | 87.00 (240.00) | 65.05 (249.48) | −2.181 | 0.029* |
Comparison between the group with stressful life events and the group without stressful life events. *P < 0.05.
AFT, Animal Fluency Test; BNT, Boston Naming Test; DSB, digit span backwards; DSF, digit span forward; TMT‐A, Trail‐Making Test‐A; TMT‐B, Trail‐Making Test‐B.
DISCUSSION
In the present study, the prevalence of MCI with type 2 diabetes mellitus was 68.7%, higher than previously reported 41 , 42 , which might be due to the difference in the population enrolled. The participants in our study were outpatients or inpatients in the hospital, whereas the participants in the previous studies were community‐dwelling. Patients who come to the hospital might have more severe and complex conditions than those in the community, which might lead to an increased prevalence of cognitive impairment.
The present study showed that stressful life events, such as the death of an offspring or parent, were associated with an increased risk of MCI even after adjustment for age and education level in midlife and elderly type 2 diabetes mellitus patients.
A cohort study, which aimed to evaluate the association between adverse life events and the risk of cognitive decline in Chinese elderly individuals, concluded that the death of a spouse and a financial crisis were associated with a higher risk of cognitive impairment 21 . Another study collected 18 years of data and carried out a retrospective analysis to estimate cognitive impairment onset. The results showed that midlife marital dissolution was associated with higher odds of cognitive impairment onset in later life 22 . Johansson et al. followed up 1,462 middle‐aged women for 35 years, and found an association of psychological stress in midlife with a higher risk of dementia in late‐life 43 . The aforementioned studies are cohort studies with large sample sizes, and the results showed that SLEs in middle age, especially about marital relationships, were associated with cognitive impairment in later life. In the present study, the incidence of the death of a spouse was 10.14% among patients with MCI compared with 5.05% among those without MCI, but this event was not associated with a higher risk of cognitive impairment. In addition, marital separation was also not associated with a higher risk of cognitive impairment. The relationship between life events in marriage and cognitive impairment was inconsistent with previous studies, which might be related to the sample size or different lifestyles and cultural backgrounds of the participants.
Further support was provided by a study using MRI to predict brain age, which suggested that people who experienced more midlife negative life events, especially related to interpersonal relationships, showed a brain age that was more advanced than their biological age 44 . In the present study, we did not distinguish the exact time of SLEs, and our results suggested that adverse life events were related to cognitive impairment, participants who experienced the death of an offspring or parent had lower scores in language, attention and executive function than those who did not experience the life event.
However, some studies have shown that life events are not related to cognitive impairment. Sundstrom et al. 45 collected prospective data from a longitudinal study on aging and cognition, and found no correlation between negative or positive life events and dementia. Another study analyzed life events in dementia patients and elderly individuals with normal cognition, and no causal relationship between life events and the pathogenesis of dementia was found 46 . Some studies have also shown that early‐life adversity has a protective effect on cognitive function 47 . A Chinese prospective study followed up individuals without dementia, but with adverse life events, for a mean of 5.2 years, and showed a significant negative association between life events and the risk of cognitive decline among older adults without depression 27 . To some extent, these contradictory findings in the literature might be due to differences in the study methodologies, study population and sample size.
Some researchers believe that the experience of stress is both constructive and destructive to the brain 48 . In the short term, mild stress results in mobilized adaptive adjustment in physiology and behavior, which helps individuals cope with the needs of environmental challenges and strengthens brain function 49 . However, long‐term and excessive stress leads to maladaptive changes in the brain and then induces cognitive impairment 50 . The midlife participants who experienced high working pressure and career changes were shown to have a lower risk for cognitive decline in the current study, and the participants who experienced high working pressure showed better performance in memory, language, attention and executive domains.
Previous studies found that experiencing adverse life events or being under pressure for a long time leads to hypertension, blood hypercoagulability and cerebrovascular disease. These vascular factors contribute to cerebral ischemia and even stroke, and affect cognitive function 51 , 52 . In the present study, the prevalence of hypertension in patients with and without MCI was 55.30% and 43.43%, respectively, and the systolic blood pressure in patients with MCI was significantly higher than that in patients without MCI. This signified vascular cognitive impairment in our study.
Some studies have also shown that depression plays an important role in the cognitive impairment of patients who experience SLEs 21 , 53 . As a chronic disease, diabetes often occurs concomitantly with depression 41 . In our study, the prevalence of depression in the general population was 41.14%, but there was no significant difference between the two groups with and without MCI, which might be due to the insufficient degree of SLEs experienced. In addition, some researchers believe that the dysregulation of the hypothalamic–pituitary–adrenal axis contributes to the correlation between SLEs and cognitive impairment 54 , 55 , 56 . As a kind of hormone released on exposure to a stressful situation, glucocorticoids are considered to be closely related to cognitive function 57 . It has been confirmed in animal studies that the cognitive decline caused by chronic stress is related to disordered cortisol secretion and damage to the hippocampus 58 , 59 . A few population‐based studies also showed that chronic stress was related to cognitive decline due to increased cortisol release 20 , 60 . However, a longitudinal study of mixed mild cognitive impairment found that cortisol had a protective effect against cognitive decline 61 . Unfortunately, information on the concentration of cortisol in participants was not available in the present study, so there was no direct evidence to prove the relationship between abnormal secretion of cortisol and cognitive function.
There were several limitations to the present study. First, this was only a cross‐sectional study, and we carried out on evaluation through a series of scales without follow up; if we carried out two questionnaire evaluations with an interval of 3 months for each participant, it would be better to validate the stressful events and cognitive function of these patients. Second, our data on stressful life events included only information on “yes” or “no,” not the time of the occurrence or the extent and duration of the personal impact, and we could not measure the relationship between the depth of the impact of life events on individuals and cognitive decline risk in the current study. Third, the present findings were from patients with type 2 diabetes mellitus who came to the hospital, and the results might not apply to the entire population with type 2 diabetes mellitus. Fourth, although severe cerebrovascular disease through detailed medical history collection was excluded from our study, computed tomography/magnetic resonance imaging examination was not carried out to examine the brain structure for all patients. Fifth, we did not measure the cortisol level or blood coagulation function of the participants, and could not provide mechanistic support for the relationship between SLEs and cognitive function.
In conclusion, the present results showed that stressful life events were related to cognitive function in middle‐aged and elderly patients with type 2 diabetes mellitus. Stressful life events, such as the death of an offspring or parents, were risk factors for cognitive impairment, whereas high work pressure in middle‐aged people was a protective factor for cognitive function. In the future, we will expand the sample size, and combine cortisol levels, insulin resistance and other biomarkers to confirm the causal relationship between SLEs and the risk of cognitive impairment in patients with type 2 diabetes mellitus.
Disclosure
The authors declare no conflict of interest.
Approval of the research protocol: This study abided by the Declaration of Helsinki, and was reviewed and approved by the Research Ethics Committee of the First Hospital of Hebei Medical University (20210502).
Informed consent: The participants provided written informed consent to participate in this study. No potentially identifiable human images or data are presented in this study.
Registry and the registration no. of the study/trial: This study was registered on 15 September 2021, with the registration number ChiCTR2100051164.
Animal Studies: NA.
Acknowledgments
This work was supported by The Science and Technology Project of the People's Livelihood in Hebei Province (20377707D), Special Funding for Local Science and Technology Development Guided by the Central Government (206Z7701G), and the Key Projects of Hebei Administration of Traditional Chinese Medicine (Z2022015).
Contributor Information
Huimin Zhou, Email: zhouhuimindoctor@163.com.
Shunjiang Xu, Email: xushunjiang@hebmu.edu.cn.
References
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