Association of Stressful Life Events with Dementia in North Indian Populations
Keywords: ACTH, Alzheimer's disease, cortisol, DASS, dementia, mild cognitive impairment, PSLES, prolactin
Various factors like hypertension, diabetes, smoking, alcohol, low level of education, family history, and chronic stress may act as the risk factors of dementia. Amongst these, chronic stress is fetching growing importance along with other factors. Mild stress is beneficial in cognitive tasks and performance but persistently high stress may lead to neuropsychiatric illnesses such as cognitive impairment and dementia. Prolonged stress predisposes susceptible individuals to a number of physiological disorders including cardiovascular disease, obesity, and gastrointestinal disorders, as well as psychiatric and neurodegenerative disorders.
A few studies established the linkage between stressful life events and psychiatric disorders across diverse population including older persons different races and ethnicity. Contrary to the general belief, the forms of stressors in the elderly are unique and are attended with their limited coping abilities.
The autonomic nervous system provides a rapid response to stress by the release of Corticotropic Releasing Hormone (CRH) orcortisol as a subject's response to stress. The constantly increased levels of cortisol, as a response to stress, may subsequently lead to neural degeneration.,, High levels of cortisol may have a damaging effect on the hippocampus suggesting a potential role of cortisol in precipitating the early development of MCI.
Keeping all these factors in view, the aim of this study was to explore the association of stressful events with dementia in the elderly population.
The methodology adopted during the experimental procedure is detailed in the sub-sections to follow.
The study was conducted in the All India Institute of Medical Sciences (AIIMS), New Delhi, among the diseased subjects suffering from either mild cognitive impairment (MCI) or Mild Alzheimer's Disease (AD). The study subjects were selected after a clinical diagnosis and investigations in the Out Patient Cognitive disorders clinic of the Department of Neurology.
The case group included the cognitively impaired subjects with the cause of impairment either mild cognitive impairment (MCI) or Alzheimer's disease (AD) type dementia and was distributed either in MCI or in mild ADgroup. The cognitively impaired subjects with the cause of impairment other than MCI or AD were excluded from the study.
The cases of mild cognitive impairment were screened using modified Peterson criteria while dementia screening was based on Diagnostic and Statistical Manual of Mental Disorders V, AD type dementia was identified following National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA), (NINCDS-ADRDA criteria). The severity of cognitive decline was assessed using Clinical Dementia Rating Scale.
A sample size of 60 subjects was enrolled in case group (age group 55-75 years; M:F = 7:3). All consecutive cases of the case group subjects were segregated into two sub-groups, namely MCI (n = 34) and Mild AD (n = 26). The AD cases were diagnosed clinically ruling out other conditions and based on their FDGPET (fluoro-deoxy-glucose (FDG)-positron emission tomography) which was positive showing asymmetric hypo-pigmentation in the region of posterior cingulate and parietal cortices. Case group comprised of subjects who were not under any medication and were diagnosed with the disease for the first time. Control group consisted of two subgroups: related control group comprised of subjects (n = 60) related to patients, primary caregivers; and unrelated control group comprised of subjects (n = 60) who did not have any co-relation (genetic relation, caregivers or friends) with patients. The subjects belonging to unrelated control group category had never reported to any clinical center with any neurological disorder and were selected from the community. Control group was framed by matching the criteria of case group on the basis of age, gender, and sociodemographic variables.
The study was approved by theEthics Committee. Written informed consent was obtained from each of the study participants before induction. Other ethical safeguards such as confidentiality, right to withhold or withdraw consent were also maintained during the study period. Treatment was not altered in any manner whether the patients agreed or refused to participate in the study. Required precautions were taken during invasive investigations.
Severity of cognitive impairment was assessed using cognitive dementia rating (CDR) scale with a scale rating of 0.5, 1, 2 and 3 categorised respectively into very mild, mild, moderate and severe cases. Subjects with a CDR score of 0.5 and 1 were included into MCI and mild AD groups respectively, while subjects with CDR score of 2 and 3 were excluded from the study. The subjects with a CDR score of 0 were included in control group.
Stressful life events for last one year was assessed using Presumptive Stressful Life Event Scale (PSLES) with a score of more than 300 considered as severe one. Present stress situation was assessed (for control group only) using Depression Anxiety Stress Scales (DASS) with a score of more than 26 considered as severely stressed. Alongside, their impairment in daily activities was also estimated using the Instrumental Activities of Daily Living Scale (IADL) which produced a percentage level of impairment. The stress levels were compared and validated with the serum and plasma levels of cortisol and ACTH respectively.
The data collected from the application of scales was based on responses from the caregiver of the subjects who were associated with the diseased subjects for a period of approximately 20-30 years and NOT from the subjects themselves as the subject response was not reliable.
Process of blood sample collection and storage
A quantity 6 ml of blood sample was collected from each participant following the diurnal rhythms of the hormones cortisol and ACTH (8:00 a.m.-10:00 a.m.).
Each blood sample was allowed to clot for 30 minutes at room temperature (25°C). Both plasma and serum tubes were centrifuged at 3000 rpm for 10 minutes. Serum and plasma in supernatant form were separated using a micropipette and stored in 4 different aliquots in micro-centrifuge tubes (MCT). The tubes were labelled and 3 aliquots were stored at -20°C until further use in the study. The 4th part of aliquots was stored in -80°C for future usages.
The data wereanalysed by Two-sample Wilcoxon rank-sum (Mann-Whitney) test and Kruskal-Wallis equality-of-populations rank test. There was no missing data in our data set.
Based on the procedure explained in section 2, the following results were obtained in the enrolled subjects that are presented in the sub-sections to follow.
The demographic data were estimated in terms of n (n%) for all the variables except age. The ages of the recruited subjects followed normal distribution and hence were determined as mean ± standard deviation. The variables with P value <0.5 were considered to be non-uniformly distributed.
All 4 groups were distributed statistically uniformly with the subjects of matched age groups (P value = 0.810). The other variables like, gender (P value = 0.038), socioeconomic status (P value = 0.010), education (P value = 0.017), religion (P value <0.001) and financial condition (P value = 0.018) did not follow normal distribution among 4 groups and were non-uniformly distributed. The number of male gender in diseased MCI group as well as in AD group was more as compared to that of females. Control group consisted of both genders with equal statistical probability. An exceptional majority of subjects were married and belonging to Hindu religion in each group (P value <0.243). The socioeconomic status of majority of subjects in all groups belonged to middle class. Majority of subjects in diseased group were from the highest education zone i.e., higher than twelfth standard, while the related and un-related healthy controls were majorly from matriculate category. The financial dependence was markedly less in both diseased and un-related healthy control groups. Financially dependent and independent subjects were almost uniformly distributed in related control group. There was a significant impairment in daily activities in case group as compared to both control groups with a statistically significant P value of 0.0001. The subjects of AD showed the highest degree of impairment in their daily activities. It was observed that IADL scores were higher in females as compared to that of males in mild cognitive impairment group while in AD group, males and females exhibited no statistically significant difference in IADL scores.
Results on estimated stress levels
The stress levels in the enrolled subjects were evaluated based on two co-ordinates namely, (i) stress due to life events and (ii) self-reported stress. The statistical evaluation on the stress levels were tabulated and detailed in the following sub-sections.
Stressful life events
[Table 1] presents a statistical comparison of PSLES scores depicting the stressful life eventsamong the subjects belonging to four (MCI, AD and 2 control sub-groups) groups. The results on PSLES scores revealed statistical significance (P value = 0.0001) among all groups.
The statistical comparison of self-reported stress among the control groups is presented in [Table 2]. The results exhibited a high statistical significance with a P value of 0.0001 among both compared groups.
Stress response hormone levels
Evaluation of stress level by stress response hormones in the blood serum of the subjects was carried out with the help of ELISA kits. Cortisol (the primary stress hormone) and ACTHwere evaluated for validation and the results obtained are stated below.
The results of estimatedcortisol levels are shown in [Table 3]. It reveals that there was distinctive different cortisol level between unrelated controls and case group subjects irrespective of the gender with high statistical significance.
[Table 4] shows the results obtained from ACTH evaluation. The observed levels of ACTH are tabulated in [Table 4]. The evaluated ACTH levels varied from one to the other. It was also noticed that related and unrelated control group subjects exhibited distinctly different ACTH level.
All the participated study subjects belonging to 4 groups were screened through CDR score based on the level of impairment. The subjects of related control group declared themselves healthywhile getting their MCI relatives enrolled into the study. But the results of this work revealed that this group had also been suffering from stress as evident from [Table 1] to [Table 4]. The self-reported stress (DASS) scores projected an implication that related control group subjects suffered from major mood swings which might be due to sharing life events with the affected persons. The findings of this study repeated the conclusion of multiple previous studies,,, that there exists a strong association of stress and dementia.
It appears from the studies,, that even a single stressful life event may act as a potential chronic stressor leading to neural degeneration and subsequent development of dementia. Further the observations made on the life events, which might have acted as chronic stressors in one's life, revealed that the subjects who were suffering from mild cognitive impairment and Alzheimer's disease suffered from maximum number of stressful life events. It has been observed that majority of the subjects suffered from family and/or maritalconflicts. The most impacting factor is the “death of spouse” or “death of a close family member”. The majority of sufferers were males (n = 42) rather than females (n = 18) which could have been because of possibility inbetter coping styles of females. It has been observed that subjects, who had lost their loved ones majorly spouse, slipped into the diseased state rapidly (within <1 year) in comparison with other stress events. And the rate of rapiditywas observed to affect the male members compared with that of females. Secondfactor was the component “retirement” that had contributed in a great way in developing disease but rapidity was observed to be slower than the demise of spouse. It could be concluded that inactivity or stagnant lifestyle itself was acting as a major stress factor. Individual coping style during retired life might reverse the proximity towards the disease during retired phase of life. This was the finding of this study and also confirms the observations of the previous study.,
All the above observations associating chronic stress due to stressful life events (as defined in previous studies,, and dementia, were based on the estimated outcome measures of this study. In order to confirm our data on the subjective levels of stress, the related stress response hormones were also assessed in blood. The major stress hormones observed were cortisol and ACTH, the precursor hormone to cortisol. Studies,,, showed that chronic stress led to accumulating primary stress hormone “cortisol” in blood and constant elevation in the level of this hormone developed in neuronal degeneration subsequently resulting in dementia.
It was observed highly elevated levels of both cortisol and ACTH in the blood stream of diseased subjects while the controls had near to normal levels of these hormones. The results supported the observations produced by scales on the subjects that they had experienced chronic stress, by the raised levels of stress hormones.
Anotherworthy finding to be reported that the subjects related to the diseased could not be designated as standardised reference (control) group cases as estimated to have pronounced elevated stress including both subjective as well as objective parameters. This observation led to the present authors in reporting that chronic and uncontrolled stress of the diseased subjects influenced the caregivers who had been constantly managing/assisting their ownailed ones. Hence the diseased-unrelated subjects may be considered to constitute the control/reference cases.
With the limitation of a small sample size, it may be concluded that chronic stress, which could be due to stressful life events, might be associated with cognitive decline and dementia (of which 70% cases are reported as Alzheimer's disease). The major cause of neural degeneration which leads to the diseased state is the accumulation of cortisol hormone, the standardised stress hormone as a response to a stressful situation.
However, these observations may be confirmed by carrying out in a larger population involving various environments and race. Long term prospective studies in this direction are going on.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]