|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 6
| Issue : 3 | Page : 151-158 |
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The Role of Cortisol in the Development of Post-Stroke Dementia: A Narrative Review
Isabella Edwards, Indu Singh, Roselyn B Rose'meyer
School of Pharmacy and Medical Sciences, Griffith University, Gold Coast Campus, Southport, Queensland, Australia
| Date of Submission | 01-Sep-2022 |
| Date of Acceptance | 14-Sep-2022 |
| Date of Web Publication | 30-Sep-2022 |
Correspondence Address:
Dr. Indu Singh
School of Pharmacy and Medical Sciences, Griffith University, Gold Coast Campus, Southport, Queensland
Australia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_32_22
Stroke is defined as a neurological deficit which lasts more than 24 h or leads to death, which is caused by a focal acute injury to the central nervous system with a vascular origin. Strokes are one of the greatest challenges in public health. As an acutely stressful event, strokes have been associated with an increased release in the stress hormone cortisol. Elevated cortisol has been linked to deleterious impacts on the brain, particularly the hippocampus, and has been associated with the development of dementia, though the mechanisms behind this remain unclear. Dementia is also an important stroke outcome, affecting approximately a third of stroke survivors in the long term. This review explores the relationship between strokes and cortisol, to determine the association between cortisol and hippocampal/neuronal damage and poststroke dementia and cortisol.
Keywords: Cortisol, hippocampus, stroke, dementia
How to cite this article:
Edwards I, Singh I, Rose'meyer RB. The Role of Cortisol in the Development of Post-Stroke Dementia: A Narrative Review. Heart Mind 2022;6:151-8 |
| Introduction | |  |
For a number of years, the impact of continuous exposure to high levels of glucocorticoids (GCs) on neurological health has been investigated. In particular, chronic hypercortisolemia has been associated with a worse performance in hippocampus-dependent tasks[1] and observed in a number of conditions such as Cushing's disease and in those consuming long-term oral corticosteroids.[2] As a highly stressful event, acute stroke is also associated with high cortisol levels, and in some cases, this prolongs the activation of the hypothalamic–pituitary–adrenal (HPA) axis,[1] causing dysregulation which is attributed to a number of factors, including age and the pathological response to stroke.[2] Much like individuals with Cushing's disease, individuals with higher cortisol levels are more likely to suffer from cognitive impairment.[3] The “GC cascade hypothesis” postulated by researchers to explain these results suggests that stress-induced increases in cortisol levels lead to an inhibition of neurogenesis, a deterioration of dendritic processes, and neurotoxic effects within the hippocampus.[4],[5] These effects subsequently result in a poorer cognitive performance and the development of degenerative conditions, such as dementia.[4] Since the hippocampus plays a major role in the negative feedback circuit of the HPA axis, high cortisol levels are increased further by damage to the hippocampus and the process becomes self-sustaining.[4] This suggests an association between cortisol levels and the long-term neurological impacts of an acute stroke, in particular the development of poststroke dementia (PSD). PSD is associated with earlier permanent institutionalization and shorter survival times.[6],[7] Previous studies have proposed that continuously high cortisol levels, present after an acute stroke, are associated with the development of dementia.[1] A diagnostic biomarker for identifying patients at risk of developing PSD has still not been identified.[2] Furthermore, the mechanisms involved in the development of dementia have not been fully explained. As a result, treatment and preventative measures (other than reducing the risk of stroke itself) have not been implemented.[1] The key areas involved in this investigation were to (i) explore the relationship between strokes and cortisol levels, (ii) determine whether there is an association between cortisol and hippocampal/neuronal damage, and (iii) evaluate the selected studies investigating PSD and the role of cortisol.
| Stroke Causes and Diagnosis | | |
Traditionally, a stroke has been defined as a neurological deficit which lasts more than 24 h or leads to death, caused by a focal acute injury to the central nervous system with a vascular origin.[8] There are two main categories of strokes: cerebral hemorrhage and ischemic stroke.[9] Cerebral hemorrhages cause 20% of stroke cases, including subarachnoid hemorrhages and intracerebral hemorrhages. Subarachnoid hemorrhages cause a quarter of cerebral hemorrhagic strokes and occur when a blood vessel near the surface of the brain bursts, causing a pooling of blood in the subarachnoid space. Intracerebral hemorrhages are divided further into lobar hemorrhages, which involve the cortex, and subcortical hemorrhages.[10] Hemorrhages are more common in elderly individuals and often have a genetic basis if they occur in younger patients.[9] Ischemic strokes make up 90% of strokes.[11] Common causes include large artery disease, small vessel disease, and cardioembolism.[10] Large artery strokes include 20% of all strokes and are most commonly due to carotid artery stenosis, while small vessel disease comprises about a quarter of all ischemic strokes.[9] Other causes include carotid and vertebral dissection, genetic diseases, and prothrombotic factors.[9] Classic stroke symptoms include numbness, rapid-onset unilateral weakness, difficulty with speech, lack of voluntary coordination of movements, diplopia, and vertigo (nonorthostatic).[10] Multiple tests, including the Face, Arm and Speech Test and the Recognition of Stroke in the Emergency Room (Rosier) score, may be used as screening tools. Determining the type of stroke requires magnetic resonance imaging or computed tomography screening, as it is difficult to clinically differentiate between cerebral infarction and intracerebral hemorrhage.[10]
| Stroke and Cortisol | | |
When a stroke occurs, a number of endocrine processes are activated,[12] including the major stress pathway associated with the HPA axis.[13] Regulated by the brain, this neuroendocrine system results in release of GCs from the adrenal glands.[2] The increased activation of the HPA axis and a rise in cortisol levels are often observed during episodes of acute stress, including stroke.[2] A number of studies have reported that cortisol levels within the 1st week after a stroke were well above the reference range [Table 1];[14],[15],[16],[17],[18],[19],[20] however, three studies found no association.[15],[28],[34] Furthermore, for a significant subset of patients (up to 40% of patients), this can result in prolonged hypercortisolism and a loss of diurnal variation of cortisol levels.[35],[36] These abnormalities in endocrine function may be due to a number of causes, including age, which has been associated with HPA axis dysregulation, but may also be due to reasons specific to stroke, including cytokine release in response to neuronal injury and destruction of HPA inhibitory areas of the brain by the stroke lesion itself.[37] In patients suffering from ischemic or hemorrhagic strokes, the National Institutes of Health Stroke Scale and Scandinavian Stroke Scale were most often used to measure the severity of the stroke.[38]
In a number of studies, cortisol levels have been correlated with an increased mortality rate.[26] In these same studies, many have also suggested that the neurotoxic effects of cortisol, especially the exacerbation of hypoxic neuronal injuries, play a role in increased mortality, particularly in the long term.[28] These studies reported an association between increased mortality and elevated cortisol levels (although this was not statistically significant for 2 studies).[21],[22],[23],[25],[27],[28],[31],[32],[33],[39],[40],[41] Follow-up periods ranged from 7 days to 44 months, suggesting that cortisol may predict both short-term and long-term mortality.[21],[27]
| Hippocampus Structure and Function | | |
Located deep within the temporal lobe, the hippocampus is a deposit of densely packed neurons, which make up an extension of the temporal part of the cerebral cortex.[42] Externally seen as a ridge of gray matter, this complex structure can be distinguished by its curled S-shape, which lies on the edge of the temporal lobe.[43] The hippocampus also contains numerous receptors for GCs, estrogen, and progesterone.[44] Due to its location, the hippocampus is classified as part of the limbic system, an area known as the “primitive brain.” While the hippocampus is primarily known for its role in learning and memory, it is also involved in spatial navigation, emotional behavior, and the regulation of hypothalamic activity. Importantly, the hippocampus also plays an integral role in endocrine function. Multiple studies have reported that when the hippocampus was stimulated, a decrease in HPA axis activity occurred.[13],[42] The opposite effect was observed in individuals with hippocampal lesions, reinforcing the role of the hippocampus in controlling the negative feedback of the HPA axis.[45]
| Rates, Types, and Causes of Dementia | | |
Due to its role in the consolidation of memories, the hippocampus plays a major role in the progression of dementia. Dementia is defined as “a syndrome due to diseases of the brain, usually of a chronic or progressive nature, in which there are disturbances of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement.” Dementia affects 50 million individuals globally, with nearly 10 million new cases each year. Elderly women have a marginally greater probability of developing dementia, mostly because of an increased age-adjusted risk of developing Alzheimer's disease (AD).[46] Types of dementia include AD, which is most prevalent, Lewy body dementia, vascular dementia, and frontotemporal dementia, as well as dementias stemming from infections. AD accounts for approximately 60% of all dementia cases, and the disease often presents as memory loss which often progresses to a loss of cognition[47] and is associated with neurofibrillary tangles and amyloid plaques within the brain tissue. The formation of these abnormal structures is followed by neurovascular abnormalities, chronic inflammation, and cell signaling disruption. These processes lead to neuronal damage and brain atrophy.[48]
Vascular dementia accounts for 20% of dementia cases and is more prevalent in men than women, with the risk heavily influenced by age.[48],[49] This category covers dementia caused by hemorrhagic or ischemic lesions, with multi-infarct dementia considered the main type of vascular dementia.[38] A further 15%-20% of cases fall under the category of Lewy body dementia. This disease has distinct microscopic characteristics with Lewy bodies (cytoplasmic inclusions containing alpha-synuclein protein) and amyloid plaques found within cortical and subcortical brain regions.[48] 5% to 20% of dementia cases are attributed to frontotemporal dementia. Damage occurs to the frontotemporal lobe, and individuals have an average survival of 7–9 years after diagnosis.[48] Strokes are also a major factor in the development of dementia, with up to a third of stroke victims presenting with dementia in the long term.[38] These cases, often referred to as PSD, do not follow a specific neuropathological process but comprise a combination of both vascular insults and neurodegenerative processes. There is a significant overlap between the definitions of PSD and vascular dementia; however, the two conditions differ in that vascular dementia refers to fully developed dementia caused by a well-defined vascular event.[50] It is also currently impossible to distinguish between PSD and AD, again implying similarities between the pathology involved in these two conditions.[38]
| Dementia Associated with Damage to Hippocampus | | |
The relationship between dementia and hippocampal damage is prominent in AD, where the hippocampus is the earliest region affected and the most severely impacted. In a number of clinical trials, hippocampal atrophy has been used as a diagnostic and prognostic marker in the progression of AD.[51] Vascular dementia has also been associated with hippocampal atrophy, though not to the same extent as AD.[52] Clinically, hippocampal atrophy leads to disorientation and difficulty in spatial navigation, memory loss, and behavioral and emotional changes, all signs associated with dementia.[53] Beyond overall atrophy, the perforant hippocampal pathway is affected in dementia cases, where synaptic loss within this pathway is a major contributor to dementia, particularly in elderly patients.[52]
| Evidence Describing Role of Cortisol in Hippocampal Damage | | |
Since dementia is associated with hippocampal damage, it has been suggested that the proposed damaging impact of GCs on the hippocampus may play a role in the development of this disease.[12] Much of the clinical research into the damaging effects of cortisol has focused around investigations into Cushing's syndrome, which is characterized by hypercortisolemia with low levels of ACTH production.[54] This has allowed for a better understanding of the isolated effects of elevated cortisol levels.[13] Sixty percent of the individuals with Cushing's syndrome experience depression, and premature cortical atrophy and cognitive impairments are often observed in these patients.[55] The damaging impacts of cortisol are mediated through the hippocampus, an area rich in GC receptors,[56] and are integral to memory function as well as inhibition of the HPA axis.[57] The findings of the studies investigating the effects of cortisol on cognitive function [Table 2] found that high levels of cortisol, both acute and chronic, were associated with worse cognitive function over time.[13],[57],[60],[61],[63] Aside from memory and cognitive function, further clinical research has been conducted on the effects of cortisol on hippocampal volume specifically.[64] These findings are depicted in [Table 3].
These studies reported a significant association between elevated cortisol levels and reduced hippocampal volume,[54],[56],[67],[69] with one study providing results that weakly supported the hypothesis.[68] It should be noted that there were significant differences in the methods used in terms of cortisol measurements and additional long-term investigations to may be needed to further confirm these findings.[68],[70] However, in most studies, there was a relatively strong association between cortisol levels and hippocampal volume as seen through the provided correlation coefficients. These results have been attributed to the deleterious effects of GCs on the hippocampus.[71] As described by Sapolsky, GCs damage the hippocampus via several mechanisms including GC-induced atrophy, GC neurotoxicity, and GC neuroendangerment.[72] GC-induced neuronal atrophy can occur after 3 weeks of increased levels of GCs.[64] In this reversible atrophy, GCs cause a reduction in the amount of apical dendritic branch points as well as a reduction in the length of dendrites located in the CA3 region of the hippocampus.[72] Normal cognitive function returned and psychological problems subsided in Cushing's syndrome patients when cortisol levels were returned to normal.[55] GC neurotoxicity describes the effects of sustained high levels of GCs. After months of sustained stress and elevated GC levels, neuronal loss occurs, specifically in the CA3 region of the hippocampus.[73] Finally, GC neuro-endangerment refers to the ability of GCs to endanger neurons[74] where exposure to GCs of an inadequate degree or duration to induce neurotoxicity or atrophy may still impact the neurons through hindering their ability to survive subsequent insults.[75] In addition to these effects, more recent research has also highlighted the role of chronic stress in inhibiting adult neurogenesis.[76] While this begins as self-correcting and reversible, there comes a point when hypersecretion of cortisol induces irreversible damage.
Continuous exposure to high levels of GCs causes a downregulation of GC receptors[77] and may underpin the shift from reversible damage to permanent cell death. In stressful events, the energy stores within the hippocampus are reduced, and the ability to effectively respond to a metabolic challenge is impaired.[13] When the two events of high GC levels and a metabolic challenge coincide, irreversible cell damage occurs. As the hippocampus has an important role in endocrine function, GC-induced damage further activates the HPA axis by removing control of the negative feedback system, leading to chronically elevated cortisol levels. This observation was further supported by findings in rats, demonstrating that when exposure to GCs was reduced, both hippocampal degeneration and decline in cognitive function decreased.[45] Similar findings were also observed in human studies and were particularly prominent in elderly individuals, as advancing age has been linked to a tendency for dysregulation of the HPA axis. Furthermore, metabolic events are more likely to occur in older age groups, increasing the likelihood of hippocampal damage.[35]
In addition, while GCs were originally thought of as exclusively anti-inflammatory substances, recent findings have challenged this view.[78],[79] Findings in animal studies suggested cortisol and increased stress actually induced neuroinflammation in AD pathology. It has also been suggested that this increase in inflammation is again receptor mediated.[80] Overstimulation of GC receptors has also been recently linked to neurogenesis.[81] This area of research is still developing, but it has been found that adult neurogenesis occurs within the dentate gyrus, and GC receptors may play an integral role in regulating this process.[81]
| Glucocorticoids and Apoptosis | | |
Another possible mechanism is the pro-apoptotic effects of cortisol. In immune cells, GC regulation induces apoptosis in both thymocytes and mature peripheral blood lymphocytes.[82] This action is GR-mediated, as demonstrated through the use of receptor blockers. As shown in the model proposed by Dong et al., GCs cause the upregulation of the Bcl-2-like protein 11 (Bim).[83] The activation of the cAMP signaling pathway also occurs, resulting in the activation of the phosphatase 2A protein, which then causes the dephosphorylation of the Bcl-2-associated death promoter (BAD). BAD then translocates to the mitochondria and binds to anti-apoptotic proteins within the cancer cells. Bim is then released from these proteins and binds with a further protein, Bax, to make permeable the membrane of the mitochondria, leading to apoptosis.[84] While the apoptotic effects of GCs on the human hippocampus have not been confirmed, apoptosis within the hippocampus has been observed in both rodent and other animal studies.[73],[85] In particular, a study conducted on chronically stressed pigs found a significant correlation between apoptosis in the left dentate gyrus and basal cortisol levels in saliva. Neuronal numbers in the left dentate gyrus were negatively correlated with cortisol levels.[86]
| Association of Cortisol and Cognitive Function Following Stroke | | |
Most of the published studies into the relationship between stroke, cortisol levels, and cognitive function [Table 4] investigated predominately elderly individuals (with a median age well over 50), with relatively equal distributions of male and female subjects. Interestingly, the study conducted by Casas et al. found that cortisol had a particularly pronounced effect on cognitive function in female stroke sufferers, suggesting another factor may play a role in elderly females suffering acute ischaemic stroke (AIS) and was attributed to the decreased secretion of sex steroids following menopause.[87] This finding should be noted as it emphasizes the importance of controlling for gender within study designs. The method and timing of cortisol measurements vary significantly between studies using blood plasma or hair samples. Most samples were taken on admission, with two studies taking further samples for a week after admission.[89],[90] One study took samples on days 1 and 4, while another took samples over the course of a year.[21],[88] Several cognitive assessments were utilized in the studies listed in [Table 4]. These included Mini-Mental State Examinations, Photo-memory test, Pfeiffer mental status score, Montreal cognitive assessment, and NeuroTrax computerized cognitive testing.[87] Most studies completed testing upon admission and after a follow-up period; however, there is a notable absence of extensive long-term studies. The longest follow-up period was conducted by Ben Assayag et al., who completed cognitive testing at 6 months, 12 months, and 24 months' poststroke.[1]
| Conclusion | | |
This review has shown a correlation between cognitive function and cortisol levels. These associations suggest that stroke sufferers with higher cortisol levels are at a greater risk of cognitive impairment. Due to a number of potential confounding factors, such as stroke severity, further evidence is needed to confirm whether cortisol is a significant cause of neuronal damage or a secondary consequence of stroke. Overall, priorities for further research identified include (i) more detailed examinations over time of cortisol levels and cognitive assessment following stroke, (ii) studies specifically examining whether hypercortisolism is a primary cause of neuronal damage or a secondary marker of stroke severity, and (iii) further studies examining the underlying biological mechanisms involved. Understanding the biological mechanism behind the cognitive decline that follows stroke may provide new strategies for the clinical treatment of PSD[95].
Ethical statement
The ethical statement is not applicable for this article. This is a review article.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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