Dr. Damian Sendler in Addison's Disease, Sleep, Cognition, and Cortisol All Play a Role
Damian Sendler: When it comes to our health and well-being, sleep is an essential part of the equation. Cortisol levels have been implicated as a mediator in the link between sleep disruption and memory loss, according to recent research in the field of neuroscience. Glucocorticoid replacement therapy for Addison's disease (AD) causes patients to experience periods of sub- and supra-physiological cortisol concentrations, disrupting sleep and impairing memory. Because replacement regimens fail to restore a normal circadian rhythm of cortisol secretion, these disruptions and impairments could be related. Available evidence supports theoretical frameworks that suggest sleep disruption is a key biological mechanism underlying the memory loss that many Alzheimer's disease (AD) patients experience, as well as other neuroendocrine, neurological, and psychiatric disorders. Future efforts should focus on improving patients' cognitive performance (as well as their overall quality of life) by prioritizing and optimizing sleep, in light of the research linking sleep disruption and cognitive impairment in Alzheimer's disease. Cortisol concentrations have been shown to play a significant role in the relationship between sleep and cognition in patients with Alzheimer's disease (AD).
Damian Jacob Sendler: We all know that sleep is a vital biological process that is necessary for normal human functioning. However, until recently, there were still some unanswered questions about the functions of sleep, such as whether it is required for anything other than simple physical and mental restoration. Research in neurology suggests that healthy, uninterrupted sleep is essential for the smooth and efficient consolidation of memory traces acquired during waking hours, which is one of the questions being asked. Because of its role in maintaining the integrity of sleep architecture, cortisol appears to play a significant role in mediating the relationship between sleep and memory (1, 2).
Dr. Sendler: Lifelong glucocorticoid replacement therapy is necessary for patients with Addison's disease (AD). A replacement medication, on the other hand, does not restore the circadian rhythmic release of cortisol and patients continue to have elevated levels of sub/supraphysiological cortisol despite strict adherence to the regimen. Both poor-quality sleep and cognitive difficulties are reported by patients with Alzheimer's disease (AD). There is a possibility that the periods of sub- and supra-physiological cortisol concentrations experienced by these patients may have a specific negative impact on processes of sleep-dependent memory consolidation, but this is still an unexplored possibility.
Cortisol concentrations, sleep disturbance, and cognitive functioning in patients with Alzheimer's disease (AD) are examined in this review. Despite mounting evidence that sleep is an essential biological process with benefits that go far beyond simple physical and mental recovery, only a small number of studies have examined whether sleep disruptions are a contributing factor to the memory deficits that patients with Alzheimer's disease experience.
When we sleep, we experience a reduction in our ability to respond to external stimuli as well as a temporary loss of consciousness. Homeostatic, circadian, and ultradian processes all play a role in regulating sleep, each with a specific role in determining its timing and structure (9, 10).
There are four to six cycles of rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, with each cycle lasting approximately 90–120 120 minutes. Certain aspects of human sleep patterns can be predicted with reasonable accuracy. Electroencephalogram (EEG) findings show that sleep onset is marked by rhythmic alpha waves, particularly in the occipital regions (EEG). NREM (Stages 1-4 (N1-N4)) sleep follows before the first episode of rapid eye movement (REM). Stage 1 (N1), which lasts between 1 and 7 minutes after the onset of sleep, is the most common stage of the first sleep cycle. K-complexes indicate the onset of stage 2 (N2), which can last anywhere from 10 to 25 minutes. SWS begins as N2 progresses and high-voltage slow-waves appear. Stage 3 (N3) of SWS lasts only a few minutes, while Stage 4 (N4) lasts anywhere from 20 to 40 minutes. N1-N3 stages of sleep may be entered for approximately 5 minutes before a REM episode begins. The duration of this episode ranges from one to five minutes. As the night wears on, the REM and NREM sleep cycles alternate cyclically, with REM cycles getting longer and slow-wave sleep (SWS) getting shorter. During the latter stages of the night, a small number of people wake up for a brief period of time (13).
The 24-hour circadian rhythmicity interacts with the sleep-wake cycle to cause daily oscillations in the release of nearly all hormones (9, 14–16). The suprachiasmatic nucleus (SCN) hypothalamus, light, and ultradian rhythms generate circadian rhythms (17, 18). In order to anticipate and respond to changes in our environment, the SCN has an internal master clock (19, 20). The master clock of the SCN keeps these oscillators in time with one another (21). An endogenous pacemaker generates 24-hour rhythms, and output pathways project to other brain regions and peripheral organs, all of which are part of the circadian clock's timing mechanism. The SCN contains all three of these components, making up the circadian clock's timing mechanism (9). It is the circadian clock that regulates temperature, melatonin and cortisol production, as well as other physiological processes such as sleep and wakefulness (22). Circadian oscillators can also be found in the liver, lungs, heart, and adrenal glands, as well as in the brain. The master clock keeps these oscillators in sync (21). An important role in the body's homeostatic processes is played by the hypothalamic-pituitary-adrenal (HPA) axis, which also helps regulate sleep and coordinate the body's response to stress. Various hormones are controlled by the HPA-axis, but the release of cortisol is of particular interest to this review.
The diurnal secretory pattern of cortisol is well-defined in healthy individuals. In the early morning hours, the concentrations are at their highest, peaking just after waking. For most people, the daily nadir occurs about three hours after the beginning of nocturnal sleep, and concentrations gradually decrease throughout the day. Between 22:00 and 03:00, concentrations rise and remain elevated until the time of waking. The rise in cortisol during the night is thought to be due to the brain's increased energy needs as the night draws to a close (23–26). daily rhythm of cortisol, corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) all peak in the morning and fall to their lowest point at around midnight (12, 25, 27). When light and growth hormone (GH) levels are at their highest in the early stages of sleep, the pineal gland releases melatonin, which is thought to be linked to the HPA and hypothalamo-pituitary-somatotrophic (HPS) systems (21).
For example, the circadian rhythmicity of specific hormones (such as melatonin and cortisol) plays an important role in sleep timing (28, 31–33), as well as distributing sleep stages throughout the night. Attenuated cortisol activity in the first half of the night is caused by inhibitory HPA-axis actions, particularly during SWS. The HPA-axis is in a resting state during the first half of the night, when sleep-wake cycles (SWS) are at their peak. As soon as SWS begins, cortisol concentrations fall rapidly, and this inverse relationship persists throughout the duration of the sleep cycle (15, 24, 34–37). In the early stages of sleep, optimal levels of cortisol can increase SWS through feedback inhibition of CRH (28, 33). Regulatory mechanisms are reduced in the second half of the night and HPA secretory activity gradually increases (15, 38). Activity in the sympathetic nervous system (SNS) increases as the night progresses. In the final phase of sleep, cortisol rises in tandem with an increase in REM sleep (39). To summarize, while cortisol concentrations and sympathetic tone decrease as sleep depth increases during SWS, high levels of autonomic and cortisol activity occur during REM cycles (25, 33).
Growth hormone releasing hormone (GHRH) and CRH play an important role in the regulation of sleep, as do their reciprocal relationships. In the early stages of sleep, GHRH suppresses HPA-axis activity, stimulating NREM and thus aiding sleep, whereas CRH suppresses SWS, heightens vigilance and REM, and thereby disrupts sleep (27, 40, 41). In other words, this pattern suggests a connection between the HPS and HPA systems, as well as sleep architecture, and the hormones they secrete. GHRH's sleep-promoting role and CRH's sleep-disrupting effect have been confirmed in older adults, while in both older adults and depressed younger adults, increased CRH levels contribute to the sleep disruptions that are typically observed in both groups (27, 42).
Finally, the sleep-regulating hormones ACTH and melatonin play a role. Cortisol secretion occurs primarily as a result of ACTH acting as a primary inducer of sleep (29, 35). When it comes to melatonin production, the light-dark cycle has a significant impact. Melatonin production is at its highest during sleep periods (43). Melatonin, on the other hand, can induce sleep even if the body's homeostatic drive to sleep is weak. To treat insomnia and circadian rhythm disorders, melatonin administration has been used because it can prevent the desire to wake up and shift the circadian clock so that sleep occurs at a desired time (44).
Cortisol secretion appears to be influenced directly by quality of sleep. To put it another way, the onset of sleep is linked to a reduction in cortisol production in the body. After the onset of sleep, these effects last for 1–2 hours (34, 45). Cortisol levels rise when a person wakes up or is woken up from a deep sleep (29, 46). The release of cortisol and subsequent inhibition of cortisol secretion occur during nocturnal awakenings (34, 40, 46).
ACTH and cortisol levels rise rapidly during arousals, whether they occur in the middle of the night or at the end of the day. An hour after awakening, the cortisol awakening response (CAR) causes a 50–60 percent increase in cortisol secretion (47–50), which lasts for an hour and peaks 30 minutes after awakening. The physiological expectation that sleep will come to an end at a certain time, or the anticipation of the stress of waking, may trigger the release of ACTH and cortisol during late sleep, according to some research (51–53).
HPA-axis activation and the disruption of the normal circadian pattern of cortisol secretion are all caused by abrupt changes in the sleep-wake cycle, such as napping during the day or jet lag and shift work (34, 54–59).
Poor sleep quality is associated with an increase in basal cortisol levels, even if it is only perceived. Sleep disturbances are worsened by such stimuli, which increase arousal while also decreasing tiredness (as shown by empirical studies such as those in references 16–24–60–61).
A number of studies have found that sleep deprivation causes elevated cortisol concentrations throughout the following day and night (33, 59, 62–66). According to some researchers, this physiological pattern can be explained by the activation of the HPA axis during sleep deprivation, as well as a decrease in the negative feedback regulation of the HPA axis during this period. After that, being awake for an extended period of time increases sleep pressure (the increased need to sleep after periods of being awake), causes fatigue and sleepiness, and blunts HPA-axis activity (34).
The circadian rhythm of the HPA-axis hormones, however, is not the only thing disrupted by sleep deprivation. Disrupted sleep negatively impacts health, quality of life, mood and cognition, which is not surprising given the importance of sleep in physiological repair, emotional regulation and memory encoding processes.
Memory is based on three main processes: encoding, consolidation, and retrieval. Encoding involves the conversion of new information into a form that can be stored in the brain (68, 69). The consolidation of memories is one of the most important effects of sleep on cognition (70–72). consolidating memories involves strengthening the memory tracks that store information about past experiences and connecting those memories to previously acquired facts and understandings (69, 73).
It is possible to record and retrieve memories of environmental events during waking hours, but memory consolidation is incompatible with awake consciousness because it involves reconstructing previously acquired information (1). Memory consolidation is most likely to occur when the organism is effectively unconscious for several hours while sleeping. We have come to accept that the most important role played by sleep is the consolidation of memories encoded while we are awake and the subsequent transfer of those memories into long-term memory storage (1, 74). Reactivation of information encoded while awake and transformation of newly acquired unstable memories into stable representations appear to be the two main components in sleep-dependent memory consolidation, as shown in Figure 2. This appears to lead to the formation of long-term memories. This means that new memories are transferred from temporary to long-term stores while the organism is "off-line" during sleep, when there isn't the same kind of interference as when you're awake (75, 76). It's still up in the air as to exactly how these steps are carried out, and which neural regions and neurobiological processes are necessary to support them.
In order to perform at their best, people need to have enough cortisol in their bodies. For declarative memory consolidation, as well as for new information acquisition, the prefrontal cortex (PFC) is critical (97–105), while the hippocampus (HC) plays a similar role in sensory integration, evaluation of environmental cues, and processing of previously encoded information (106–110). Glucocorticoid receptors (111) in both structures are highly concentrated, so any changes in cortisol secretion have a significant impact on their functioning. Cortisol concentrations have been shown to have a negative impact on memory and executive functioning tasks involving the hippocampal and PFC systems. (94, 112–120) This includes word list and paragraph recall tasks, as well as tests assessing set-shifting, attention, abstract thinking, cognitive flexibility, and mental rotation.
Chronically elevated glucocorticoids have been shown to impair hippocampal-dependent memory in numerous studies (130–134).
1. Stress induction procedures (127, 139, 141–143) and studies using exogenous corticosteroids (126–148) have shown that elevated cortisol has a negative impact on verbal declarative memory performance when the hormone is elevated in the body. Kirschbaum et al. (94) found that increased cortisol levels, as well as the oral administration of hydrocortisone, resulted in a decrease in verbal memory retention. The same dose of cortisone acetate (25mg) significantly impaired both free and cued recall of verbal material, while leaving recognition memory (which is not dependent on hippocampal substrates) unaffected, and that the same dose of cortisone acetate impaired cued recall for a series of word pairs (149, 150). There was a decrease in blood flow to the medial temporal lobe (MTL), which includes the hippocampus in that study, when cortisone acetate was administered at stress levels. Increased cortisol levels in humans have been linked to decreased performance on spatial memory and navigation tasks in several research studies (94–146). However, studies on the effects of cortisol on spatial memory in animals are more prevalent. Cortisol has been shown to impair verbal memory in the presence of high levels of cortisol, but human studies investigating spatial memory and cortisol have produced more variable results.
Cortisol increases impair hippocampal-dependent memory, but non-hippocampal memory (e.g. procedural memory) appears unaffected (e.g., 117, 163, 164). According to Kirschbaum and colleagues (94), oral administration of cortisol to healthy subjects impaired performance on a declarative (word list) memory task, but not a procedural one (word priming test). The verbal declarative memory appears unaffected by elevated levels of cortisol, while the nonverbal memory appears unaffected (165, 166). When given oral cortisol for four days, young adults performed worse on a paragraph recall task, but not as poorly on tasks requiring them to remember geometric line drawings or to locate objects in space, according to Newcomer and colleagues (146).
For declarative memories, the PFC plays an important role in the encoding and retrieval of this brain structure's involvement in memory processing (167). It is only after retrieval that the PFC can determine if an event took place in a specific location (168,169), allowing for accurate memories to be created Working memory is facilitated by the PFC (WM). Humans can use it to control their attention, suppress inappropriate responses, and keep a mental "sketch" of important information safe from both internal and external distractions. Consequently, the PFC facilitates cognitive flexibility and goal-oriented behavior (121, 122).
Dendritic atrophy in the PFC (170) is caused by chronically elevated cortisol concentrations, which also strengthens the noradrenalin system, reducing neuronal firing within the structure (122, 171). Dopaminergic activity and glutamate levels in the prefrontal cortex are both elevated when cortisol levels rise in response to stress (129, 172). The PFC's glutamate receptor-mediated synaptic transmission is crucial for WM (173, 174). Acute glutamate elevations benefit WM (129), but excessive elevations impair WM function. Noradrenaline, dopamine, and glutamate all have an inverted-U effect on WM, with too little or too much impairing the proper operation of the PFC in either case (122).
Damian Jacob Markiewicz Sendler: Alzheimer's disease (AD) is diagnosed based on the presence of low plasma cortisol levels, low aldosterone levels, and high renin levels. AD patients must receive glucocorticoid replacement therapy (GC) for the rest of their lives if they are to live (205). In most cases, cortisol is replaced with oral hydrocortisone, prednisone, or cortisone acetate (all of which activate primarily GRs, predominantly), as well as a mineralocorticoid (fludrocortione) for sodium and potassium regulation (206, 207). With regard to cortisol and circadian rhythmicity, medication regimens used by patients may affect their general well-being and sleep patterns due to GCs on circadian rhythmicity. (24, 25) Figure 3 shows an example of a typical GC replacement schedule, which calls for two daily dose replacements, for a daily dosage of 15-30mg. Morning: The highest dose (half to two-thirds) is taken, afternoon: a reduced dose is taken, and (if necessary) a third dose in the late afternoon/evening [typically around 5pm; (208–210)] Imitating the normal diurnal cortisol rhythm, this schedule is designed to reflect the peak of cortisol secretion at dawn and to avoid over-replacement in the nadir at night (208, 211). In spite of efforts to find the best replacement regimen in terms of dosage and timing (211–213), there are still supra-physiological peaks during the day and lower concentrations in the early hours of the morning. The biochemical properties of replacement medications are to blame for this over- and under-replacement. To achieve maximum levels one hour after intake, oral hydrocortisone (HC) is rapidly absorbed (220). To compensate for its relatively short plasma half-life, HC replacement results in highly variable peak concentrations within a supra-physiological range, which are quickly followed by rapid declines to less than 100 nmol/l at 5-7 hours after ingestion (221). (around 1.5-1.8 hours; 215, 222). In other words, patients will need to take their medication on a regular basis, but they will still suffer from cortisol deficiency, especially overnight and in the early morning (223). Additionally, GC-replacement therapy does not adequately mimic the rise in cortisol levels that healthy people experience in the morning. If you're healthy, your body's cortisol levels naturally peak during REM sleep around the time that you wake up, whereas when you take hydrocortisone in the morning, your levels peak a few hours later (206). Patients with AD may experience symptoms such as fatigue, nausea, and headaches in the early morning, which subside within an hour of taking their morning dose of hydrocortisone (224). Traditional hormone replacement therapy does not restore the normal circadian rhythm of hormone production (215, 225). Over-replacement occurs immediately following therapeutic administration, and then under-replacement occurs within a few hours, which may have important implications for sleep regulation.
Cortisol rhythms are being mimicked in newer treatments because standard replacement therapy doesn't. It is hoped that these new treatments will improve biochemical control over the release of cortisol and reduce the long-term adverse effects typically associated with standard replacement regimens (220). It's possible to treat opioid addiction with both continuous subcutaneous HC infusion and modified release HC (MR-HC).
It's been shown that giving HC to AD patients improves their quality of life by simulating the circadian rhythms of healthy people (QoL; 226, 227). CSHI was found to normalize morning cortisol and ACTH levels in patients with Alzheimer's disease, and patients' 24-hour cortisol curves approached normal circadian variation when compared to conventional oral replacement in a crossover randomized clinical trial (N = 33 AD patients treated with CSHI or thrice-daily conventional therapy for three months). Oral replacement therapy had a higher AUC during the day (8 a.m.-midnight) and CSHI had a higher AUC at night (midnight-8 a.m.), but the AUC over a 24-hour period did not differ between infusion and conventional oral therapy. Despite the fact that the Pittsburgh Sleep Quality Index (PSQI) and actigraphy showed an increase in sleep length, the infusion did not improve sleep (228). In another clinical trial (N = 10 patients with Alzheimer's disease), researchers compared CSHI to standard GC therapy to see if it improved quality of life (QoL) and fatigue (fatigue) (229). In AD patients with mild well-being deficits, CSHI did not improve health status. Some patients appear to benefit from CSHI in that it restores normal circadian cortisol rhythms and improves their quality of life (226).
The impracticality of subcutaneous infusions is a major drawback of this method. Patients who use HC can also take their medication at 3am in the morning by waking up and taking it then. Additionally, this alternative may cause more daytime fatigue as well as supra-physiological peak levels of exhaustion. Cortisol circadian rhythms can be normalized using MR-HC because of its immediate and long-lasting hormone release characteristics. The natural circadian rhythm of cortisol in the body can be mimicked by MR-HC (230, 231). The circadian rhythms of cortisol, with the exception of the early morning cortisol peak, were more closely mimicked by taking a single morning dose of either 5 or 20mg MR-HC, according to Johannsson and colleagues (231). The rise in cortisol that occurs in the early hours of the morning can be mimicked if MR-HC is taken late at night (which allows for a delayed and sustained release). For instance, Debono et al. (230) demonstrated that healthy controls were able to mimic the circadian rhythm of physiological cortisol by taking 15-20mg of MR-HC at 23h00 and 10mg at 07h00 (see Figure 4). Cortisol levels peaked in this study's participants on average at 08h32 and fell steadily throughout the day, settling at a low point of 00h18 on average. Plenadren (DR-HC; Plenadren) is a hydrocortisone with both an immediate and an extended release coating. Improves patients' quality of life (232–234) by better mimicking the normal cortisol profile (218). Dr-HC has shown to have little effect on cognitive functioning or sleep despite normalizing cortisol patterns (235). In spite of the fact that Krekeler and colleagues (235) found that patients with adrenal insufficiency treated with DR-HC had better executive functioning than those on conventional HC, other cognitive domains appeared unaffected, and they found no between-group differences in sleep quality.
Numerous studies show that clinically relevant fatigue persists despite replacement therapy in patients with AD, according to the findings of these studies. While receiving cortisone and fludrocortisone, patients with Alzheimer's disease (AD) had a decreased sense of well-being and vitality, according to Lvás and colleagues. Like van der Valk and colleagues (237), who found that 48% of their patient sample (N = 328) self-reported abnormal fatigue and 61% reported severe fatigue, we found similar results. Patients with Alzheimer's disease (AD) are more likely to report feeling fatigued during the day, and researchers believe this may be due to a decreased quality of sleep, as well as higher doses of HC.
Damien Sendler: Polysomnography data on the impact of low cortisol concentrations on sleep architecture is sparse in terms of objectively measured quality. Similarly, only a few studies have examined the effects of conventional replacement medication on sleep in patients with AD. A study by Gillin et al. (239) found that patients with AD whose replacement medication was withheld for more than 24 hours (and thus had undetectable levels of cortisol at bedtime) showed an increase in SWS and a decrease in REM sleep time when the medication was taken away. According to Garcia-Borreguero et al. (238), patients with AD who were denied glucocorticoid medication 1.5 hours prior to bedtime (and who, as a result, had undetectable cortisol levels at bedtime) showed increased WASO and REM latency and decreased time spent in REM sleep, in comparison to patients who took their medication just before bedtime. This was in contrast to patients who took their medication just before bedtime. These findings suggest that cortisol helps initiate and maintain REM sleep. There is evidence that high cortisol concentrations reduce the amount of time spent in SWS and that lower cortisol concentrations in healthy controls (metyrapone administration) and patients with AD (replacement medication withheld) are associated with increased delta sleep time (27, 35, 241). (239).
Damian Sendler
Patients with AD slept similarly to controls when medication was administered via conventional replacement, but it took them significantly longer to fall asleep and they spent significantly more time in delta sleep, as reported by Gillin et al. (239). (i.e., SWS). For the first time, patients with AD (compared to healthy matched controls) spent less time in SWS when medication was administered by conventional replacement, according to Henry and colleagues (4). Patients also had significantly shorter REM latency and more time in Stage 2 sleep when medication was administered by conventional replacement.
The lack of objective assessments of sleep in patients with Alzheimer's disease (AD) is surprising, given the abundance of scientific evidence suggesting that these patients are at risk of experiencing negative effects on their sleep architecture due to the disruptions in their cortisol circadian rhythms. Depression and PTSD patients, for example, have shorter SWS times, shorter REM latency times, higher REM sleep densities, and sleep discontinuity due to elevated cortisol levels (238, 241–244). Additionally, in Cushing's disease patients, findings show that SWS is decreased, REM latency is shortened, and there are abnormalities in the sleep continuum due to excessive cortisol production (244, 245). According to one study, elevated cortisol levels in 11 Cushing's disease patients were linked to decreased REM activity and more sleep awakenings (245). Hydrocortisone-treated AD patients and healthy controls with artificially elevated cortisol levels showed similar patterns of reduced REM latency and/or increased REM sleep duration (41, 238). Sub-physiological cortisol levels and sleep are rarely studied in patients with Alzheimer's disease who are taking replacement medication as part of their routine treatment. As a result, little is known about the impact of the disease and treatment on sleep quality and architecture in people with Alzheimer's disease.
As cortisol plays a critical role in regulating sleep, patients with AD may experience sleep disturbances if their nighttime cortisol levels are low or high (28, 35). (228). Despite this, there isn't enough research on the effects of altered circadian cortisol patterns and the resulting disruption of sleep that has been done. Disrupted sleep, for example, may hinder the consolidation of sleep-dependent memories. Corticosteroid use has been linked to changes in sleep and memory, so more research is needed to determine the impact of replacement medication on the processes that influence sleep-dependent memory consolidation in patients with AD.
Alzheimer's disease patients frequently exhibit both subjective and objective cognitive impairments, such as poor memory and inability to concentrate, despite the use of replacement therapy (206, 207, 221). Understanding how memory, attention, and executive functioning are affected by changes in cortisol concentrations is important in patients with Alzheimer's disease (115, 146, 246). Very few studies, however, have looked at how Alzheimer's disease impacts cognitive function.
Klement et al. (247) found that patients with AD on replacement therapy performed significantly worse on a declarative memory test than healthy controls. A test of verbal learning by Schultebraucks and colleagues (185) found that patients outperformed control subjects significantly more poorly than did a test of verbal learning and memory by Henry and colleagues (6). (and that patients made significantly more false alarms [incorrectly saying a word on the list when it was not present] when recalling information). In two different declarative memory tasks, Henry et al. (5) found that healthy controls learned and retained more information than patients with AD, but no significant differences between groups were found for procedural memory tasks. Tiemensma and colleagues (248) discovered that patients' verbal and visual memory scores were significantly lower than those of healthy controls on memory tests. In the second study, researchers discovered mild executive dysfunction and noticeably slower processing speeds in the patient group. Cortisol concentrations were significantly lower in another group of patients with Alzheimer's disease who delayed HC intake, but cognitive performance was not affected. Also, patients who had AD for a longer period had a slower speed of processing and those diagnosed later in life had poorer declarative and working memory as well as a slower speed of processing and an overall greater cognitive impairment, according to Henry et al. (6)'s research. Patients with AD (20 PAI and 20 SAI) performed significantly worse than controls on an attention test, according to Blacha et al. (249). (but found no difference in memory and other cognitive domains). High doses of HC reduced attention, visuo-motor skills, and executive function; however, they found no effect on cognitive performance from the length of therapy. Similarly, Harbeck et al. (223) discovered that patients who received a short-term hydrocortisone infusion at night had lower short-term memory scores when their cortisol levels were elevated. Deteriorations in declarative memory (verbal and visual) appear to be the most common cognitive deficits in patients with Alzheimer's disease (including attention and processing speed).
There are likely two main causes of a person's declarative memory performance being impaired. Sleep disturbances are directly linked to a disruption in cortisol secretion patterns. Second, as a direct result of the elevated levels of cortisol that patients on short-acting hydrocortisone experience (250). In areas of the brain with a high concentration of glucocorticoid receptors, such as the hippocampus and the PFC, supra-physiological glucocorticoid has a greater impact (105, 251). Degeneration of hippocampal neurons (252), altered organization of PFC dendrites (253), and impaired performance on tasks requiring declarative memory are just a few of the side effects (121, 254). These findings are supported by research showing a correlation between increased cortisol concentrations in the elderly population and changes in the brain's hippocampus volume (154, 252, 253, 255–257). Increasing cortisol levels in healthy subjects by giving hydrocortisone exogenously (once or twice a day for a few days) impairs verbal memory, working memory, spatial memory, and executive function (96, 146, 150, 191, 258, 259). Dexamethasone and prednisone administered exogenously to healthy individuals also impair memory (117, 191, 259, 260). Chronically elevated hydrocortisone levels have been linked to the death of hippocampus dendrites, reduced glucose uptake in the hippocampus, impaired synaptic plasticity (262, 264), and a decreased number of newly generated neurons in the hippocampus (252).
Damian Jacob Sendler
Differential activation of MRs and GRs, as discussed earlier, may explain the memory deficits observed in patients with Alzheimer's disease (AD). Glucocorticoids interact with MRs and GRs to mediate the effects of cortisol on the hippocampus and prefrontal cortex (134). Encoding requires the activation of MRs, while memory consolidation and retrieval require the activation of GRs (94, 135). For optimal memory performance, both receptors must be activated (135). Using a declarative memory recall task, Tytherleigh et al. (207) found that AD patients who had been adequately treated performed significantly better when both receptor types were activated, compared to when only one or the other was activated. It is true that a small amount of cortisol is required to improve cognition (a shift towards greater MR activation and less GR activation), but prolonged exposure and/or high concentrations of cortisol (a shift toward greater GR activation) have detrimental effects (135, 265–267). Schultebraucks et al. (185) used a repeated-measures crossover design and either administered patients with AD fludrocortisone (resulting in a high MR occupation) or withheld the same drug from them (resulting in low MR occupation). Executive function and verbal memory were both improved when MR occupation was high. This was particularly true of the former.
The effects of elevated cortisol levels on cognitive functioning are predictable and can be explained neurobiologically, according to previous research (105, 142, 166, 252). Because hydrocortisone has such a short half-life (about 1.5 hours), cortisol concentrations fluctuate a lot in AD patients — sometimes rising well above basal levels (e.g., after hydrocortisone administration) or falling (e.g., after hydrocortisone administration; (223)). Cortisol concentration variability in patients with AD may play an important role in their cognitive functioning because the relationship between cognition and GCs usually follows an inverted-U shape pattern. It's also important to understand how other factors (like sleep disruption) may contribute to patients with Alzheimer's disease (AD) having poor memory performance because of the correlation between low cortisol and poor performance on standardized memory tests, as well as the correlation between low cortisol and sleep disruption.
Memory consolidation is greatly aided by a smooth transition from rapid eye movement (REM) sleep to slow wave sleep (SWS) (1). When certain physiological conditions (such as slow oscillations in neocortical networks and suppression of the HPA axis) allow the reactivation of memories encoded while awake, consolidation begins during slow wave sleep (268). Long-term potentiation of memories is facilitated during REM sleep by physiological conditions (such as norepinephrine suppression, increased levels of acetylcholine and serotonin, and theta waves) that allow reactivated memories to be integrated with preexisting knowledge (269). The role of cortisol in healthy sleep is explained by the fact that it plays an important role in the initiation and maintenance of sleep stages (68). Although a well-known link exists between a good night's sleep and good memory (270), only a few studies have looked at this link in patients with Alzheimer's disease.
Data from self-reported questionnaires by Henry and colleagues (7) suggests that memory impairment in Alzheimer's disease may be mediated by sleep disturbances. Adrenal function and objectively measured sleep and cognitive performance were studied by Henry et al. (5). Patients with Alzheimer's disease did not benefit from periods of sleep rather than wakefulness when it came to declarative memory retention, however, healthy controls did. Research has shown that a full night of uninterrupted sleep improves memory, and these findings are consistent with this. Patients with Alzheimer's disease (AD) may not have been able to successfully consolidate their memories because their circadian rhythms are out of whack. Some people with Alzheimer's disease (AD) have a general feeling of exhaustion, and therefore their performance suffers regardless of whether or not they get enough sleep. There were no considerations for the fact that patients with Alzheimer's disease may suffer from general fatigue, which could result in poor performance in this study. Another finding from this research was that patients performed better on a story recall test when learning and recall were separated by a period of wake rather than wake (counterintuitive to the body of literature that sleep is an offline process beneficial for the consolidation of learned information). AD patients may not be getting enough sleep to properly consolidate what they've learned, according to this study. On a test of procedural memory, no significant differences between groups (AD versus controls) or conditions (Sleep versus Wake) were found, in contrast to the patterns of data on declarative memory tests. Due to the fact that declarative memory tasks require the use of the hippocampus, whereas procedural memory tasks do not, these findings may have come to light. This suggests that patients with AD have normal procedural memory, since hydrocortisone has no effect on hippocampal integrity, but it does have an effect on areas associated with response-based sequence learning (e.g., the motor cortex, the caudate nucleus). Procedural memory has never been studied in patients with Alzheimer's disease, so this finding that it is not impaired in AD patients is a new one.
Patients with Alzheimer's disease (AD) are known to suffer from cognitive impairments, particularly in the areas of declarative memory (verbal and visual) and executive functioning (specifically, attention and processing speed). These patients appear to have normal procedural memory (although very few studies have investigated this). As a result, they sleep less soundly and their slumber patterns are altered. Sleep deprivation, which reduces the ability to retain new information, has been linked to immediate-release hydrocortisone use. In addition, patients with Alzheimer's disease may have cognitive deficits as a result of exhaustion in general. The long-term use of replacement therapy may also have detrimental effects on the brain's ability to perform at its best (e.g., the hippocampus and PFC). Brain scans, however, are needed to confirm this theory.
Only a few studies have used objective measures to evaluate the patients' sleep patterns or memory impairments, despite the fact that prior research suggests that patients with AD frequently report both cognitive and sleep complaints. As a result of inadequate cortisol replacement therapy, patients with Alzheimer's disease (AD) experience sleep disruptions and cognitive impairments. Patients with Alzheimer's disease may benefit from these treatment modalities if the pharmacokinetics of replacement therapy are tweaked. AD patients provide an excellent opportunity to study the effects of hyper- and hypocortisolism on sleep quality, memory performance and sleep-dependent memory consolidation simultaneously from a broader neuroscientific perspective. If these patients are carefully studied, we may be able to learn more about the distinct roles that sub- and supra-physiological GC concentrations play in the regulation and structure of sleep and in the consolidation of sleep-dependent memory..
Sub- and supra-physiological cortisol concentrations have been observed even though current replacement therapy aims to mimic the natural circadian rhythm. Low and high levels of cortisol are both detrimental to mental and physical health. Cortisol levels, sleep patterns, and cognition are all affected by the dosage, duration, and type of GC therapy used in patients with Alzheimer's disease (AD).
Cortisol concentrations, sleep, and cognitive performance can all be affected by a variety of factors, including food and caffeine intake, smoking, intense exercise, and stressful situations (287). It is important to keep these potential confounding factors in mind when conducting studies on sleep and cognition in AD. In patients with Alzheimer's disease, nocturnal hypoglycemia and adrenal crises could have a significant impact on cognition and sleep (288). However, few studies have taken this into account when examining the relationship between sleep and cognition. It is critical to distinguish between impairments caused by the illness itself, the complications that accompany it, or the therapy that patients receive.
Using objective measures, more research is needed to examine the hypothesis that poor sleep is a biological mechanism underpinning memory impairment in patients with Alzheimer's disease (AD). Patients with Alzheimer's disease (AD) need more polysomnographic studies to fully understand their sleep patterns. The results of these studies could help explain why patients' memory consolidation is not enhanced by sleep as it is in healthy individuals. In clinical trials and intervention studies, modified-release or dual-release hydrocortisone could be used to confirm this association and investigate whether the same pattern of sleep and memory deficits are present in patients. For patients with AD, if it is established that disrupted sleep is a primary mechanism for the impaired consolidation of previously learned information, clinicians should prioritise treatment of disrupted sleep in patients.