No morning cortisol response in patients with severe global amnesia

Activity of the hypothalamus pituitary adrenal (HPA) axis is characterized by a pronounced circadian rhythm. An acute increase in cortisol levels occurs after awakening in the morning with continuously declining levels over the course of the remaining day. The morning cortisol increase probably reflects an activational response of the HPA axis aimed at preparing the body for the day. Some studies found patterns of enhanced or blunted waking cortisol responses observed under chronic stress, burnout, or post traumatic stress disorder. The present study wanted to characterize the morning cortisol response and the circadian cortisol day profile in a sample of six male patients with severe amnesia due to hypoxia, herpes simplex encephalitis or closed head injury. Age and gender matched relatives or friends served as controls. Cortisol was measured from saliva samples collected at home on two consecutive days. The patients were woken up in the morning by their partners or caregivers. The morning cortisol increase typically observed in healthy subjects and also observed in the control group was absent in the amnesic patients. In contrast, a normal circadian day profile was found in the amnesic patients, with a pronounced circadian cortisol decrease. Further studies are needed to understand the neurological or psychological mechanisms leading to a missing morning cortisol response in amnesic patients.     

Awakening cortisol responses are influenced by health status and awakening time but not by menstrual cycle phase

Recent evidence suggested that the free cortisol response to awakening is influenced by awakening time in healthy younger adults (Edwards et al., 2001). In order to investigate this association further, 179 community-dwelling subjects of a large age range (4-75 yrs) participated in the present study. The sample consisted of 99 women, 67 men and 13 children. Subjects were instructed to obtain saliva samples directly after awakening as well as 15, 30, 45, and 60 minutes thereafter. A first analysis revealed that salivary cortisol profiles after awakening in healthy subjects differed from profiles in subjects who reported health problems or a chronic disease (p = 0.02) with healthy subjects showing a larger cortisol response. Therefore, only healthy subjects were included in the following analyses. Subjects woke up between 0455 and 1203 h. Time of awakening strongly influenced the course of morning cortisol levels. Cortisol profiles differed significantly between two wake-up groups (p<0.001). Similarly, group differences for cortisol increase (p = 0.03) and area under the curve (p = 0.05) were also significant, with more pronounced responses in early awakeners compared to late awakeners. The findings are discussed with respect to the circadian cortisol rhythm and the effects of light exposure. Age was correlated with the cortisol levels immediately after awakening (r = 0.2, p = 0.04), the area under the cortisol curve ( r = -0.20, p = 0.05), and with time of awakening (r = -0.21, p = 0.04), respectively. No differences were found between males and females, or between profiles obtained during the follicular or luteal menstrual cycle phase. Also, no differences were observed between habitual smokers vs. non-smokers. These data suggest that the morning cortisol response is influenced by the awakening time but not by menstrual cycle phase. Moreover, health status and age appear to have an impact on this marker of adrenocortical activity. Wake-up time, health status and age should therefore be controlled for in future studies measuring cortisol responses to awakening.     

Is the cortisol awakening rise a response to awakening?

A distinct rise in cortisol levels that occurs after morning awakening is increasingly used as an indicator of adrenocortical activity which is associated with different pathologies. Although it was previously assumed that the transition from sleep to wake is essential for the occurrence of the cortisol morning rise, this has never been tested. Here, we examined 16 healthy young men (20-33 yrs) between 2300 and 0800 h under sleep laboratory conditions. Serum cortisol and plasma adrenocorticotropin (ACTH) as well as salivary cortisol levels (after subjects were woken up at 0700 h) were repeatedly assessed. In a supplementary study condition, salivary cortisol levels in the first hour after awakening were measured at the subjects' home on two consecutive days. Comparison of pre- and post awakening measurements revealed significantly steeper increases in cortisol and ACTH after awakening. The rise in cortisol upon awakening under laboratory conditions did not significantly differ from that observed at home. We conclude that the cortisol increase after awakening is a response to morning awakening that is distinct from the circadian rise in hypothalamo-pituitary-adrenal (HPA) activity in the morning hours. Although the cortisol awakening response is modulated by circadian influences, it primarily reflects phasic psychophysiological processes specific to the sleep-wake transition.     

The morning salivary cortisol response in burnout

OBJECTIVES: The aim of the present study was to examine the free salivary cortisol response to awakening in men and women reporting low, moderate, and high levels of burnout. METHODS: Twenty-two patients on sick leave due to burnout were compared with 22 working participants with low and 20 working participants with intermediate scores on the Shirom-Melamed Burnout Questionnaire (SMBQ), with regard to the free salivary cortisol response to awakening. Saliva samples were collected upon awakening and at +15, +30, and +60 min thereafter. RESULTS: Female burnout patients had higher cortisol levels than did the females with low burnout at awakening and at +15, +30, and +60 min after awakening. They also had a greater area under the curve (AUC) for salivary cortisol than did the female participants with low burnout. Male participants with moderate levels of burnout had higher cortisol levels at +60 min after awakening compared with males with low burnout. CONCLUSIONS: The results of the present study indicate a dysregulation in hypothalamic-pituitary-adrenocortical axis (HPA axis) activity, characterised by elevated morning salivary cortisol levels, among female burnout patients. Among males, increased cortisol levels were observed among participants with moderate levels of burnout, but not among patients or healthy controls.     

Association between cognitive function, behavioral syndromes and two-year clinical outcome in Chinese subjects with late-onset Alzheimer's disease

OBJECTIVE: To examine associations between behavioral and psychological symptoms of dementia (BPSD), cognitive function and clinical deterioration over 2 years. METHODS: One hundred and four Chinese subjects with late-onset Alzheimer's Disease (AD) who presented to psychogeriatric clinics were followed for an average of 22.5 months. BPSD subgroups were categorized by latent class analysis using the Neuropsychiatric Inventory. Comprehensive cognitive profiles were performed with the Mattis Dementia Scale, the Hong Kong List Learning Test (HKLLT) and the Category Verbal Fluency Test. Interactions between cognitive function and behavioral syndromes were evaluated. Potential predictors for clinical deterioration were computed with logistic regression analysis. RESULTS: Three latent classes of subjects with similar behavioral syndromes were identified: Low BPSD (44%), Affective (32%) and Psychosis (24%) groups. Association between cognitive functions and BPSD was not significant. At follow-up, a higher proportion of subjects in the Affective (70%) and Low BPSD (49%) groups remained stable at the same Clinical Dementia Rating. Baseline scores in the "recognition" test of the HKLLT and age were significant predictors for "deceased" status at 2-year follow-up. CONCLUSION: The lack of association between behavioral syndromes and cognitive function suggests that these relatively independent dimensions of dementia should be examined individually for different prognostic significance.     

Salivary cortisol awakening response in mild Alzheimer disease, caregivers, and noncaregivers

Alterations in the hypothalamic-pituitary-adrenal axis have been noted in people with Alzheimer disease (AD) and in the people caring for them. In a case-control study, we assessed whether the cortisol response at awakening and diurnal cortisol would reflect these changes. AD patients, their caregivers, and healthy senior noncaregivers collected saliva within 5 minutes of waking, 30 minutes after waking, before lunch, 1 hour after lunch, and at 11 pm or when getting ready for bed. They also completed a Perceived Stress Scale. Total cortisol for the day after adjusting for antidepressant use revealed a group effect [F(2,39)=12.49, P<0.0001], with mild AD patients and caregivers having higher cortisol values. Unlike the noncaregivers (t=-1.15, df=14, P>0.27), both cortisol values of the AD caregivers (t=-2.96, df=16, P<0.03) and the AD patients' (t=-2.5, df=14, P<0.01) increased between awakening and 30 minutes afterward. There were also group differences at awakening [F(2,48)=4.6, P=0.012] adjusting for antidepressant use and 30 minutes after waking adjusting for antidepressant use and awakening cortisol [F(2,46)=4.7, P=0.014<0.02). AD patients (r=0.45, P=0.08) and caregivers (r=0.44, P=0.10) with higher cortisol values 30 minutes after waking also showed a trend toward higher perceived stress scores. Salivary cortisol and cortisol response on awakening may enhance future studies relating free cortisol to subjective psychologic and physiologic markers.     

Sleep Disturbances and Predictive Factors in Caregivers of Patients with Mild Cognitive Impairment and Dementia

Background and Purpose

We examined the characteristics of sleep disturbances and sleep patterns in the caregivers of patients with amnestic mild cognitive impairment (aMCI) and dementia.

Methods

We prospectively studied 132 patients (60 with aMCI and 72 with dementia) and their caregivers, and 52 noncaregiver controls. All caregivers and controls completed several sleep questionnaires, including the Pittsburgh Sleep Quality Index (PSQI). The patients were administered neuropsychological tests and the neuropsychiatric inventory to evaluate their behavioral and neuropsychiatric symptoms of dementia (BPSD).

Results

The PSQI global score was 6.25±3.88 (mean±SD) for the dementia caregivers and 5.47±3.53 for the aMCI caregivers. The Insomnia Severity Index (ISI) and short form of the Geriatric Depression Scale (GDS-S) predicted higher PSQI global scores in aMCI caregivers, and higher scores for the ISI, Epworth Sleepiness Scale (ESS), and GDS-S in dementia caregivers. BPSD, including not only agitation, depression, and appetite change in dementia patients, but also depression, apathy, and disinhibition in aMCI patients, was related to impaired sleep quality of caregivers, but nighttime behavior was not. Age and gender were not risk factors for disturbed sleep quality.

Conclusions

Dementia and aMCI caregivers exhibit impaired quality of sleep versus non-caregivers. ISI, GDS-S, and ESS scores are strong indicators of poor sleep in dementia caregivers. In addition, some BPSD and parts of the neuropsychological tests may be predictive factors of sleep disturbance in dementia caregivers.     

Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community

BACKGROUND: Despite many studies about the association between caregiver burden and behavioral and psychological symptoms of dementia (BPSD), there have been no population-based studies to evaluate caregiver burden associated with each BPSD. OBJECTIVE: To evaluate caregiver burden associated with the individual BPSD in elderly people living in the community. METHODS: The subjects were 67 participants with dementia living with their caregivers (diagnosed in the third Nakayama study): 51 Alzheimer's disease, 5 vascular dementia and 11 other. The Neuropsychiatric Inventory (NPI) and NPI Caregiver Distress Scale (NPI-D) were used to assess subjects' BPSD and related caregiver distress, respectively. RESULTS: In the subjects exhibiting BPSD, aberrant motor behavior had the highest mean NPI score, and depression/dysphoria had the lowest. Agitation/aggression had the highest mean NPI-D score, and euphoria/elation had the lowest. Delusion, agitation/aggression, apathy/indifference, irritability/lability and aberrant motor behavior showed a correlation between the NPI and NPI-D scores. CONCLUSION: The burden associated with BPSD is different for each symptom and does not always depend on frequency and severity of BPSD. These findings suggest that some symptoms, such as agitation/aggression and irritability/lability, may affect the caregivers significantly, although their frequency and severity are low.     

The relation between early life adversity, cortisol awakening response and diurnal salivary cortisol levels in postpartum women

Early life adversity has been associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in both children and adults. However, in adulthood, most studies have focused on the effects of early adversity on HPA axis stress reactivity rather than the cortisol awakening response or diurnal cortisol profiles. The goal of this study was to examine the cumulative effects of early life adversity on the cortisol awakening response (CAR) and diurnal cortisol profiles in a sample of postpartum women. Ninety women between 2 and 6 months postpartum completed two retrospective reports assessing adverse early life experiences (maltreatment and consistency of care). Eighteen women reported having experienced both parental loss and some form of childhood maltreatment and 36 women reported having experienced one type of early life adversity, either parental loss or maltreatment. HPA axis function was assessed through salivary cortisol collections over two consecutive days for measurement of the cortisol awakening response (n=61) and diurnal cortisol rhythm (n=90). Women who reported experiencing adverse early life experiences exhibited a tendency towards higher levels of awakening cortisol compared to women who reported no adverse early life experiences (p=.07). These higher awakening cortisol levels were sustained throughout the morning in the groups who experienced early adversity, with all groups exhibiting the typical diurnal decline in the afternoon and evening (p<.05). Women reporting early adversity exhibited more heterogeneity in their diurnal cortisol levels across the two collection days (p<.01). Our findings suggest that in a community sample of postpartum women, early adversity is associated with current HPA axis function. These findings may have implications for the nature of mother-infant interactions.     

A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients.

BACKGROUND: Behavioural and psychological symptoms (BPSD) are common during the course of dementia and present severe problems to patients and their caregivers. OBJECTIVES: To assess the therapeutic efficacy and safety of haloperidol and risperidone in treating BPSD in Chinese dementia patients. METHODS: A 12-week double-blind randomised comparison of haloperidol and risperidone treatments was conducted in 58 patients with DSM-IV diagnosis of dementia of Alzheimer's type or vascular dementia. They were randomly assigned to receive flexible doses (0.5 to 2 mg/day) of haloperidol or risperidone. Clinical response was evaluated using the Cohen-Mansfield Agitation Inventory (CMAI), the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), Simpson-Angus Scale, Functional Assessment Staging and Cantonese version of the Mini-Mental State Examination. RESULTS: The mean doses at the last week were 0.90 mg/day of haloperidol and 0.85 mg/day of risperidone. Both haloperidol and risperidone significantly reduced the severity of BPSD (scores on CMAI and BEHAVE-AD), with no significant between-group differences. Haloperidol-treated patients showed a worsening on Simpson-Angus scale while there was no significant change in this measure in risperidone-treated patients. CONCLUSIONS: Low-dose haloperidol and risperidone were well tolerated and associated with reductions in the severity and frequency of behavioural symptoms in subjects with dementia. Risperidone may have a more favourable risk-benefit profile in view of its lower propensity to induce extrapyramidal symptoms.     

Psychiatric morbidity in dementia patients in a neurology-based memory clinic

The behavioral and psychological symptoms of dementia (BPSD) often present major problems for patients and their caregivers. In the past, neurologists paid less attention to such symptoms than to the cognitive symptoms of dementia. This prospective study investigated the prevalence of psychiatric morbidity in a neurology-based memory clinic and the stress of caregivers. Our patients with dementia were found to have a high prevalence of BPSD. The most frequent were anxiety, apathy, and delusion; the most distressing to caregivers were agitation, anxiety, delusion, and sleep disturbance. Using Clinical Dementia Rating (CDR), we compared BPSD between patients with mild dementia and those with moderate dementia. Only hallucinations and agitation were different significantly. Moderate dementia patients experienced these symptoms more frequently. The high prevalence of these symptoms might be explained by the fact that the cognitive symptoms were neglected or no enough information were received by many family members of patients with dementia until their own life quality was interfered and then they began to seek medical help. These symptoms and their effect of caregiver distress can be effectively reduced by pharmacologic and nonpharmacoloic managements, caregiver-focused training and education. They can be better approached by assessing neuropsychiatric symptoms regularly, educating the general population better, and treating these patients earlier.     

Circadian regulation of cortisol after hippocampal damage in humans.

BACKGROUND: There is substantial evidence that the hippocampus (HC) regulates the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Damage to the HC in animals produces a transient alteration in diurnal and stress-related HPA activity. This study was designed to examine the effects of HC damage on basal cortisol secretion in humans. METHODS: Salivary cortisol was measured in 22 patients with HC damage (12 with bilateral damage and 10 with unilateral damage), 7 brain-damaged comparison participants, 10 healthy, age-matched comparison participants, and 6 of the patients' caregivers. Salivary cortisol samples were taken immediately after awakening, 30 min after awakening, at 8:00 am, 11:00 am, 3:00 pm, 6:00 pm, and at bedtime on a single day. Brain-injured patients underwent a structural magnetic resonance imaging scan to examine quantitative volumes of the HC. RESULTS: Both bilateral and unilateral HC damage abolished the cortisol response to awakening documented in the comparison groups. Caregivers of bilateral HC patients showed a reduced response to awakening. The remainder of the circadian pattern was not affected in the HC patients; all groups showed a significant diurnal variation. There was no association between HC volume and cortisol secretion. CONCLUSIONS: Hippocampal damage in humans abolishes the cortisol response to awakening, whereas the remainder of the diurnal cycle is unaffected in these patients. These data suggest a unique role of the HC in the control of basal cortisol secretion.     

The contribution of neuropsychiatric symptoms to the cost of dementia care

OBJECTIVE: To estimate the contribution of behavioral and psychological symptoms of dementia (BPSD) to the costs of care. METHOD: A one-year prospective study of resource utilization recorded monthly by 500 caregivers of community dwelling patients with dementia. The effect of behavior on total, direct and indirect costs of care was examined. RESULTS: The total cost of care was $1,298 per month and there was a significant independent relationship between costs and BPSD. The incremental cost of a one point increase in Neuropsychiatric Inventory score was $30 per month (95% CI: $19-$41). CONCLUSION: BPSD contribute significantly to the overall costs of dementia care. Interventions targeted at BPSD may help to reduce the staggering societal costs of this illness.     

The impact of neuropsychiatric symptoms of dementia on distress in family and professional caregivers in Singapore

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are a source of distress and burden for caregivers. This study attempts to determine the neuropsychiatric symptoms, demographic characteristics, and referral patterns of outpatients with dementia compared with patients admitted to the acute psychogeriatric wards of Woodbridge Hospital. We also assessed the impact of neuropsychiatric symptoms on distress in family and professional caregivers. METHOD: Eighty-five consecutive patients with a first-time diagnosis of dementia were recruited. They were assessed using the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D). The professional caregiver distress questions were rephrased to assess the "occupational disruptiveness" of behaviors in the nursing home version (NPI-NH). RESULTS: Neuropsychiatric symptoms were common and were positively correlated with caregiver distress. Family caregivers were significantly more distressed than professional caregivers over the delusion, agitation, depression and aberrant motor domains, although the severity of the behavioral disturbances reported was not higher in the sample. The median NPI scores for the agitation and disinhibition domains were significantly higher in the inpatient group, contrasting with a higher score for the depression domain among the outpatient group. CONCLUSIONS: This study highlights the prevalence of neuropsychiatric symptoms in dementia and illustrates the strong correlation between the severity of behavioral disturbances and caregiver distress.     

Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.     

Role of the home visit medical service for patients with behavioral and psychological symptoms of dementia (BPSD) living in the community

Background: It is important for patients with behavioral and psychological symptoms of dementia (BPSD) in the community, who refuse to go to clinics, to be medically served by means of home visits. However, there are a few clinics in Japan that are specialized in home visits for BPSD. Methods: The home visit medical service provided to several patients with BPSD was reviewed and the strategy for the treatment of BPSD was analyzed. Results: It was found that the medical approach of home visits for patients with BPSD needed to be based on daily life information as well as medical information. Conclusions: The medical service alone is not enough to provide appropriate care for patients with BPSD who are living in the community. Using the case studies presented herein, we have demonstrated the importance of ‘daily life information’ for medical intervention. Issues relating to the exacerbation of BPSD and the cooperation of caregivers in the drug monitoring system at home are also considered.     

Increased saliva cortisol awakening response in patients with mild cognitive impairment

BACKGROUND: It is unknown whether HPA-axis dysfunction is present in patients with mild cognitive impairment (MCI). The aim of the present study was to investigate whether cortisol levels are elevated among patients with MCI and/or whether the individuals have adequate feedback control of their HPA axis. MATERIAL AND METHODS: 27 patients with MCI and 15 healthy controls were included in the study. Saliva samplings were performed 5 times a day before intake of 0.5 mg dexamethasone, and 5 times a day after intake of dexamethasone, respectively. RESULTS: Significantly higher cortisol levels were found 15 min after awakening among patients with MCI in comparison with the controls, both before and after dexamethasone administration (p<0.05). Also, the ratio between cortisol at awakening time and 15 min after awakening was lower in the patient group after dexamethasone administration (p<0.05). There were no significant differences in basal cortisol levels before or after dexamethasone between groups. CONCLUSION: The results indicate that there is an HPA-axis disturbance, with normal basal cortisol levels and increased awakening response among patients with MCI. The dissociation between basal values and the awakening response may be of pathophysiological importance for the cognitive impairment.     

Characteristics of behavioral and psychological symptoms in the oldest patients with Alzheimer's disease

Background: Advancing age increases the risk of developing dementia. Recent studies have clarified characteristic cognitive changes in very old patients with dementia. Although non‐cognitive symptoms are frequent in dementia, relatively little attention has been paid to the nature of behavioral and psychological symptoms of dementia (BPSD). Methods: A retrospective review of a database was performed to compare 27 very old patients with Alzheimer's disease (AD) (onset age ≥ 85) with 162 less old patients (onset age < 85). Cognitive decline, ability to carry out activities of daily living (ADL), and overall severity were rated. BPSD were evaluated using a 16‐item questionnaire to the compare frequency of each symptom between old and very old groups. Results: Cognitive decline was equivocal in both old and very old groups. In contrast, very old patients were more impaired in ADL, and BPSD were more frequent in very old patients. Delusions, irritability, and delusional misidentification syndrome were frequent in both groups, but were more prominent in very old patients. Behavioral abnormalities such as excitement, delirium, reversed diurnal rhythm, and wandering were not prominent in old patients, but were frequent in very old patients. Conclusions: Very old AD patients presented more frequent BPSD than old AD patients. Troublesome behavioral abnormalities particularly prominent in the older patients might represent a heavy burden for caregivers.     

New therapeutic strategies for behavioral and psychological symptoms of dementia]

Interventional studies, with the aim of reducing the burden of care through drug or non-drug therapies of behavioral and psychological symptoms of dementia (BPSD), have been scarce. However, we are now able to do pharmacological management for BPSD with new drugs such as atypical neuroleptics, SSRIs, and cholinesterase inhibitors. Delusions of theft are one of the most frequently observed BPSD in patients with AD. In addition, the delusions and ensuing aggression and anxiety are major factors that increase the burden of caregivers. Delusions of theft in patients with AD were eliminated or reduced with low-dose atypical neuroleptics (risperidone). This significantly reduced the burden of care overall for caregivers. New therapeutic strategies such as cholinesterase inhibitors for visual hallucinations in DLB and SSRIs for overeating and stereotyped behavior in FTLD might also remarkably reduce the burden of care for these patients. For many dementia patients, there are still no drugs that offer a principal cure. It is, therefore, important to evaluate their BPSD correctly at the earliest possible time, so that the burden of caring can be reduced through appropriate drug treatment. This reduction is critical for the continuation of satisfactory at-home care and might contribute to the health economics.