Dawn simulation and bright light in the treatment of SAD: a controlled study.

BACKGROUND: Some small controlled studies have found that dawn simulation is effective in treating seasonal affective disorder (SAD). With a larger sample size and a longer duration of treatment, we compared dawn simulation with bright light therapy and a placebo condition in patients with SAD. METHOD: Medication-free patients with SAD were randomly assigned to one of three conditions: bright light therapy (10,000 lux for 30 min, from 6:00 AM to 6:30 AM), dawn simulation (1.5 hour dawn signal from 4:30 AM to 6:00 AM peaking at 250 lux), and a placebo condition, a dim red light (1.5 hour dawn signal from 4:30 am to 6:00 AM peaking at 0.5 lux.) Over the subsequent 6 weeks, the subjects were blindly rated by a psychiatrist using the Structured Interview Guide for the Hamilton Depression Rating-Seasonal Affective Disorder Version (SIGH-SAD). We modeled the profiles of the remissions (SIGH-SAD < or = 8) and response (> or =50% decrease in SIGH-SAD) to treatment over time using Cox proportional hazards models. RESULTS: The sample consisted of 95 subjects who were randomized to the three conditions: bright light (n = 33), dawn simulation (n = 31) and placebo (n = 31). Dawn simulation was associated with greater remission (p <.05) and response (p <.001) rates compared to the placebo. Bright light did not differ significantly from the placebo. Dawn simulation was associated with greater remission (p <.01) and response (p <.001) rates compared to the bright light therapy. The mean daily hours of sunshine during the week before each visit were associated with a significant increase in likelihood of both remission (p <.001) and response (p <.001). CONCLUSIONS: Dawn simulation was associated with greater remission and response rates compared to the placebo and compared to bright light therapy. The hours of sunshine during the week before each assessment were associated with a positive clinical response.

Estrogen replacement therapy moderates the sleep disruption associated with nocturnal blood sampling.

STUDY OBJECTIVES: To determine whether chronic oral estrogen replacement therapy (ERT) (1) improves the sleep of older, non-symptomatic postmenopausal women; and (2) reduces the sleep disruption associated with a stressor (frequent remote nocturnal blood-sampling through an intravenous catheter). DESIGN: Descriptive, cross-sectional, secondary analysis of a larger study. SETTING: The General Clinical Research Center at the University of Washington Medical Center. PARTICIPANTS: Women aged 57-80 (mean age = 70) at least 5 years past menopause were recruited from the community. Hot flashes and significant sleep difficulties were exclusion criteria. The ERT group (n=37) consisted of women on chronic oral ERT for > or = 2 years. The NERT group (n=56) consisted of women not using estrogen (NERT) for > or = 2 years. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Following an adaptation night, polysomnographic measures were collected for 2 consecutive nights. A blood sample was collected every 20 minutes for the last 24 hours (including Night 2), through an intravenous catheter. The only group difference in sleep on the baseline (non-catheter) night was that NERT women had a shorter sleep latency. Sleep on the catheter night was characterized by increased wakefulness, longer sleep latency, and decreased REM sleep for both groups relative to the baseline. However, the impact of nocturnal blood sampling was much greater for NERT than for ERT women: they experienced significantly greater percent changes in more sleep-wake variables, particularly slow-wave sleep (SWS). CONCLUSIONS: In this cross-sectional study, the use of chronic oral ERT was associated with little effect on the sleep of older postmenopausal women not experiencing hot flashes, except in the presence of a challenge to sleep. ERT ameliorated the disruptive effect of nocturnal blood sampling on both objectively assessed and subjectively assessed sleep.

Sleep impairments in healthy seniors: roles of stress, cortisol, and interleukin-1 beta.

STUDY OBJECTIVES: Increased stress responsivity and a longer-lasting glucocorticoid increase are common findings in aging studies. Increased cortisol levels at the circadian nadir also accompany aging. We used 24 h free urine cortisol to assess these age changes in healthy seniors. We hypothesized that free cortisol levels would explain individual differences in age-related sleep impairments. DESIGN: The study compared sleep, cortisol, and sleep-cortisol correlations under baseline and "stress" conditions in men and women. SETTING: Subjects were studied in the General Clinical Research Center under baseline conditions and a mildly stressful procedure (24 h indwelling intravenous catheter placement). PARTICIPANTS: Eighty-eight healthy, nonobese subjects (60 women and 28 men) from a large study of successful aging participated in the study. Mean ages were 70.6 (+/-6.2) and 72.3 (+/-5.7) years for women and men, respectively. MEASUREMENTS: The 24 h urines were collected for cortisol assay (radioimmunoassay [RIA]); blood was sampled at three diurnal time points for assay (enzyme-linked immunosorbent assay [ELISA]) of interleukin-1 (IL-1) beta; sleep architecture and sleep electroencephalograms (EEGs) were analyzed (after an adaptation and screening night) on baseline and stress nights via polysomnography and EEG power spectral analysis. RESULTS: Healthy older women and men with higher levels of free cortisol (24 h urine level) under a mild stress condition had impaired sleep (lower sleep efficiency; fewer minutes of stages 2, 3, and 4 sleep; more EEG beta activity during non-rapid eye movement sleep [NREM] sleep). Similar results were obtained when stress reactivity measures were used (cortisol and sleep values adjusted for baseline values), but not when baseline values alone were used. Gender differences were apparent: Men had higher levels of free urine cortisol in both baseline and mild stress conditions. Cortisol and sleep correlated most strongly in men; cortisol stress response levels explained 36% of the variance in NREM sleep stress responses. In women, but not men, higher cortisol was also associated with earlier time of arising and less REM sleep. Higher cortisol response to stress was associated with increased circulating levels of IL-1beta, explaining 24% of the variance in a subset of women. CONCLUSION: These results indicate that free cortisol (as indexed by 24 h urine values) can index responses to mild stress in healthy senior adults, revealing functional correlations (impaired sleep, earlier times of arising, more EEG beta activity during sleep, more IL-1beta) and gender differences.

Thyroid hormones: positive relationships with cognition in healthy, euthyroid older men.

BACKGROUND: Although the association of clinical hypothyroidism with cognitive deficits is well known, the cognitive effects of thyroid hormones in euthyroid subjects are less studied and understood. The purpose of this study was to examine thyroid-cognition relationships in healthy, euthyroid older men. METHODS: We examined healthy men (N = 44, mean age = 72), excluding clinically hypothyroid/hyperthyroid or diabetic/hyperglycemic subjects and those with dementia, depression, CNS medications, or recent illness. Plasma samples obtained across a 24-hour period were pooled, then assayed for total thyroxine (TT4), total triiodothyronine (TT3), and T3 resin uptake. Free thyroxine index (FT4I) was calculated. A broad cognitive battery (including the Wechsler Adult Intelligence Scale-Revised [WAIS-R], the Dementia Rating Scale [DRS], and the Rivermead Behavioral Profile [PROFILE]) was administered to all subjects. RESULTS: Regression analyses controlling age and education showed TT4 and FT4I to have significant positive relationships with measures of overall cognition; TT4 accounted for 8% to 12% of the variance in omnibus cognitive measures such as WAIS Performance, WAIS Verbal score, and GLOBAL cognitive scores. CONCLUSIONS: Our findings suggest that within "normal" range of variation in plasma thyroid hormones, TT4 but not T3 positively associates with general cognition in healthy elderly men.

Growth hormone in postmenopausal women after long-term oral estrogen replacement therapy.

Studies of estrogen effects on growth hormone (GH) and its pulsatile release in postmenopausal women have typically utilized estrogen replacement therapy (ERT) of relatively short duration (days to weeks). The purpose of this study was to compare GH measures from healthy postmenopausal women who were on oral ERT for 3 years or more (n = 24; mean ERT duration = 16.1 years) with women not on ERT (NERT; n = 40). Blood samples were drawn remotely every 20 min for 24 h and then analyzed for mean 24-h GH, mean GH during sleep, and mean 24-h insulin-like growth factor-I (IGF-I). GH peak analyses were also performed. Mean 24-h GH and GH during sleep were significantly higher and IGF-I was significantly lower in ERT women compared with NERT women. In addition, use of long-term ERT was associated with more GH peaks relative to women not on ERT, but no change in GH peak amplitude or area. GH was not related to age in either group. GH was strongly and negatively correlated with measures of adiposity in NERT women but not in ERT women. In conclusion, long-term oral ERT is associated with increased circulating GH and decreased IGF-I levels, even after many years of treatment.

Memory-scanning task performance in Alzheimer's disease.

Individuals with mild Alzheimer's Disease (AD) and healthy normal control (NC) older adults performed a varied-set version of the Sternberg memory-scanning task with Set Sizes 1, 2, 3, and 4. The AD group (N = 23) had slower and more variable reaction times (RT) than the NC group (N = 38). RT differences between groups were bigger for NO than for YES responses. The linear relationship between RT and set size was not as strong for the AD group as for the NC group. However, in contrast to earlier studies with fewer subjects, participants with AD and healthy older individuals did not differ in the rate at which they scan items in the memory set.

Potential applications of GH secretagogs in the evaluation and treatment of the age-related decline in growth hormone secretion.

The two classes of GH secretagogs--GH-releasing hormone (GHRH) and the GH-releasing peptides and their analogs (GHRP's)--retain their ability to endogenous GH secretion in healthy and frail elderly subjects. They have very limited utility in assessment of the state of the GH/IGF-I axis except to confirm an intact pituitary, but they are attractive potential alternatives to GH as therapeutic agents. There is wide interest in the possibility that elevating GH and IGF-I might increase muscle mass, physical strength and performance, and possible sleep and cognition in aging. The GH secretagogs, like GH, can produce a sustained stimulation of this axis; in contrast to GH, they preserve feedback regulation at the pituitary level and stimulate a near-physiologic pulsatile pattern of GH release. GHRP's and their nonpeptide analogs are also active when given orally, a significant practical advantage. Short-term treatment studies have shown that GHRH and the GHRP's can enhance GH secretion and elevate IGF-I and IGFBP-3 levels; that GHRH may promote sleep; and that these agents are generally well tolerated. Longer-term studies assessing effects upon body composition and physical and psychological function are underway.

Circadian temperature and cortisol rhythms during a constant routine are phase-delayed in hypersomnic winter depression.

Circadian temperature, cortisol, and thyroid-stimulating hormone (TSH) rhythms during a constant routine were assessed in 6 female controls and 6 female patients with hypersomnic winter depression (seasonal affective disorder, SAD) before and after morning bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bed rest for 27 hours while rectal temperature, cortisol, and TSH levels were assessed. The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared to the controls 5:42 AM vs. 3:16 AM (p < .005); with bright light treatment, the minimum advanced from 5:42 AM to 3:36 AM (p = .06). The minimum of the cortisol rhythm was phase-delayed in the SAD group compared to the control group, 12:11 AM vs. 10:03 PM (P < .05); with bright light treatment, the minimum advanced from 12:11 AM to 10:38 PM (P = .06) [corrected]. The acrophase of the TSH rhythm was not significantly phase-delayed in SAD subjects compared to control, though the trend appeared to be toward a phase-delay (p = .07). After bright light therapy, the TSH acrophase was not significantly different in the SAD subjects; the trend was a phase-advance (p = .09). Overall, the data suggest that circadian rhythms are phase-delayed relative to sleep in SAD patients and that morning bright light phase-advances those rhythms.

Successful 6-month endurance training does not alter insulin-like growth factor-I in healthy older men and women.

BACKGROUND: Lean body mass, strength, and endurance decline with advancing age, changes paralleled by declines in anabolic hormones, including growth hormone (GH) and insulin-like growth factor-I (IGF-I). Acute exercise has been shown to stimulate the GH/IGF-I axis, and long-term exercise increases GH. This study examined the effect of endurance training on IGF-I in healthy older men and women. METHODS: Thirty-one healthy older men (66.9 +/- 1.0 yrs, mean +/- SEM) and 21 healthy older women (67.1 +/- 1.7 yrs) were randomized to either 3d/wk, 6-month endurance (ET3) or stretching/flexibility (SF3) protocols. Another group of 15 healthy older men (69.0 +/- 1.3 yrs) participated in a more intensive 5d/wk, 6-month endurance protocol (ET5). Before and after training, subjects were weight stabilized and participated in maximal exercise tolerance testing, body composition assessment, and fasting blood sampling. RESULTS: ET3 training resulted in a significant increase (14%) in maximal aerobic power (VO2max), significant decreases in body weight (BW), fat mass (FM), and waist/hip ratio (WHR), and a significant increase in fat-free mass (FFM). No significant VO2max or body composition changes were observed in the SF3 group. For the ET5 group, a significant increase (22%) in VO2max and significant decrease in BW, FM, and WHR were observed. No significant changes in IGF-I were observed for any of the three groups. Pre- versus post-training IGF-I values were very stable (r = .86, p < .001) across subjects. CONCLUSIONS: Within-subject basal levels of IGF-I in healthy seniors were extremely stable between pre- and post-training assessments. Two endurance training protocols of magnitudes sufficient to significantly increase aerobic capacity and decrease measures of body adiposity did not significantly increase basal levels of IGF-I in healthy older men and women.

Objective sleep quality of healthy older men and women is differentially disrupted by nighttime periodic blood sampling via indwelling catheter.

Elucidation of sleep-endocrine relationships requires frequent blood sampling during sleep recording. Unfortunately, such sampling can itself affect sleep and indirectly, hormonal patterns. We examined the effect of catheterization and frequent nighttime blood sampling on the sleep of a large sample of healthy older men and women. A total of 113 healthy older [69.1 +/- 0.6 years, mean +/- standard error of the mean (SEM) adults (68 women and 45 men) were studied. Following an adaptation night sleep was recorded during an undisturbed night and a night of periodic blood sampling via i.v. catheter. Lights out and lights on were significantly delayed and advanced, respectively, on the catheterization night, resulting in a significantly shorter time in bed (TIB). Total sleep time and sleep efficiency were significantly reduced, and sleep latency, total wake time and the number of awakenings from sleep of > or = 1 minute were significantly increased. Rapid eye movement (REM) sleep percentage of TIB was significantly reduced. Stages 3/4 sleep [slow wave sleep (SWS)] percentage of TIB was significantly reduced, as was total delta energy during SWS. With the exception of total sleep time and sleep latency, all sleep-wake and delta variables were significantly correlated between nights. This was particularly the case for SWS and the delta energy variables. When examined separately by gender, both men and women showed significant catheter-based sleep disturbance. However, SWS and delta energy measures in men were unaffected by catheterization. The data clearly demonstrate that both the sleep maintenance and sleep architecture of healthy older men and women are significantly impacted by nighttime blood sampling procedures. Of the various measures examined here, SWS measures appear to be the least disrupted, particularly in men. These findings need to be taken into account in any study examining sleep-endocrine relationships utilizing older subjects.

Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men.

BACKGROUND: Sleep quality declines with age, with less time in deep or slow wave sleep (SWS) and reduced amplitude of the delta waves that characterize it. Age-related declines also occur in lean body mass, growth hormone (GH), and insulin-like growth factor 1 (IGF-1). These changes in sleep quality and anabolic status may be related, as administration of GH or growth hormone releasing hormone (GHRH) can enhance SWS and decrease awakenings in young men. Here we examine the relationship between plasma IGF levels and delta sleep quality in older men. METHODS: The sleep EEG of 30 healthy elderly men (64 +/- 6 yrs; range 50-75) was recorded on the second of 2 consecutive nights. Plasma samples were drawn within 3 weeks of EEG recording, and IGF levels were assayed by RIA after acid extraction. RESULTS: IGF explained 28% (semi-partial correlation coefficient r = .53; p = .003) of the variance in average delta energy per epoch of SWS, after age-related variance was removed. Higher IGF was associated with higher average delta energy. Similar results were obtained for total delta energy during SWS (r = .37, p = .04) 4nd time spent in SWS (r = .42, p = .02). Other measures of sleep quality (e.g., wakefulness, REM sleep) were not correlated with IGF. The IGF delta relationship was minimally influenced by moderator variables such as thyroxine (T3, T4), and/or body mass index (BMI). CONCLUSION: We conclude that age-adjusted IGF levels in healthy senior men co-vary significantly with SWS and the delta energy that characterizes it.

Sleep and sleep disorders in older adults.

Complaints of sleep disturbance increase with age. Objective sleep assessments using polysomnography reveal sleep impairments (increased wakefulness and arousal from sleep; decreased slow wave sleep) even in healthy seniors. Both polysomnographic sleep and subjective sleep worsen in the presence of health impairments related to drug use, pain, cardiovascular disease, diabetes, depression, or other emotional disorders. In addition to normal aging and chronic disease, sleep complaints can also result from poor sleep habits, specific occult disorders during sleep, or some combination of these factors. Occult disorders include sleep apnea syndrome, periodic leg movements, and restless legs syndrome during sleep. Diagnosis and treatment of these and other sleep disorders is discussed. Both pharmacological and nonpharmacological treatments are considered, with an emphasis on behavioral and educative treatment approaches.

A note on the night-to-night stability of stages 3 + 4 sleep in healthy older adults: a comparison of visual and spectral evaluations of stages 3 + 4 sleep.

Night-to-night variability in the minutes of slow-wave sleep (SWS: combined minutes of stages 3 and 4 sleep) was examined for 50 healthy adults: 23 women (56-82 years old) and 27 men (54-74 years old). Visually rated SWS was more variable night to night than computer-evaluated SWS using power spectral techniques. The night-to-night correlation of the visually rated SWS was 0.61. The night-to-night correlation of the spectrally evaluated SWS was 0.91.

C STAGE, automated sleep scoring: development and comparison with human sleep scoring for healthy older men and women.

Using the sleep records of 200 men and women (age 55-85 years), we have developed a human-assisted computer scoring system, C STAGE. The system can have many applications, including quantitative electroencephalographic (EEG) analysis during specific stages of sleep. C STAGE classifies sleep/wake stages using power spectral analysis and other techniques applied to one channel of EEG data. Here we report comparability data between C STAGE- and human-rated sleep-stage scoring using Rechtschaffen and Kales criteria for 70 normal subjects (a subset of the 200). Because the method was developed using these subjects, we also report comparability data for an independent validation sample of 45 normal older men and women. For waking measures, sleep stages 3 and 4, and total sleep time, C STAGE yielded ratings comparable with the human rater (r = 0.73-0.91; p < 0.001). For sleep stages 1 and 2 and REM sleep, C STAGE correlated less well with human ratings (r = 0.59-0.81; p < 0.001). Overall, these correlations compare well with other currently available computer stage-scoring methods. Epoch-by-epoch comparisons in the validation sample revealed a mean proportion of agreement of 0.74 and a mean Kappa coefficient of 0.57, indicating the two methods provide reasonable agreement on an epoch-by-epoch basis. We conclude that C STAGE is a valid sleep/waking scoring system for healthy older adults.

Predicting long-term outcome in individuals at risk for Alzheimer's disease with the Dementia Rating Scale.

The Dementia Rating Scale, previously shown to be sensitive to dementia progression, was used to differentiate among normal control subjects, patients with Alzheimer's disease (AD), and those judged to be at risk for AD on the basis of subclinical memory impairment. The memory scale of the Dementia Rating Scale predicted with 93% accuracy which at-risk individuals would develop AD at 4- to 6-year follow-up.

Dim light melatonin onset and circadian temperature during a constant routine in hypersomnic winter depression.

The onset of melatonin secretion under dim light conditions (DLMO) and the circadian temperature rhythm during a constant routine were assessed in 6 female controls and 6 female patients with winter depression (seasonal affective disorder, SAD) before and after bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bedrest for 27 h while core temperature and evening melatonin levels were determined. The DLMO of the SAD patients was phase-delayed compared with controls (2310 vs 2138); with bright light treatment, the DLMO advanced (2310 to 2135). The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared with the controls (0542 vs 0316); with bright light treatment, the minimum advanced (0542 vs 0336).

Major unipolar depression and mild Alzheimer's disease: differentiation by quantitative tonic REM EEG.

In a previous report, tonic REM sleep epochs from the all-night sleep EEG were processed and analyzed to produce a diagnostic that discriminated mild Alzheimer's disease (AD) from cognitively unimpaired control subjects. Here, we examine the specificity of this diagnostic in distinguishing depression from AD. Twenty-four cognitively unimpaired seniors (aged 63 +/- 1.3) with major depressive disorder (unipolar) were monitored for all-night EEG in a manner identical to that used in our previous report. Tonic REM EEG epochs were preconditioned, spectrally analyzed and compared with known populations of control and AD EEG spectra. Instances when a given depressed subject's spectra fell within spectral zones unique to control or AD populations formed a diagnostic score (control, AD, neither of these). Diagnostic scores correctly identified 88% (21/24) of cognitively unimpaired seniors with major depressive disorder (unipolar). This can be compared with 89% (31/35) of mild AD subjects and 100% (43/43) of control subjects correctly identified in our previous report. This diagnostic also correctly classified as to eventual clinical AD/not AD outcome 8 subjects with both major depressive disorder and validated memory complaints. The diagnostic discrimination of AD is based on the fact that AD subjects have significantly less tonic REM EEG energy in the 13-30 Hz frequency range and more in the 1-10 Hz range than control or depressed subjects, as shown in conventional spectral analysis.

Letter matching: effects of age, Alzheimer's disease, and major depression.

We compared Alzheimer's disease (AD) patients and Major Depressive Disorder (MDD), Aged normal, and Young normal controls on a letter-matching task designed to measure the time needed to access overlearned linguistic information in long-term memory. Name identity (NI) and physical identity (PI) reaction time and the NI-PI difference were compared for ADs, MDDs, and Aged normals and separately for Aged and Young normal groups. AD subjects had slower NI and PI reaction times and a bigger NI-PI difference than Aged normal and MDD subjects, suggesting that speed of access to overlearned letter-name information in long-term memory is slowed for ADs. There were no reliable differences between Aged normal and MDD subjects. Aged normals had slower NI and PI reaction times and a bigger NI-PI difference than Young normals, suggesting that the highly practiced operations needed to access letter-name information slow with age. A discriminant analysis was used to evaluate the usefulness of the "easy to perform" letter-matching task for diagnostic purposes. Ninety percent of normal and MDD subjects but only 68% of AD subjects were classified correctly.

Sleep in Alzheimer's disease and the sundown syndrome.

Approximately 10% of the elderly population have a dementing illness that manifests itself clinically by significant cognitive deficits. Half of these individuals have Alzheimer's disease (AD), a progressive degeneration of cortical and subcortical neurons. Disturbances of sleep and the sleep-wake rhythm are a common clinical observation in AD, as is "sundowning," the onset or exacerbation of delirium during the evening or night. Here we describe the neurologic basis for the disturbed sleep of patients with AD, the phenomenology of that disturbance, and its implications. Further, we describe the prevalence, possible causes, and treatment of sundowning.

Quantitative analysis of the EEG during tonic REM sleep--methodology.

Frequency and amplitude characteristics of the clinical (waking) electroencephalogram (EEG) can be diagnostically useful in neuronal degenerative disorders such as Alzheimer's or other cortical dementias. However, interpretation of the clinical EEG may be limited by many factors, including movement and muscle artifacts and uncontrolled variations along the alert/drowsy continuum. Moreover, the clinical EEG involves subjective judgement by experts whose opinions often differ. In an effort to address these problems, we have developed a computer-automated technology that examines the digitized, all-night sleep EEG for frequency and amplitude characteristics of potential diagnostic relevance to Alzheimer's dementia. Robust time series analysis techniques and a modified power spectral analysis (Z-spectra) are used to suppress artifactual information and to automatically select samples of tonic REM sleep EEG. The spectra (amplitude vs. frequency relationship) of this specific EEG state is then assessed for diagnostically relevant information.