Common genetic variants in the glucocorticoid receptor and the 11ß-hydroxysteroid dehydrogenase type 1 genes influence long-term cognitive impairments in patients with Cushing's syndrome in remission.

CONTEXT: Cognitive function is impaired in patients with Cushing's syndrome (CS) in remission. OBJECTIVE: The objective of the investigation was to study the effects of polymorphisms in genes associated with glucocorticoid (GC) sensitivity on cognitive function in patients with CS in long-term remission. DESIGN: This was a cross-sectional, case-controlled, single-center study. PATIENTS: Fifty-three patients with CS in remission and 53 controls matched for age, gender, and educational level participated in the study. MAIN OUTCOME MEASURES: Cognitive function, studied using standardized neuropsychological testing, and polymorphisms in the GC receptor (NR3C1; Bcl1 and A3669G), mineralocorticoid receptor (NR3C2; I180V), 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1; rs11119328), and ATP binding cassette B1 (ABCB1; rs1045642) genes were measured. The association between cognitive function and polymorphisms were analyzed using linear regression with adjustments for age and educational level. RESULTS: The mean age in patients and controls was 53 ± 14 years. The median (interquartile range) duration of remission was 13 (5-18) years. In patients, the single-nucleotide polymorphism rs11119328 was associated with impairments in processing speed, auditory attention, auditory working memory, and reading speed. This association was not seen in matched controls. The Bcl1 polymorphism was associated with fatigue and worse visual attention and working memory. The remaining single-nucleotide polymorphisms were not associated with cognitive performance. CONCLUSION: In this study, polymorphisms in the 11ßHSD1 and NR3C1 genes were associated with impaired cognitive function, indicating that GC sensitivity and prereceptor regulation of GC action may play a role in the long-term consequences of CS. The study provides a novel insight into the etiology of cognitive dysfunction in patients with CS in remission.

The use of overnight pulse wave analysis for recognition of cardiovascular risk factors and risk: a multicentric evaluation.

OBJECTIVES: Conventional methods for cardiovascular disease risk stratification are based on quantification of recognized risk factors or assessment of biomarkers during the wake period. We evaluated an algorithm on the basis of a photoplethysmographic pulse wave recording during sleep for cardiovascular risk assessment. METHODS: Five hundred and twenty individuals (346 men, age 55.0 ± 13.4 years, BMI 29.9 ± 6.  kg/m) with suspected sleep apnoea were randomly recruited at five sleep centres. Individual cardiovascular risk scores were calculated in accordance with established cardiovascular risk matrixes (ESH/ESC, Framingham, SCORE, PROCAM scores). A digital photoplethysmographic pulse wave signal was continuously recorded during the night using an oximeter sensor. An algorithm based on eight separate hypoxic and pulse wave derived parameters was trained in 130 individuals and validated in 390 individuals for low/high cardiovascular risk classification. RESULTS: All derived parameters were associated with elevated ESH/ESC risk in univariate analysis and five in the multiple logistic regression model [discrimination index C = 0.8, Chi-square (7) = 69, P < 0.0001]. The combined algorithm detected high-risk patients (validation set, ESH/ESC risk classes 4 and 5) with a sensitivity, specificity, positive predictive value and negative predictive value of 74.5, 76.4, 69.0 and 81.0%, respectively. Significant associations were also found for the Framingham, SCORE and PROCAM scores. The computed risk scores in individuals with/without (n = 34/356) a previous history of cardiovascular event (myocardial infarction, transitory ischemic attack or stroke) were 0.71 ± 0.27 and 0.42 ± 0.34 (P < 0.001), respectively. CONCLUSION: Parameters derived from modified pulse oximetry during sleep may provide information on cardiovascular function. Combined signal analysis may be used for recognition of individuals with established cardiovascular risk in a sleep laboratory cohort.

Neurodegenerative and inflammatory biomarkers in cerebrospinal fluid in patients with Cushing's syndrome in remission.

OBJECTIVE: Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission. DESIGN: A cross-sectional, single-center study. PATIENTS: Twelve women previously treated for CS and six healthy subjects. MEASUREMENTS: Neurodegenerative CSF markers: total tau, hyperphosphorylated tau, amyloid beta peptides, soluble amyloid precursor protein alpha and beta, neurofilament light proteins, glial fibrillary acidic protein, and monocyte chemoattractant protein 1; and inflammatory CSF markers: interferon gamma, interleukin (IL) 1B, IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, and tumor necrosis factor alpha. RESULTS: The mean age (mean±S.D.) was similar in patients with CS in remission (44.9±14 years) and healthy subjects (42.3±15.7 years; P=0.726). No differences were observed in the concentrations of any neurodegenerative biomarkers between the patients and healthy subjects. Nor were the concentrations of inflammatory biomarkers different between the groups. CONCLUSIONS: The pattern of neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission does not differ from that of the healthy subjects. The underlying mechanisms of the cognitive deficits in patients with CS in remission are different from those observed in patients with neurodegenerative disorders and remain to be explained.

Impaired vigilance and increased accident rate in public transport operators is associated with sleep disorders.

OBJECTIVES: Sleep disturbances can impair alertness and neurocognitive performance and increase the risk of falling asleep at the wheel. We investigated the prevalence of sleep disorders among public transport operators (PTOs) and assessed the interventional effects on hypersomnolence and neurocognitive function in those diagnosed with obstructive sleep apnea (OSA). METHODS: Overnight polygraphy and questionnaire data from 101 volunteers (72 males, median age 48 range [22-64] years, 87 PTOs) employed at the Gothenburg Public Transportation Company were assessed. Treatment was offered in cases with newly detected OSA. Daytime sleep episodes and neurocognitive function were assessed before and after intervention. RESULTS: At baseline, symptoms of daytime hypersomnolence, insomnia, restless legs syndrome as well as objectively assessed OSA (apnea hypopnea index (AHI, determined by polygraphic recording)=17[5-46]n/h) were highly present in 26, 24, 10 and 22%, respectively. A history of work related traffic accident was more prevalent in patients with OSA (59%) compared to those without (37%, p<0.08). In the intervention group (n=12) OSA treatment reduced AHI by -23 [-81 to -5]n/h (p=0.002), determined by polysomnography. Reduction of OSA was associated with a significant reduction of subjective sleepiness and blood pressure. Measures of daytime sleep propensity (microsleep episodes from 9 [0-20.5] to 0 [0-12.5], p<0.01) and missed responses during performance tests were greatly reduced, indices of sustained attention improved. CONCLUSIONS: PTOs had a high prevalence of sleep disorders, particularly OSA, which demonstrated a higher prevalence of work related accidents. Elimination of OSA led to significant subjective and objective improvements in daytime function. Our findings argue for greater awareness of sleep disorders and associated impacts on daytime function in public transport drivers.

Association between short total sleep time and hypertension: the Skara Sleep Cohort.

OBJECTIVES: Apnea hypopnea index (AHI) is used to study the association between obstructive sleep apnea (OSA) and hypertension, but the independent contributions of total sleep time (TST) and apnea/hypopnea event count to hypertension have not been previously investigated. We studied the relationship between polysomnographically assessed TST and hypertension in a sex-balanced community-dwelling cohort of hypertensive patients and normotensive controls (Skara Sleep Cohort). METHODS: Participants (n = 344, men 173, age 61.2 ± 6.5 years, BMI 28.6 ± 4.8 kg/m, mean ± SD) underwent ambulatory home polysomnography. Hypertension was defined according to contemporary Swedish national guidelines. A multivariate logistic regression model was used to predict hypertension status from TST and apnea/hypopnea count (total events/night) adjusting for sex, age and BMI. RESULTS: OSA was highly prevalent in this population (AHI 26 ± 4 events/h). Hypertensive patients had shorter TST than normotensive patients (353 ± 81 vs. 389 ± 65 min, P < 0.001), whereas total apnea/hypopnea count did not differ (167 ± 138 vs. 146 ± 148 events/night, P = 0.2). Multivariate logistic regression analysis revealed that short TST was associated with hypertension status [odds ratio 2.0; 95% confidence interval (95% CI) 1.2-3.3; P = 0.0015]. The significant association between apnea/hypopnea count and hypertension status was nonlinear (odds ratio 2.6; 95% CI 1.2-5.8; P = 0.04). The type of antihypertensive treatment was not found to significantly influence TST. CONCLUSION: Short sleep time assessed by polysomnography was associated with hypertension in this community-dwelling population. Short sleep and presence of sleep apnea appear to independently link to hypertension.

Long-term cognitive impairments and attentional deficits in patients with Cushing's disease and cortisol-producing adrenal adenoma in remission.

CONTEXT: Cognitive function is impaired in patients with active Cushing's syndrome (CS). OBJECTIVE: The aim was to study cognitive function in patients with CS in long-term remission. DESIGN: We conducted a cross-sectional, case-controlled, single center study. PATIENTS: Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. METHODS: Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. RESULTS: Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± SD age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. CONCLUSION: Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.

Self-reported features of sleep, utilization of medical resources, and socioeconomic position: a Swedish population survey.

This study examined aspects of self reported qualities of sleep and daytime functioning attributed to sleep, including the utilization of physician consultations and prescription medications, and their relationships with age, gender, and educational attainment in the Swedish population using telephone interviews of 1,000 random households. Women were twice as likely to use hypnotics and experienced more poor quality sleep and excessive daytime sleepiness (EDS). Lower educational attainment was associated with twofold increased hypnotic use, life impacts of sleep problems, and EDS, but not dimensions reflecting poor quality sleep. This study demonstrates that educational attainment, gender, and age combine to shape both the attributions of the effects of sleep on wakeful functioning and patterns of using medical resources.

Oximeter-based autonomic state indicator algorithm for cardiovascular risk assessment.

BACKGROUND: Cardiovascular (CV) risk assessment is important in clinical practice. An autonomic state indicator (ASI) algorithm based on pulse oximetry was developed and validated for CV risk assessment. METHODS: One hundred forty-eight sleep clinic patients (98 men, mean age 50 ± 13 years) underwent an overnight study using a novel photoplethysmographic sensor. CV risk was classified according to the European Society of Hypertension/European Society of Cardiology (ESH/ESC) risk factor matrix. Five signal components reflecting cardiac and vascular activity (pulse wave attenuation, pulse rate acceleration, pulse propagation time, respiration-related pulse oscillation, and oxygen desaturation) extracted from 99 randomly selected subjects were used to train the classification algorithm. The capacity of the algorithm for CV risk prediction was validated in 49 additional patients. RESULTS: Each signal component contributed independently to CV risk prediction. The sensitivity and specificity of the algorithm to distinguish high/low CV risk in the validation group were 80% and 77%, respectively. The area under the receiver operating characteristic curve for high CV risk classification was 0.84. ß-Blocker treatment was identified as an important factor for classification that was not in line with the ESH/ESC reference matrix. CONCLUSIONS: Signals derived from overnight oximetry recording provide a novel potential tool for CV risk classification. Prospective studies are warranted to establish the value of the ASI algorithm for prediction of outcome in CV disease.

Increased neck soft tissue mass and worsening of obstructive sleep apnea after growth hormone treatment in men with abdominal obesity.

BACKGROUND: Risk factors for obstructive sleep apnea (OSA) are male gender, obesity and abnormalities in neck soft tissue mass. OSA is associated with both growth hormone (GH) excess and severe GH deficiency in adults. Adults with abdominal obesity have markedly suppressed GH secretion. AIM: To study the effect of GH treatment on OSA in abdominally obese men with impaired glucose tolerance. PATIENTS AND METHODS: Forty men with abdominal obesity and glucose intolerance were randomized in a prospective, 12-month double-blind trial to receive either GH or placebo. The treatment groups had similar BMI and waist circumference. Overnight polysomnography and computed tomography to assess muscle and fat distribution in the neck and abdomen were performed at baseline and after 12 months. RESULTS: GH treatment increased insulin-like growth-factor-1i from (mean [SD]) 168 (72) to 292 (117) microg/L, the apnea-hypopnea index from (n/h) 31 (20) to 43 (25) and oxygen-desaturation index from (n/h) 18 (14) to 29 (21) (p = 0.0001, 0.001, 0.002). Neck transverse diameter, circumference and total cross-sectional area (p = 0.007, 0.01, 0.02) increased, while abdominal visceral adipose tissue (p = 0.007) was reduced. No between-group differences in total sleep time, REM sleep, NREM sleep, and time spent in supine position were found. The Epworth sleepiness scale score was unchanged. CONCLUSIONS: GH treatment increased the severity of OSA in abdominally obese men. The possible mechanism appears to be reflected by the GH-induced increase of measures of neck volume. The present results, to some extent, argue against that low GH/IGF-I activity is a primary cause of OSA in abdominally obese men.

A double-blind, crossover study of Doxazosin and Enalapril on peripheral vascular tone and nocturnal blood pressure in sleep apnea patients.

OBJECTIVE: Pulse wave attenuation, which occurs in association with obstructive sleep apnea (OSA), is sympathetically mediated. We compared the effect of Doxazosin (DO, a peripheral alpha-receptor inhibitor) and Enalapril (EN, an ACE inhibitor) on digital vasoconstriction and nocturnal blood pressure (BP) in hypertensive OSA patients. METHODS: A double-blind, crossover study comparing equipotent dosages of DO (4 mg/day for 2 weeks with 8 mg/day for an additional 2 weeks) and EN (10mg/day and 20mg/day, respectively) was undertaken in 16 male OSA patients (age 55+/-7 years, body mass index 30.1+/-3.8 kg/m(2)) with hypertension. Assessments including ambulatory 24-h BP, full-night polysomnography with simultaneous peripheral arterial tone (PAT) and beat-to-beat finger BP monitoring (Finapres) were made at the end of each treatment period. Nighttime BP and digital vasoconstrictions associated with apneic events (measured as the ratio of PAT amplitudes during and after apneas) were analyzed. RESULTS: There were no differences between the two treatments in the 24-h BP profile and OSA severity. But the nighttime average beat-to-beat finger BP was significantly higher under DO treatment (systolic BP 129+/-13 vs. 119+/-23 mm Hg, P=0.02; diastolic BP 81+/-12 vs. 74+/-14 mm Hg, P=0.04, DO and EN respectively). In a linear mixed effects regression model, the PAT ratio during apnea increased 5.3% under DO compared with EN (P<0.0001). Each percentage decrease of apneic related oxygen desaturation was associated with 0.9% decrease in the PAT ratio (P<0.0001). REM sleep was associated with 2.2% decrease of PAT ratio compared to NREM sleep (P=0.002). CONCLUSION: Digital vasoconstrictions associated with apneic events are alpha-receptor mediated. DO compared to EN has a proportionally poor effect on nocturnal BP control in OSA patients, which may be due to the enhanced sympathetic nervous system activity characteristic of this condition.

Nocturnal pulse wave attenuation is associated with office blood pressure in a population based cohort.

OBJECTIVE AND BACKGROUND: Pulse wave amplitude (PWA) derived from the digital vascular bed has been used in sleep studies. The nocturnal attenuation of PWA has been shown to reflect sympathetic activation during sleep. We assessed the relationship between nocturnal PWA attenuation and office blood pressure (BP). METHODS: Eighty-one subjects (46 men; age 60+/-7 years; body mass index [BMI] 28.2+/-4.3 kg/m(2); apnea hypopnea index [AHI], 25.4+/-22.6 events/h; systolic BP 137+/-15 mm Hg; diastolic BP 79+/-7 mm Hg) recruited from a population based cohort underwent simultaneous ambulatory polysomnography (PSG) and peripheral arterial tonometry (PAT) recording. Episodic attenuations of PWA derived from the pulse waveform of the PAT signal were identified and characterized. Generalized least squares regression models were used to identify the associations between median PWA attenuation (PWA.att), office BP and sleep-related disordered breathing. RESULTS: We found that the association between PWA.att and office BP was independent of gender, age, BMI, antihypertensive medication, number of attenuation episodes, AHI, oxygen desaturation 4% index (ODI4) and arousal index. Each 10% increase in PWA.att was associated with increases of 5.0 mm Hg systolic BP (P=0.02) and 3.0 mm Hg diastolic BP (P=0.005). We also found independent relationships between systolic/diastolic BP and BMI (P=0.0006/0.001), AHI (P=0.03/0.1) and ODI4 (P=0.03/0.03). CONCLUSIONS: The degree of PWA attenuation during the night is associated with office BP independent of sleep-disordered breathing. Continuous assessment of PWA during sleep may provide novel insights into cardiovascular physiology and morbidity.

Sympathetic nerve and cardiovascular responses to auditory startle and prepulse inhibition.

While sudden (startling) sensory stimuli are generally thought of as inducing sympathetic excitation, in humans there is a short-lasting inhibition of limb muscle sympathetic nerve activity (MSNA). This study is the first to examine and contrast the effects of acoustic startle and the prepulse inhibition of startle (PPI) on MSNA, blood pressure, heart rate, and eye blinks. Startle elicited a two-component withdrawal of MSNA: an early inhibition of one sympathetic burst followed by a second inhibition. PPI abolished the early, but not the late MSNA inhibition. Prepulse stimuli alone had no early inhibitory effects on MSNA. Early MSNA inhibition, which may occur at latencies of approximately 100 ms, appears to be part of a CNS-generated startle reflex which subserves automatic defensive responses to potential threats. The late MSNA inhibition coincided with the stimulus-induced blood pressure increase and is probably an inhibitory reflex response.

Obstructive apneic events induce alpha-receptor mediated digital vasoconstriction.

STUDY OBJECTIVE: To characterize the role of alpha-receptors in autonomic control of digital skin blood flow change in response to obstructive apnea-hypopnea events. DESIGN: Experimental intervention study. SETTING: Sleep laboratory in a university hospital. PATIENTS: Eight male patients with severe obstructive sleep apnea (OSA). INTERVENTIONS: Patients received four cumulative dosage steps of phentolamine (0.066, 0.2, 2 and 5 [n=3] microg/min/100 ml forearm tissue) via brachial artery infusion during nonrapid eye movement sleep (stage 1 and 2). MEASUREMENTS AND RESULTS: The pulse amplitude determined with peripheral arterial tonometry (PAT) was periodically attenuated during the immediate post apnea-hypopnea period coinciding with arousal. PAT ratio (smallest pulse amplitude post apnea divided by largest pulse amplitude during apnea), was determined as a measure of digital vasoconstriction. We found that, compared with baseline, PAT ratio dose-dependently increased during phentolamine (0.2, 2 and 5 microg) infusion by 11.2+/-1.7%, 24.4+/-2.1% and 30.9+/-4.1%, respectively (P<0.001). Systemic blood pressure and heart rate were largely unaffected by the pharmacological intervention. CONCLUSION: OSA related alteration of the pulse amplitude includes a constriction of digital skin vasculature that to a large extent is mediated via sympathoadrenergic alpha-receptors.

Selective alterations of the first NREM sleep cycle in humans by a dopamine D1 receptor antagonist (NNC-687).

This paper details the first study of the effects of dopamine D1 receptor antagonism on the regulation of human sleep EEG (electroencephalogram). The investigational drug NNC-687 (NNC 01-0687/CEE 03-310) was administered to 20 healthy young men in doses of 5, 10, and 15 mg in a double blinded, placebo controlled, crossover design. In rats, dopamine D1 receptor antagonism can produce large increases in the amounts of both rapid eye-movement (REM) and non-rapid eye-movement (NREM) sleep. In this study, drug effects were most prominent in the first NREM period. D1 antagonism markedly reduced the peak-amplitude of delta EEG waves but increased their instantaneous frequency as well as enhancing the total number, incidence, and burst-duration of sleep spindles. The length of the first NREM period was increased up to 47% over baseline. Despite these large increases in NREM sleep time, the amount of delta EEG power accumulated over the first NREM period was conserved at baseline levels. We note that the sleep-EEG profile of D1 antagonism is very similar to that of GABAA (gamma-aminobutyric acid) receptor modulators and suggest that D1 antagonism may alter the properties of the neuronal networks which generate delta and spindle, and K-complex EEG waveforms through the upstream modulation of GABAA receptor activity.

Is dawn simulation effective in ameliorating the difficulty awakening in seasonal affective disorder associated with hypersomnia?

BACKGROUND: Patients with winter depression, (seasonal affective disorder, SAD) frequently complain of difficulty awakening in the morning. Dawn simulation has been found effective in treating SAD, but its effect on difficulty awakening has not been assessed. METHODS: Fifty medication-free patients with SAD associated with hypersomnia were randomized to receive either 1 week of dawn simulation (250 lux) or a dim (0.2-2 lux) placebo signal. The patients assessed their level of drowsiness upon awakening during the baseline week and during the treatment week using the Stanford sleepiness scale (SSS). A psychiatrist rated difficulty awakening after the baseline week and after the treatment week. RESULTS: Dawn simulation lowered both the difficulty awakening score (P<0.05) and the SSS score (P<0.05) compared to the placebo dawn signal. LIMITATIONS: Replication is necessary. No biological markers of circadian phase were measured. CONCLUSIONS: Compared to a placebo condition, dawn simulation appears effective in decreasing both prospectively assessed morning drowsiness and retrospectively assessed difficulty awakening. The symptom of difficulty awakening is consistent with the phase delay hypothesis of SAD. Assessment of difficulty awakening could prove useful in the evaluation of SAD.

CEE-03-310 CeNeS pharmaceuticals.

CEE-03-310 is a selective dopamine D1-like receptor antagonist with no appreciable binding affinity for other receptors. Although originally developed by Novo Nordisk A/S as NNC-687 for the treatment of schizophrenia, the company changed its therapeutic focus in the mid-1990s and the full rights to CEE-03-310 and several related compounds were subsequently granted to CeNeS Pharmaceuticals in 1999. CeNeS is currently investigating the drug's potential in the treatment of insomnia and alcohol dependency [340965], [382293], [401496],[416026]. A phase II, double-blind, placebo-controlled trial of CEE-03-310 demonstrated a dose-dependent enhancement of NREM sleep at the beginning of the night without any effects on the quantity of REM sleep [410739].