The low dopamine hypothesis: A plausible mechanism underpinning residual urine, overactive bladder and nocturia (RON) syndrome in older patients.

INTRODUCTION: Aging is associated with a combination of several lower urinary tract (LUT) signs and symptoms, including residual urine, overactive bladder and nocturia. One of the mechanisms of this LUT dysfunction that has not been discussed in dept so far is the role of dopamine (DA). METHODS: In this narrative review, we explore the dopaminergic hypothesis in the development of this combination of LUT signs and symptoms in older adults. RESULTS: DA is one of the neurotransmitters whose regulation and production is disrupted in aging. In synucleinopathies, altered DAergic activity is associated with the occurrence of LUTS and sleep disorders. Projections of DAergic neurons are involved in the regulation of sleep, diuresis, and bladder activity. The low dopamine hypothesis could explain the genesis of a set of LUT signs and symptoms commonly seen in this population, including elevated residual urine, Overactive bladder syndrome and Nocturia (discussed as the RON syndrome). This presentation is however also common in older patients without synucleinopathies or neurological disorders and therefore we hypothesise that altered DAergic activity because of pathological aging, and selective destruction of DAergic neurons, could underpin the presentation of this triad of LUT dysfunction in the older population. CONCLUSION: The concept of RON syndrome helps to better understand this common phenotypic presentation in clinical practice, and therefore serves as a useful platform to diagnose and treat LUTS in older adults. Besides recognizing the synucleinopathy "red flag" symptoms, this set of multi-causal LUT signs and symptoms highlights the inevitable need for combination therapy, a challenge in older people with their comorbidities and concomitant medications.

Periodic leg movements in sleep in elderly patients with Parkinsonism and Alzheimer's disease.

BACKGROUND: Periodic leg movements in sleep (PLMS) are non-epileptiform, repetitive movements of the lower limbs that have been associated with apparent dopamine deficiency. We hypothesized that elderly patients with a disease characterized primarily by dopamine depletion (Parkinsonism) would have higher rates of PLMS than age-matched controls or a different neurodegenerative condition not primarily involving a hypodopaminergic state, Alzheimer's disease (AD). METHODS: We compared rates of PLMS derived from in-laboratory overnight polysomnography in patients with Parkinsonism (n = 79), AD (n = 28), and non-neurologically impaired, community-based controls (n = 187). RESULTS: Patients with Parkinsonism not receiving levodopa had significantly higher rates of PLMS than did patients with Parkinsonism receiving levodopa as well as higher rates than seen in AD and controls. Other medications did not appear to exert the pronounced effect of levodopa on PLMS in this Parkinsonian patient population. The symptom of leg kicking was reported more frequently in Parkinsonism and was associated with higher rates of PLMS. Caregiver reported leg kicking was unrelated to PLMS in AD. CONCLUSIONS: Results are broadly compatible with a dopaminergic hypothesis for PLMS in Parkinsonism. The clinical significance of the negative findings in patients with AD requires further investigation.

Self-rated sleep characteristics and bother from nocturia.

PURPOSE: The aim of this study was to evaluate if men with varying degrees of bother from a similar number of nocturia episodes differ with respect to self-rated sleep characteristics and fatigue. MATERIALS AND METHODS: As part of the baseline assessments during a nocturia treatment trial, 55 participants reported frequency and bother of nocturia using the AUA Symptom Inventory and completed 7-day sleep diaries prior to treatment. Participants who reported moderate nocturia (either two or three episodes nightly) were further grouped into categories of LOW (nocturia is no problem or a very small problem) or HIGH bother (nocturia is a big problem). Information from the participant completed sleep diaries was abstracted, including information on daytime napping, total sleep time, mean time needed to return to sleep, nighttime ratings of fatigue, and daytime ratings of fatigue. RESULTS: Of the 55 individuals who completed the pilot study, 24 study participants reported two or three episodes of nocturia and had either HIGH (n = 11) or LOW (n = 13) bother. Participants categorised with HIGH bother were significantly more likely than those with LOW bother to report difficulty initiating sleep (47.7 ± 34.4 vs. 23.5 ± 13.6 min, p = 0.05), difficulty returning to sleep after an awakening (28.9 ± 16.1 vs. 15.4 ± 9.6 min, p = 0.03) and greater morning fatigue (3.3 ± 0.7 vs. 2.5 ± 1.0, p = 0.04 on a 7-point scale). CONCLUSIONS: Since bother related to nocturia is linked to sleep quality, interventions targeting fatigue and sleep maintenance may provide useful targets in the management of nocturia in men.

Disturbed sleep and preterm birth: a potential relationship?

PURPOSE: Many women report disturbed sleep during pregnancy, but its impact on clinical outcomes remains unknown. This study examined subjective sleep quality and daytime sleepiness in relation to preterm birth. METHODS: A convenience sample of 220 pregnant women completed the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Perceived Stress Scale (PSS) during the second trimester. Women who had preterm and full-term births were compared on these measures. RESULTS: The preterm birth rate of the sample was 14.6%. Sleep latency, the period from lights out to sleep onset, was significantly longer in the preterm group, which also reported a tendency to use more sleep medications, but had lower PSQI daytime dysfunction scores. Perceived stress did not differentiate preterm and full-term groups. CONCLUSION: Disturbed sleep in pregnancy may be associated with preterm birth. Future studies should examine specific physiological factors that underlie this increased vulnerability.

Nighttime administration of high-dose, sustained-release melatonin does not decrease nocturnal blood pressure in African-American patients: Results from a preliminary randomized, crossover trial.

OBJECTIVES: This preliminary study tested whether a high-dose, sustained-release form of melatonin reduced 24-hour blood pressure in African-Americans. DESIGN: Randomized, placebo-controlled, crossover pilot study of 40 self-defined African-American patients with essential hypertension. SETTINGS/LOCATION: Urban, academic medical center and associated outpatient clinics. INTERVENTIONS: Patients ingested either melatonin (high dose [24 mg], sustained-release formulation] or placebo in randomized order over a 4-week period. OUTCOME MEASURES: Mean nighttime and daytime systolic and diastolic blood pressures, as measured with 24-hour ambulatory blood pressure monitors. The primary outcome was mean nighttime systolic blood pressure. RESULTS: There were no statistically differences between melatonin and placebo conditions in mean nighttime or daytime systolic or diastolic blood pressures. CONCLUSIONS: In contrast with studies in other populations, this preliminary study showed that nighttime dosing of continuous-release melatonin had no significant effect on nocturnal blood pressure in African Americans with essential hypertension when compared to placebo.

Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a condition characterized by an urge to move the legs, usually accompanied by lower limb paresthesias. These symptoms worsen at rest, are relieved by activity, and are worse at night. Previous studies have suggested that dopaminergic drugs such as L-dopa and dopamine agonists, as well as benzodiazepines and opioids, can treat RLS successfully. The purpose of this study was to test the clinical efficacy of ropinirole, a D2/D3 agonist, in the treatment of RLS in a double-blind, short-term, placebo-controlled clinical trial. PATIENTS AND METHODS: After undergoing successful open-label titration and dose adjustments with ropinirole for RLS symptoms over a period of 4 weeks, 22 RLS patients (mean age=50.8; mean duration of symptoms=26.1 years) were randomized to receive either placebo (n=13) or ropinirole (n=9) for 2 additional weeks. Outcome measures included assessment of periodic leg movements in sleep (PLMS) recorded with nocturnal polysomnography and RLS symptoms as assessed with the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale. Secondary outcomes included sleep macroarchitecture. RESULTS: Results indicated that relative to placebo, ropinirole, at a mean dose of 1.4mg HS significantly decreased PLMS and RLS symptoms. Sleep macroarchitecture did not change. Side effects were typical of all dopamine agonists and were dose related. The majority of patients elected to continue treatment with ropinirole upon study completion. CONCLUSIONS: Ropinirole successfully treated long-standing RLS and can be considered a viable short-term treatment for this condition.

Laboratory sleep correlates of nightmare complaint in PTSD inpatients.

BACKGROUND: Nightmares are rare in the sleep laboratory, even in patients with posttraumatic stress disorder for whom nightmare complaints are diagnostic. Nevertheless, it is possible that laboratory conditions do not preclude the observation of telltales-nightmare-related modifications of tonic sleep-given sufficiently large samples. METHODS: Sixty-three unmedicated, nonapneic Vietnam combat veterans undergoing inpatient treatment for posttraumatic stress disorder underwent polysomnographic testing and assessment of nightmare complaint. RESULTS: Trauma-related nightmare complaint, but not non-trauma-related complaint, was associated with increased wake-after-sleep-onset in the sleep laboratory. No relationships between nightmare complaint and rapid eye movement sleep architecture were observed. CONCLUSIONS: Increased wake-after-sleep-onset was specifically associated with trauma-related nightmare complaint, confirming data from other quarters suggesting they are both phenomenologically and functionally distinct from normal dreaming.

Sleep and depression in combat-related PTSD inpatients.

The sleep of 27 unmedicated Vietnam combat-related posttraumatic stress disorder (PTSD) inpatients was monitored for 3 nights. Depressive comorbidity was considered both as a diagnostic category using DMS-III-R criteria, and as a continuous variable using the Beck Depression Inventory (BDI). Data collected included sleep architecture features that have discriminated unipolar depressives from controls in many prior studies, rapid eye movement (REM) sleep latency, and slow-wave sleep time, as well as two additional indices that have sometimes discriminated depressives from controls in waking studies-baseline heart rate and facial electromyography. Structured Clinical Interview for the DSM-III-R (SCID)-diagnosed PTSD+major depressive disorder (MDD) patients failed to exhibit shorter REM latencies, greater REM percents of sleep, or greater REM densities than PTSD-MDD patients, but did exhibit less slow wave sleep. PTSD+MDD patients also exhibited less facial (mentalis) electromyographic activity. REM densities and baseline heart rates were equivocal. REM density, baseline heart rate, and mentalis electromyography all correlated with the BDI, the former two positively, the last, negatively. In summary, SCID-diagnosed PTSD+MDD patients failed to exhibit the classic REM sleep architectural modifications associated with unipolar depression, despite the fact that several other psychophysiologic indices of dysphoria were detectable in their sleep.

Sleep disturbance produced by electrical stimulation of the locus coeruleus in a human subject.

A 25-year-old man with a chronically implanted stimulating electrode placed in the region of the locus coeruleus (LC) was monitored for 5 nights in a sleep laboratory to study the role of the LC in sleep. Sleep patterns were compared between the 2 nights in which the stimulation was applied periodically every 90 min and the 2 nights in which no stimulation was applied. In contrast to the normal sleep patterns that occurred during the 2 nonstimulation nights, electrical stimulation of the LC produced a profound disruption of sleep and significant reductions in the total amounts of NREM sleep, REM sleep, REM sleep as a percent of total sleep (NREM + REM sleep), and total sleep. Results suggest that the LC has a role in maintaining normal sleep patterns.

REM latency in Alzheimer's disease.

Latency to the first episode of rapid eye movement sleep (REML) has been proposed as a potential biomarker for Alzheimer's disease (AD). In this study, we compared REML values from 28 AD patients and 28 age- and sex-matched controls. We employed multiple definitions of REML and multiple cutoffs to classify patients and controls. Results indicated that the best REML definition and optimal cutoff criterion resulted in only 65% correct classifications. We discuss the longer REML in AD patients relative to controls in terms of both overall sleep disturbance and selective deterioration of the REM-cholinergic system. As REML may be relatively short in other forms of psychopathology (e.g., affective disorders), REML may still hold promise in the differential diagnosis of dementia and pseudodementia.

MSLT-defined sleepiness and neuropsychological test performance do not correlate in the elderly.

This study investigated whether a sensitive, physiological measure of alertness/sleepiness, the Multiple Sleep Latency Test (MSLT), was related to neuropsychological test performance in elderly individuals. We hypothesized that the greater likelihood of falling asleep during the daytime on the MSLT would be related to relatively poorer performances on a variety of neuropsychological tests. Results from a homogeneous sample of 35 relatively well-educated, high functioning, elderly community volunteers confirmed the presence of characteristic levels of daytime alertness which were stable within individuals (r = .70 to .73) and showed large variation across individuals (coefficients of variation: 54-84%). Despite this wide intersubject variability, MSLT-defined alertness/sleepiness was unrelated to neuropsychological test results. We discuss these results in terms of the performance deficits known to accompany sleepiness in experimental studies of sleep deprivation and in terms of the behavioral slowing known to occur in normal aging.

Sleep apnea in Alzheimer's disease.

Mental deterioration accompanying sleep apnea has been noted frequently. Because sleep apnea increases with age, such deficits raise the possibility that dementia in the elderly could be related to sleep apnea. In this study we investigated this possibility cross-sectionally by comparing respiration during sleep in 28 patients with Alzheimer's disease (AD) and 25 nondemented controls. We hypothesized that higher levels of sleep apnea would be present in AD patients. Our results indicated no significant differences between AD patients and controls but those few AD patients who desaturated during sleep experienced morning confusion. The findings imply that AD and sleep apnea are two separate conditions which may still interact in the aged.

Abundant REM sleep in a patient with Alzheimer's disease.

In patients with Alzheimer's disease (AD), greatly diminished REM sleep might be expected because of the cholinergic deficit in this disease and because cholinergic agonists stimulate REM sleep in humans and animals. We present here an unusual case of neuropathologically verified AD with abundant REM sleep. We suggest 4 possible explanations for this phenomenon: (1) selective cell loss in caudal midbrain/rostral pontine structures known to control sleep; (2) development of narcolepsy; (3) unrecognized affective disorder; (4) disruption of circadian timekeeping system.

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.

Habitual sleep patterns and risk for stroke and coronary heart disease: a 10-year follow-up from NHANES I.

BACKGROUND: Habitual sleep patterns may independently affect morbidity and mortality. However, the effect of habitual sleep patterns on the risk for stroke and coronary heart disease is unclear. METHODS: We evaluated the association between sleep duration and daytime somnolence (often or almost always taking daytime naps) with the incidence of stroke and coronary heart disease in a national cohort of 7,844 adults who participated in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Cox proportional hazards analyses were used to examine these relationships during the 10-year follow-up. RESULTS: After adjusting for differences in age, race, gender, education, cigarette smoking, body mass index, serum cholesterol, systolic blood pressure, and diabetes mellitus, the risk for stroke was increased in persons who reported sleeping greater than 8 hours at night compared with persons who slept between 6 and 8 hours (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.1 to 2.0). Daytime somnolence was also associated with stroke incidence (RR = 1.4, 95% CI = 1.1 to 1.8). Persons who reported both greater than 8 hours of sleep and daytime somnolence were at the greatest risk for stroke (RR = 1.9, 95% CI = 1.2 to 3.1). Similar results were also found for coronary heart disease, although the results did not reach statistical significance in the multivariate adjusted model. CONCLUSIONS: Habitual sleep patterns have significant effects on the risk for stroke.

Presentation of narcolepsy after 40.

To advance understanding of the clinical spectra of narcolepsy, we retrospectively reviewed the histories and clinical and polysomnographic features of 41 consecutive patients in whom this diagnosis was established in our center over 3 years. A total of 51% presented after the age of 40 years. Among the older patients, three subpopulations were noted: 1) narcolepsy/cataplexy with presentation delayed because of mild disease severity or misdiagnosis; 2) narcolepsy/cataplexy with diagnosis delayed until late-life expression of cataplexy; and 3) narcolepsy lacking cataplexy with later-life onset of excessive daytime sleepiness. Clinical, polysomnographic, and multiple sleep latency test assessments of rapid eye movement sleep dyscontrol and sleepiness were unrelated to age. This analysis identified older patients lacking cataplexy as the least severely affected narcoleptic subgroup. Narcolepsy, a continuum of phenotypes and severities that masks its recognition, should be considered in the differential diagnosis of sleepiness or transient loss of muscle tone in older patients.

Juvenile Parkinson's disease with REM sleep behavior disorder, sleepiness, and daytime REM onset.

We describe an unmedicated patient with juvenile PD with difficulties maintaining wakefulness and the atonia of REM sleep. Laboratory testing showed enhanced muscle activity in REM sleep consistent with a history of dream enactment behavior (i.e., REM sleep behavior disorder) and daytime sleepiness, and REM-sleep onsets on multiple sleep latency testing. The results emphasize the potential role of dopamine and basal ganglia circuits in the modulation of activated behavioral states (e.g., wakefulness and REM sleep).

Historical change in the report of daytime fatigue.

Population-based data suggesting that contemporary society does not value sleep are difficult to obtain. In this report, historical change in item endorsements relevant for disturbed sleep and daytime fatigue from the Minnesota Multiphasic Personality Inventory (MMPI) generated from normative, upper Midwestern adult populations was analyzed. Response rates from the 1930s and 1980 were compared. The data indicated that, relative to individuals in the post-Great Depression/pre-World War II era, contemporary men were more likely to report fatigue and tiredness, although they were no more likely to report disturbed nocturnal sleep. The results are compatible with the voluntary curtailment of sleep typical in modern society described in the report of the National Commission on Sleep Disorders Research.

A method for checking interobserver reliability in observational sleep studies.

Disturbances of the sleep/wake cycle occur frequently in nursing home residents. Because of the many technical difficulties in studying sleep and rhythms in such patients, systematic behavioral observations offer an alternative approach. In this study we describe a method for determining interrater reliability of such observations. Two individuals observed 39 nursing home residents four times per hour during daytime and nighttime hours. Results indicated high interrater reliability for both sleep/wake and the presence of apnea during sleep. Both day and night observations were made reliably. We found only 101 discrepancies of 1.160 tandem observations. These results suggests that behavioral observations are a viable approach in the study of the sleep/wake cycle in nursing home settings.