Yo-El Ju

Sleep Quality and Preclinical Alzheimer Disease

IMPORTANCE Sleep and circadian problems are very common in Alzheimer disease (AD). Recent animal studies suggest a bidirectional relationship between sleep and β-amyloid (Aβ), a key molecule involved in AD pathogenesis. OBJECTIVE To test whether Aβ deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep. DESIGN Cross-sectional study conducted from October 2010 to June 2012. SETTING General community volunteers at the Washington University Knight Alzheimers Disease Research Center. PARTICIPANTS Cognitively normal individuals (n = 145) 45 years and older were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimers Disease Research Center. Valid actigraphy data were recorded in 142. The majority (124 of 142) were recruited from the Adult Children Study, in which all were aged 45 to 75 years at baseline and 50% have a parental history of late-onset AD. The rest were recruited from a community volunteer cohort in which all were older than 60 years and healthy at baseline. MAIN OUTCOME MEASURES Sleep was objectively measured using actigraphy for 2 weeks. Sleep efficiency, which is the percentage of time in bed spent asleep, was the primary measure of sleep quality. Total sleep time was the primary measure of sleep quantity. Cerebrospinal fluid Aβ42 levels were used to determine whether amyloid deposition was present or absent. Concurrent sleep diaries provided nap information. RESULTS Amyloid deposition, as assessed by Aβ42 levels, was present in 32 participants (22.5%). This group had worse sleep quality, as measured by sleep efficiency (80.4% vs 83.7%), compared with those without amyloid deposition, after correction for age, sex, and APOEε4 allele carrier status (P = .04). In contrast, quantity of sleep was not significantly different between groups, as measured by total sleep time. Frequent napping, 3 or more days per week, was associated with amyloid deposition (31.2% vs 14.7%; P = .03). CONCLUSIONS AND RELEVANCE Amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality but not with changes in sleep quantity.

Sleep and Alzheimer disease pathology—a bidirectional relationship

Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid-β (Aβ) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleep–wake cycle directly influences levels of Aβ in the brain. In experimental models, sleep deprivation increases the concentration of soluble Aβ and results in chronic accumulation of Aβ, whereas sleep extension has the opposite effect. Furthermore, once Aβ accumulates, increased wakefulness and altered sleep patterns develop. Individuals with early Aβ deposition who still have normal cognitive function report sleep abnormalities, as do individuals with very mild dementia due to AD. Thus, sleep and neurodegenerative disease may influence each other in many ways that have important implications for the diagnosis and treatment of AD.

Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System

BACKGROUND The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). OBJECTIVE To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. DESIGN Repeated-measures case-control study. SETTING Washington University School of Medicine in St Louis, Missouri. PARTICIPANTS Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. MAIN OUTCOME MEASURES In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. RESULTS Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. CONCLUSIONS A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

A single-question screen for rapid eye movement sleep behavior disorder: A multicenter validation study†

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinsons disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large‐scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single‐Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.

Environmental risk factors for REM sleep behavior disorder: A multicenter case-control study

Objective: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. Methods: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. Results: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). Conclusions: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels

See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-β, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimers disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-β or other Alzheimers disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-β, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-β40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-β, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-β levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep.

Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid.

We hypothesized that one mechanism underlying the association between obstructive sleep apnea (OSA) and Alzheimers disease is OSA leading to decreased slow wave activity (SWA), increased synaptic activity, decreased glymphatic clearance, and increased amyloid‐β. Polysomnography and lumbar puncture were performed in OSA and control groups. SWA negatively correlated with cerebrospinal fluid (CSF) amyloid‐β‐40 among controls and was decreased in the OSA group. Unexpectedly, amyloid‐β‐40 was decreased in the OSA group. Other neuronally derived proteins, but not total protein, were also decreased in the OSA group, suggesting that OSA may affect the interaction between interstitial and cerebrospinal fluid. Ann Neurol 2016;80:154–159

Treatment of Sleep Disorders in Dementia

Opinion statementSleep and circadian disorders occur frequently in all types of dementia. Due to the multifactorial nature of sleep problems in dementia, we propose a structured approach to the evaluation and treatment of these patients. Primary sleep disorders such as obstructive sleep apnea should be treated first. Comorbid conditions and medications that impact sleep should be optimally managed to minimize negative effects on sleep. Patients and caregivers should maintain good sleep hygiene, and social and physical activity should be encouraged during the daytime. Given the generally benign nature of bright light therapy and melatonin, these treatments should be tried first. Pharmacological treatments should be added cautiously, due to the risk of cognitive side effects, sedation, and falls in the demented and older population. Regardless of treatment modality, it is essential to follow patients with dementia and sleep disorders closely, with serial monitoring of individual response to treatment.

Rapid eye movement sleep behavior disorder in adults younger than 50 years of age

Rapid eye movement (REM) sleep behavior disorder (RBD) occurring prior to age 50 is termed early-onset RBD. Early-onset RBD comprises a substantial minority of cases, and demonstrates the differences in demographics, comorbidities, and clinical considerations from previously described typical RBD with onset >50years. The world literature on RBD is reviewed with specific focus on features that distinguish early-onset RBD, including more gender parity, increased proportion of idiopathic cases, increased proportion of cases associated with narcolepsy, parasomnia overlap disorder, antidepressants, and possibly autoimmune disorders, and clinical presentation.

Morbidities in rapid eye movement sleep behavior disorder

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, RBD without any obvious comorbid major neurological disease), is strongly associated with numerous comorbid conditions. The most prominent is that with neurodegenerative disorders, especially synuclein-mediated disorders, above all Parkinson disease (PD). Idiopathic RBD is an important risk factor for the development of synucleinopathies. Comorbidity studies suggest that iRBD is associated with a number of other potential pre-motor manifestations of synucleinopathies such as, cognitive and olfactory impairment, reduced autonomic function, neuropsychiatric manifestations and sleep complaints. Furthermore, patients with PD and RBD may have worse prognosis in terms of impaired cognitive function and overall morbidity/mortality; in dementia, the presence of RBD is strongly associated with clinical hallmarks and pathological findings of dementia with Lewy bodies. These findings underline the progressive disease process, suggesting involvement of more brain regions in patients with a more advanced disease stage. RBD is also associated with narcolepsy, and it is likely that RBD associated with narcolepsy is a distinct subtype associated with different comorbidities. RBD is also associated with antidepressant medications, autoimmune conditions, and, in rare cases, brainstem lesions.