SUMMARY Sleep–wake disturbances are a highly prevalent and often disabling feature of Alzheimer's disease (AD). A cardinal feature of AD includes the formation of amyloid plaques, associated with the extracellular accumulation of the amyloid-β (Aβ) peptide. Evidence from animal and human studies suggests that Aβ pathology may disrupt the sleep–wake cycle, in that as Aβ accumulates, more sleep–wake fragmentation develops. Furthermore, recent research in animal and human studies suggests that the sleep–wake cycle itself may influence Alzheimer's disease onset and progression. Chronic sleep deprivation increases amyloid plaque deposition, and sleep extension results in fewer plaques in experimental models. In this review geared towards the practicing clinician, we discuss possible mechanisms underlying the reciprocal relationship between the sleep–wake cycle and AD pathology and behavior, and present current approaches to therapy for sleep disorders in AD.

Sleep–wake disturbances following traumatic brain injury (TBI) are increasingly recognized as a serious consequence following injury and as a barrier to recovery. Injury-induced sleep–wake disturbances can persist for years, often impairing quality of life. Recently, there has been a nearly exponential increase in the number of primary research articles published on the pathophysiology and mechanisms underlying sleep–wake disturbances after TBI, both in animal models and in humans, including in the pediatric population. In this review, we summarize over 200 articles on the topic, most of which were identified objectively using reproducible online search terms in PubMed. Although these studies differ in terms of methodology and detailed outcomes; overall, recent research describes a common phenotype of excessive daytime sleepiness, nighttime sleep fragmentation, insomnia, and electroencephalography spectral changes after TBI. Given the heterogeneity of the human disease phenotype, rigorous translation of animal models to the human condition is critical to our understanding of the mechanisms and of the temporal course of sleep–wake disturbances after injury. Arguably, this is most effectively accomplished when animal and human studies are performed by the same or collaborating research programs. Given the number of symptoms associated with TBI that are intimately related to, or directly stem from sleep dysfunction, sleep–wake disorders represent an important area in which mechanistic-based therapies may substantially impact recovery after TBI.

Mild traumatic brain injury causes persistent deficits in wakefulness in mice, which are mitigated by a dietary therapy containing branched-chain amino acids.

To describe the crude prevalence of rapid eye movement (REM) sleep behavior disorder (RBD) following traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) in Veterans, given potential relationships between TBI, PTSD, RBD, and neurodegeneration. Veterans (n = 394; 94% male; 54.4 ± 15.5 years of age) were prospectively/cross-sectionally recruited from the VA Portland Health Care System and completed in-lab video-polysomnography and questionnaires. TBI and PTSD were assessed via diagnostic screening and medical record review. Subjects were categorized into four groups after assessment of REM sleep without atonia (RSWA) and self-reported dream enactment: (1) “Normal,” neither RSWA nor dream enactment, (2) “Other Parasomnia,” dream enactment without RSWA, (3) “RSWA,” isolated-RSWA without dream enactment, and (4) “RBD,” RSWA with dream enactment. Crude prevalence, prevalence odds ratio, and prevalence rate for parasomnias across subjects with TBI and/or PTSD were assessed. Overall prevalence rates were 31%, 7%, and 9% for Other Parasomnia, RSWA, and RBD, respectively. The prevalence rate of RBD increased to 15% in PTSD subjects [age adjusted POR: 2.81 (1.17–4.66)] and to 21% in TBI + PTSD subjects [age adjusted POR: 3.43 (1.20–9.35)]. No subjects met all diagnostic criteria for trauma-associated sleep disorder (TASD), and no overt dream enactment was captured on video. The prevalence of RBD and related parasomnias is significantly higher in Veterans compared with the general population and is associated with PTSD and TBI + PTSD. Considering the association between idiopathic-RBD and synucleinopathy, it remains unclear whether RBD (and potentially TASD) associated with PTSD or TBI + PTSD similarly increases risk for long-term neurologic sequelae.

Across mammals, juveniles sleep more than adults, with rapid eye movement (REM) sleep at a lifetime maximum early in life. One function of REM sleep may be to facilitate brain development of complex behaviors. Here, we applied 1 week of early-life sleep disruption (ELSD) in prairie voles (Microtus ochrogaster), a highly social rodent species that forms lifelong pair bonds. Electroencephalographic recordings from juvenile voles during ELSD revealed decreased REM sleep and reduced γ power compared to baseline. ELSD impaired pair bond formation and altered object preference in adulthood. Furthermore, ELSD increased GABAergic parvalbumin immunoreactivity in the primary somatosensory cortex in adulthood, a brain region relevant to both affected behaviors. We propose that, early in life, sleep is crucial for tuning inhibitory neural circuits and the development of species-typical affiliative social behavior.

Evidence from previous studies suggests that greater sleep pressure, in the form of EEG-based slow waves, accumulates in specific brain regions that are more active during prior waking experience. We sought to quantify the number and coherence of EEG slow waves in subjects with mild traumatic brain injury (mTBI). We developed a method to automatically detect individual slow waves in each EEG channel, and validated this method using simulated EEG data. We then used this method to quantify EEG-based slow waves during sleep and wake states in both mouse and human subjects with mTBI. A modified coherence index that accounts for information from multiple channels was calculated as a measure of slow wave synchrony. Brain-injured mice showed significantly higher theta:alpha amplitude ratios and significantly more slow waves during spontaneous wakefulness and during prolonged sleep deprivation, compared to sham-injured control mice. Human subjects with mTBI showed significantly higher theta:beta amplitude ratios and significantly more EEG slow waves while awake compared to age-matched control subjects. We then quantified the global coherence index of slow waves across several EEG channels in human subjects. Individuals with mTBI showed significantly less EEG global coherence compared to control subjects while awake, but not during sleep. EEG global coherence was significantly correlated with severity of post-concussive symptoms (as assessed by the Neurobehavioral Symptom Inventory scale). Taken together, our data from both mouse and human studies suggest that EEG slow wave quantity and the global coherence index of slow waves may represent a sensitive marker for the diagnosis and prognosis of mTBI and post-concussive symptoms.