Predicting neurodegeneration from sleep related biofluid changes.

Sleep-wake disturbances are common in neurodegenerative diseases and may occur years before the clinical diagnosis, potentially either representing an early stage of the disease itself or acting as a pathophysiological driver. Therefore, discovering biomarkers that identify individuals with sleep-wake disturbances who are at risk of developing neurodegenerative diseases will allow early diagnosis and intervention. Given the association between sleep and neurodegeneration, the most frequently analyzed fluid biomarkers in people with sleep-wake disturbances to date include those directly associated with neurodegeneration itself, such as neurofilament light chain, phosphorylated tau, amyloid-beta and alpha-synuclein. Abnormalities in these biomarkers in patients with sleep-wake disturbances are considered as evidence of an underlying neurodegenerative process. Levels of hormonal sleep-related biomarkers such as melatonin, cortisol and orexin are often abnormal in patients with clinical neurodegenerative diseases, but their relationships with the more standard neurodegenerative biomarkers remain unclear. Similarly, it is unclear whether other chronobiological/circadian biomarkers, such as disrupted clock gene expression, are causal factors or a consequence of neurodegeneration. Current data would suggest that a combination of fluid biomarkers may identify sleep-wake disturbances that are most predictive for the risk of developing neurodegenerative disease with more optimal sensitivity and specificity.

Parkinsonian daytime sleep-wake classification using deep brain stimulation lead recordings.

Excessive daytime sleepiness is a recognized non-motor symptom that adversely impacts the quality of life of people with Parkinson's disease (PD), yet effective treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for PD motor signs. Reliable daytime sleep-wake classification using local field potentials (LFPs) recorded from DBS leads implanted in STN can inform the development of closed-loop DBS approaches for prompt detection and disruption of sleep-related neural oscillations. We performed STN DBS lead recordings in three nonhuman primates rendered parkinsonian by administrating neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Reference sleep-wake states were determined on a second-by-second basis by video monitoring of eyes (eyes-open, wake and eyes-closed, sleep). The spectral power in delta (1-4 Hz), theta (4-8 Hz), low-beta (8-20 Hz), high-beta (20-35 Hz), gamma (35-90 Hz), and high-frequency (200-400 Hz) bands were extracted from each wake and sleep epochs for training (70% data) and testing (30% data) a support vector machines classifier for each subject independently. The spectral features yielded reasonable daytime sleep-wake classification (sensitivity: 90.68 ± 1.28; specificity: 88.16 ± 1.08; accuracy: 89.42 ± 0.68; positive predictive value; 88.70 ± 0.89, n = 3). Our findings support the plausibility of monitoring daytime sleep-wake states using DBS lead recordings. These results could have future clinical implications in informing the development of closed-loop DBS approaches for automatic detection and disruption of sleep-related neural oscillations in people with PD to promote wakefulness.

Meningitis, meningoencephalitis and encephalitis in Bern: an observational study of 258 patients.

BACKGROUND: Depending on geographic location, causes of encephalitis, meningoencephalitis and meningitis vary substantially. We aimed to identify the most frequent causes, clinical presentation and long-term outcome of encephalitis, meningoencephalitis and meningitis cases treated in the Inselspital University Hospital Bern, Switzerland. METHODS: In this monocentric, observational study, we performed a retrospective review of clinical patient records for all patients treated within a 3-year period. Patients were contacted for a telephone follow-up interview and to fill out questionnaires, especially related to disturbances of sleep and wakefulness. RESULTS: We included 258 patients with the following conditions: encephalitis (18%), nonbacterial meningoencephalitis (42%), nonbacterial meningitis (27%) and bacterial meningoencephalitis/meningitis (13%). Herpes simplex virus (HSV) was the most common cause of encephalitis (18%); tick-borne encephalitis virus (TBEV) was the most common cause of nonbacterial meningoencephalitis (46%), enterovirus was the most common cause of nonbacterial meningitis (21%) and Streptococcus pneumoniae was the most common cause of bacterial meningoencephalitis/meningitis (49%). Overall, 35% patients remained without a known cause. After a median time of 16 months, 162 patients participated in the follow-up interview; 56% reported suffering from neurological long-term sequelae such as fatigue and/or excessive daytime sleepiness (34%), cognitive impairment and memory deficits (22%), headache (14%) and epileptic seizures (11%). CONCLUSIONS: In the Bern region, Switzerland, TBEV was the overall most frequently detected infectious cause, with a clinical manifestation of meningoencephalitis in the majority of cases. Long-term neurological sequelae, most importantly cognitive impairment, fatigue and headache, were frequently self-reported not only in encephalitis and meningoencephalitis survivors but also in viral meningitis survivors up to 40 months after acute infection.

Frequency and characteristics of drowsiness, somnolence, or daytime sleepiness in patients with advanced cancer.

INTRODUCTION: Cancer-related drowsiness (CRD) is a distressing symptom in advanced cancer patients (ACP). The aim of this study was to determine the frequency and factors associated with severity of CRD. We also evaluated the screening performance of Edmonton Symptom Assessment Scale-drowsiness (ESAS-D) item against the Epworth Sedation Scale (ESS). METHOD: We prospectively assessed 180 consecutive ACP at a tertiary cancer hospital. Patients were surveyed using ESAS, ESS, Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Hospital Anxiety Depression Scale. RESULT: Ninety of 150 evaluable patients had clinically significant CRD (ESS); median (interquartile ratio): ESS. 11 (7-14); ESAS-D. 5 (2-6); Pittsburgh Sleep Quality Index. 8 (5-11); Insomnia Severity Index. 13 (5-19); Stop Bang Scoring 3 (2-4), and Hospital Anxiety Depression Scale-D 6 (3-10). ESAS-D was associated with ESAS (r, p) sleep (0.38, <0.0001); pain (0.3, <0.0001); fatigue (0.51, <0.0001); depression (0.39, <0.0001); anxiety (0.44, <0.0001); shortness of breath (0.32, <0.0001); anorexia (0.36, <0.0001), feeling of well-being [(0.41, <0.0001), ESS (0.24, 0.001), and opioid daily dose (0.19, 0.01). Multivariate-analysis showed ESAS-D was associated with fatigue (odds ratio [OR] = 9.08, p < 0.0001), anxiety (3.0, p = 0.009); feeling of well-being (OR = 2.27, p = 0.04), and insomnia (OR = 2.35; p = 0.036). Insomnia (OR = 2.35; p = 0.036) cutoff score ≥3 (of 10) resulted in a sensitivity of 81% and 32% and specificity of 70% and 44% in the training and validation samples, respectively. SIGNIFICANCE OF RESULTS: Clinically significant CRD is frequent and seen in 50% of ACP. CRD was associated with severity of insomnia, fatigue, anxiety, and worse feeling of well-being. An ESAS-D score of ≥3 is likely to identify most of the ACP with significant CRD.

Lucid dreams, an atypical sleep disturbance in anterior and mediodorsal thalamic strokes.

BACKGROUND: Cognitive, affective, and behavioural disturbances are commonly reported following thalamic strokes. Conversely, sleep disorders are rarely reported in this context. OBSERVATIONS: Herein, we report the cases of two young patients admitted for an ischemic stroke located in the territories of the left pre-mammillary and paramedian arteries. Together with aphasia, memory complaint, impaired attention and executive functions, they reported lucid dreams with catastrophic content or conflicting situations. CONCLUSION: Lucid dreams are an atypical presentation in thalamic strokes. These cases enlarge the clinical spectrum of sleep-wake disturbances potentially observed after an acute cerebrovascular event.

Sleep and wake disturbances following traumatic brain injury.

Traumatic brain injury (TBI) is a major health concern in industrialised countries. Sleep and wake disturbances are among the most persistent and disabling sequelae after TBI. Yet, despite the widespread complaints of post-TBI sleep and wake disturbances, studies on their etiology, pathophysiology, and treatments remain inconclusive. This narrative review aims to summarise the current state of knowledge regarding the nature of sleep and wake disturbances following TBI, both subjective and objective, spanning all levels of severity and phases post-injury. A second goal is to outline the various causes of post-TBI sleep-wake disturbances. Globally, although sleep-wake complaints are reported in all studies and across all levels of severity, consensus regarding the objective nature of these disturbances is not unanimous and varies widely across studies. In order to optimise recovery in TBI survivors, further studies are required to shed light on the complexity and heterogeneity of post-TBI sleep and wake disturbances, and to fully grasp the best timing and approach for intervention.

Slow-wave sleep dysfunction in mild parkinsonism is associated with excessive beta and reduced delta oscillations in motor cortex.

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson's disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8-35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5-3 Hz) power was reduced (p = 0.038) whereas beta (8-35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = -0.65, p < 0.001). Our findings support excessive beta oscillations as a mechanism for SWS dysfunction in mild parkinsonism and could inform the development of neuromodulation therapies for enhancing SWS in people with PD.

Chronic Astrocytic TNFα Production in the Preoptic-Basal Forebrain Causes Aging-like Sleep-Wake Disturbances in Young Mice.

Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging.

Lifelong Chronic Sleep Disruption in a Mouse Model of Traumatic Brain Injury.

Chronic sleep/wake disturbances (SWDs) are strongly associated with traumatic brain injury (TBI) in patients and are being increasingly recognized. However, the underlying mechanisms are largely understudied and there is an urgent need for animal models of lifelong SWDs. The objective of this study was to develop a chronic TBI rodent model and investigate the lifelong chronic effect of TBI on sleep/wake behavior. We performed repetitive midline fluid percussion injury (rmFPI) in 4-month-old mice and monitored their sleep/wake behavior using the non-invasive PiezoSleep system. Sleep/wake states were recorded before injury (baseline) and then monthly thereafter. We found that TBI mice displayed a significant decrease in sleep duration in both the light and dark phases, beginning at 3 months post-TBI and continuing throughout the study. Consistent with the sleep phenotype, these TBI mice showed circadian locomotor activity phenotypes and exhibited reduced anxiety-like behavior. TBI mice also gained less weight, and had less lean mass and total body water content, compared to sham controls. Further, TBI mice showed extensive brain tissue loss and increased glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 levels in the hypothalamus and vicinity of the injury, indicative of chronic neuropathology. In summary, our study identified a critical time window of TBI pathology and associated circadian and sleep/wake phenotypes. Future studies should leverage this mouse model to investigate the molecular mechanisms underlying the chronic sleep/wake phenotypes post-TBI early in life.

Immune-endocrine interactions in the pathophysiology of sleep-wake disturbances following traumatic brain injury: A narrative review.

Following a traumatic brain injury (TBI), sleep-wake disturbances are one of the most prevalent and debilitating symptoms. A better understanding of the impact that sleep disturbances have on chronic TBI symptomatology is likely to maximize long-term recovery. While the current treatments of sleep-wake disturbances following TBI are disorder-specific, identifying the underlying pathology may lead to improved pharmacological and rehabilitative treatments. A TBI initiates secondary cellular and molecular cascades that include inflammation and the production of cytokines, as well endocrine dysfunction and concomitant disturbances in hormone secretions. Hormones and cytokines are mediators of the inflammatory response that also regulate endocrine function, thus, communication between the immune and endocrine systems is bidirectional. Interestingly, both the immune and endocrine systems play a critical role in sleep regulation. This narrative review summarizes sleep-wake disturbances reported after TBI and synthesizes the current human and animal literature centered on the hypothesis that immune-endocrine interactions after TBI may induce both acute and chronic disturbances of sleep and wakefulness. Furthermore, we discuss how the immune and endocrine systems may be plausible therapeutic targets to treat TBI-induced sleep disturbances.

Microglia Are Necessary to Regulate Sleep after an Immune Challenge.

Microglia play a critical role in the neuroimmune response, but little is known about the role of microglia in sleep following an inflammatory trigger. Nevertheless, decades of research have been predicated on the assumption that an inflammatory trigger increases sleep through microglial activation. We hypothesized that mice (n = 30) with depleted microglia using PLX5622 (PLX) would sleep less following the administration of lipopolysaccharide (LPS) to induce inflammation. Brains were collected and microglial morphology was assessed using quantitative skeletal analyses and physiological parameters were recorded using non-invasive piezoelectric cages. Mice fed PLX diet had a transient increase in sleep that dissipated by week 2. Subsequently, following a first LPS injection (0.4 mg/kg), mice with depleted microglia slept more than mice on the control diet. All mice were returned to normal rodent chow to repopulate microglia in the PLX group (10 days). Nominal differences in sleep existed during the microglia repopulation period. However, following a second LPS injection, mice with repopulated microglia slept similarly to control mice during the dark period but with longer bouts during the light period. Comparing sleep after the first LPS injection to sleep after the second LPS injection, controls exhibited temporal changes in sleep patterns but no change in cumulative minutes slept, whereas cumulative sleep in mice with repopulated microglia decreased during the dark period across all days. Repopulated microglia had a reactive morphology. We conclude that microglia are necessary to regulate sleep after an immune challenge.

Peripheral Clock System Abnormalities in Patients With Parkinson's Disease.

Objective: To evaluate the altered expression of peripheral clock genes, circulating melatonin levels, and their correlations with sleep-wake phenotypes including probable rapid eye movement sleep behavior disorder (pRBD) symptoms in a relatively large population of Parkinson's disease (PD) patients. Methods: We determined the expression profiles of five principal clock genes, BMAL1, CLOCK, CRY1, PER1, and PER2, in the peripheral blood mononuclear cells (PBMCs) of PD patients (n = 326), and healthy controls (HC, n = 314) using quantitative real-time PCR. Melatonin concentration in the plasma of two groups was evaluated by enzyme-linked immunosorbent assay. Then we performed comprehensive association analyses on the PBMCs clock gene expression, plasma melatonin levels and sleep characteristics. Results: Our data showed that the expression levels of BMAL1, CLOCK, CRY1, PER1, and PER2 were significantly decreased in the PBMCs of PD as compared with that of HC (P < 0.05). PD patients had reduced plasma melatonin levels compared with HC (P < 0.0001). pRBD and excessive daytime sleepiness are common in these PD patients and are associated with the expression levels of all five clock genes (r = -0.344∼-0.789, P < 0.01) and melatonin concentration (r = -0.509∼-0.753, P < 0.01). Statistical analyses also revealed that a combination of five clock genes and melatonin could reach a high diagnostic performance (areas under the curves, 97%) for PD comorbid pRBD. Conclusion: This case-control study demonstrates that peripheral BMAL1, CLOCK, CRY1, PER1, PER2, and melatonin levels are altered in PD patients and may serve as endogenous markers for sleep and wakefulness disturbances of PD.

Sleep apnea syndrome and subthalamic stimulation in Parkinson's disease.

OBJECTIVES: Τhe association between Parkinson's disease (PD) and sleep apnea syndrome (SAS) is not fully elucidated and very few studies reported on SAS outcome after deep brain stimulation (DBS). Here, we compare the clinical profile of PD patients with and without SAS and assess, for the first time, the value of pre-DBS SAS as predictor of post-DBS outcome in PD. METHODS: Fifty patients were grouped into PD with SAS (PD-SAS+,n = 22) and without (PD-SAS-,n = 28), based on the Apnea-Hypopnea-Index (AHI≥5) in polysomnography. We used novel multivariate statistical models to compare pre-DBS profiles and assess post-DBS motor, non-motor and quality of life (QoL) changes in both groups. RESULTS: In the entire cohort, 44% of patients had at least mild SAS (AHI≥5), while 22% had at least moderate (AHI≥15). Mean AHI was 11/h (NREM-AHI = 10.2/h and REM-AHI = 13.5/h). The two groups had equal demographics and PD characteristics, and did not differ in respect to unified Parkinson's disease rating scale (UPDRS)-IIOFF, Body-Mass-Index, polysomnographic features, RBD, depression, sleepiness and QoL scores. The PD-SAS+ group had significantly higher scores in UPDRS-IIIOFF (41.1 ± 17.7 vs. 30.9 ± 11.7,p < 0.05) compared to PD-SAS- group. The groups did not differ in respect to post-DBS change in UPDRS-II, UPDRS-III, Epworth sleepiness scale, Hamilton depression rating scale and PDQ39 scores. Positive airway pressure therapy had no impact on post-DBS outcome. CONCLUSIONS: In patients with PD and candidates for DBS, the presence of SAS is associated with increased motor signs, but not with a specific non-motor, QoL or sleep-wake profile. The presence of SAS prior to STN-DBS is not associated with worse outcome after surgery.

Effects of Deep Brain Stimulation on Sleep-Wake Disturbances in Patients with Parkinson's Disease: A Narrative Review.

Sleep-wake disturbances (SWD) are one of the most common non-motor symptoms in the Parkinson's disease (PD) and can appear in the early stage, even before the onset of motor symptoms. Deep brain stimulation (DBS) is an established treatment for the motor symptoms in patients with advanced PD. However, the effect of DBS on SWD and its specific mechanisms are not widely understood and remain controversial. In addition to the circuit-mediated direct effect, DBS may improve SWD by an indirect effect, such as the resolution of nocturnal motor complications and a reduction of dopaminergic medication. Here, the authors review the recent literatures regarding the impact of DBS on SWD in patients with PD. Furthermore, the selection of the DBS targets and the specific effects of applying DBS to each target on SWD in PD are also discussed.

Sleep-wake characteristics in a mouse model of severe traumatic brain injury: Relation to posttraumatic epilepsy.

Study objectives: Traumatic brain injury (TBI) results in sequelae that include posttraumatic epilepsy (PTE) and sleep-wake disturbances. Here, we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. Methods: Following controlled cortical impact (CCI) or sham injury (craniotomy only), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2, or 3) 1-week-long video-EEG recordings were performed after the injury to examine epileptiform activity. High-amplitude interictal events were extracted from EEG using an automated method. After scoring sleep-wake patterns, sleep spindles and EEG delta power were derived from nonrapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed in sham and CCI cohorts to quantify the brain lesions. We then employed a no craniotomy (NC) control to perform 1-week-long EEG recordings at week 1 and month 1 after surgery. Results: Posttraumatic seizures were seen in the CCI group only, whereas interictal epileptiform activity was seen in CCI or sham. Sleep-wake disruptions consisted of shorter wake or NREM bout lengths and shorter duration or lower power for spindles in CCI and sham. NREM EEG delta power increased in CCI and sham groups compared with NC though the CCI group with posttraumatic seizures had lower power at a chronic time point compared with those without. Follow-up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. Significance: In our TBI model, tracking changes in NREM delta power distinguishes between CCI acutely and animals that will eventually develop PTE, but further work is necessary to identify sleep biomarkers of PTE. Employing NC controls together with sham controls should be considered in future TBI studies.

The Prevalence and Stability of Sleep-Wake Disturbance and Fatigue throughout the First Year after Mild Traumatic Brain Injury.

In this prospective, longitudinal study, we aimed to determine the prevalence and stability of sleep-wake disturbance (SWD) and fatigue in a large representative sample of patients (Trondheim mild traumatic brain injury [mTBI] follow-up study). We included 378 patients with mTBI (age 16-60), 82 matched trauma controls with orthopedic injuries, and 83 matched community controls. Increased sleep need, poor sleep quality, excessive daytime sleepiness, and fatigue were assessed at 2 weeks, 3 months, and 12 months after injury. Mixed logistic regression models were used to evaluate clinically relevant group differences longitudinally. Prevalence of increased sleep need, poor sleep quality, and fatigue was significantly higher in patients with mTBI than in both trauma controls and community controls at all time points. More patients with mTBI reported problems with excessive daytime sleepiness compared to trauma controls, but not community controls, at all time points. Patients with complicated mTBI (intracranial findings on computed tomography or magnetic resonance imaging) had more fatigue problems compared to those with uncomplicated mTBI, at all three time points. In patients with mTBI who experienced SWDs and fatigue 2 weeks after injury, around half still had problems at 3 months and approximately one third at 12 months. Interestingly, we observed limited overlap between the different symptom measures; a large number of patients reported one specific problem with SWD or fatigue rather than several problems. In conclusion, our results provide strong evidence that mTBI contributes significantly to the development and maintenance of SWDs and fatigue.

Screen media use and sleep disturbance symptom severity in children.

OBJECTIVES: Few studies have sought to evaluate how screen media use relates to symptoms of sleep-wake disturbances. To extend these prior studies in a large sample of children, this study examined associations of different types of screen media with symptom severity of different classes of sleep-wake disturbances. This study was preregistered here. DESIGN: This study utilized the baseline cross-sectional survey administered within the Adolescent Brain Cognitive Development Study (ABCD; Release 2.0). PARTICIPANTS: ABCD recruited over 11,000 U.S. children age 9-10 across 21 study sites using an epidemiologically-informed school-based recruitment strategy. MEASUREMENTS: Children reported typical weekend and weekday use of TV, video, video game, social media, texting, and video chat, and parents completed reports of the child's symptom severity of sleep-wake disturbances via the Sleep Disturbance Scale for Children. RESULTS: Greater screen media use, TV, video, and video game use, was associated with decreased sleep duration, increased sleep onset latency as well as greater excessive sleepiness, insomnia, and overall sleep disturbance symptom severity. Use of these screen medias were also associated with clinically relevant sleep problems. Ethnoracial differences emerged in screen use and sleep, but did not moderate the association between screen use and sleep. CONCLUSIONS: Greater use of screen medias was not just associated with longer sleep onset latency and shorter sleep duration, but also increased severity of multiple types of sleep-wake disturbances. Future research should use longitudinal designs to determine the direction of these associations in adolescent populations.

The Potential Roles of Ghrelin in Metabolic Syndrome and Secondary Symptoms of Alzheimer's Disease.

Although the major causative factors of Alzheimer's disease (AD) are the accumulation of amyloid ß and hyperphosphorylated tau, AD can also be caused by metabolic dysfunction. The major clinical symptom of AD is cognitive dysfunction. However, AD is also accompanied by various secondary symptoms such as depression, sleep-wake disturbances, and abnormal eating behaviors. Interestingly, the orexigenic hormone ghrelin has been suggested to have beneficial effects on AD-related metabolic syndrome and secondary symptoms. Ghrelin improves lipid distribution and alters insulin sensitivity, effects that are hypothesized to delay the progression of AD. Furthermore, ghrelin can relieve depression by enhancing the secretion of hormones such as serotonin, noradrenaline, and orexin. Moreover, ghrelin can upregulate the expression of neurotrophic factors such as brain-derived neurotrophic factor and modulate the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1ß. Ghrelin alleviates sleep-wake disturbances by increasing the levels of melatonin, melanin-concentrating hormone. Ghrelin reduces the risk of abnormal eating behaviors by increasing neuropeptide Y and γ-aminobutyric acid. In addition, ghrelin increases food intake by inhibiting fatty acid biosynthesis. However, despite the numerous studies on the role of ghrelin in the AD-related pathology and metabolic disorders, there are only a few studies that investigate the effects of ghrelin on secondary symptoms associated with AD. In this mini review, our purpose is to provide the insights of future study by organizing the previous studies for the role of ghrelin in AD-related pathology and metabolic disorders.

Outcomes of Subjective Sleep-Wake Disturbances Twenty Years after Traumatic Brain Injury in Childhood.

Sleep-wake disturbances (SWD) are frequent following traumatic brain injury (TBI) in childhood. However, outcomes of SWD following transition into young adulthood remain unknown. This study investigated prevalence and factors associated with subjective sleep quality, insomnia, and excessive daytime sleepiness in young adults with a history of childhood TBI. Participants included 54 young adults with mild (n = 14), moderate (n = 27), and severe (n = 13) TBI (age: mean = 27.7, SD = 3.3), and 13 typically developing controls (TDC) (age: mean = 25.9, SD = 2.2). SWD were assessed using the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS). Compared with TDC, young adults with TBI reported a trend toward poorer sleep quality (F[1, 63] = 3.85, p = 0.054, η2 = 0.06), with a higher risk in participants after moderate TBI (mean = 2.40, SD = 0.56) than after severe TBI (mean = 1.89, SD = 0.62: p = 0.015). However, the groups did not differ on symptoms of insomnia and excessive daytime sleepiness, and SWD were less frequent after severe TBI at 20 years post-injury. Poor sleep quality in young adults with TBI was associated with high levels of anxiety and pain, and pain was also associated with higher risk of insomnia and excessive daytime sleepiness. Our findings indicate that sustaining TBI in childhood can increase risk of SWD in young adulthood, particularly following moderate TBI. Routine assessments and treatment of SWD, as well as anxiety and pain in children with TBI, should therefore continue into adulthood.

Cognitive Behavioral Therapy for Insomnia Reduces Depression in Cancer Survivors.

STUDY OBJECTIVES: The current archival analyses examine the direct and indirect effects of cognitive behavioral therapy for insomnia (CBT-I) on depression in cancer survivors. METHODS: We report on 67 cancer survivors from a 2 × 2 randomized controlled trial of CBT-I and armodafinil for insomnia, after collapsing across the noneffective study medication conditions (armodafinil/placebo) to create CBT-I (yes/no). Depression and insomnia were assessed before, during the 7-week CBT-I intervention, at postintervention, and 3 months later by the Patient Health Questionnaire and the Insomnia Severity Index, respectively. RESULTS: Mean depression at baseline for all participants was 6.44 (standard error = 0.41, range 0-15). Paired t tests showed that depression improved from baseline to postintervention by 48% (P < .001) in the CBT-I group versus 15% (P = .016) in the non-CBT-I group. Analysis of covariance controlling for baseline found that participants receiving CBT-I had significantly less depression at postintervention (effect size = -0.62; P = .001), compared to those who did not receive CBT-I. These benefits were maintained at the 3-month follow-up. Spearman rank correlations showed that changes in insomnia severity from baseline to postintervention were significantly correlated with concurrent changes in depression (r = .73; P < .001). Path analysis revealed that improvement in depression was mediated by improvement in insomnia severity (P < .001). CONCLUSIONS: Our findings provide preliminary support that in cancer survivors, CBT-I reduces depression via improvement in insomnia. Further, this reduction in depression remained stable 3 months after completing CBT-I. This suggests that a CBT-I intervention has a meaningful effect on depression. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Cognitive Behavioral Therapy +/- Armodafinil for Insomnia and Fatigue Following Chemotherapy; Identifier: NCT01091974; URL: https://clinicaltrials.gov/ct2/show/record/NCT01091974.