Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome.

BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.

Analysis of Human Peripheral Blood Mononuclear Cells in Patients with Neurodegenerative Diseases.

The role of immune system in the progression of neurodegenerative diseases has been studied for decades in animal models. However, invasive studies in human subjects remain controversial due to the heterogeneity of the presentation of different diagnostic categories at different stages of the disease. Peripheral blood mononuclear cells (PBMCs) contain immune cells including dendritic cells (DCs), monocytes, macrophages, and T lymphocytes. Isolating PBMCs from whole blood samples collected from patients provides a minimally invasive method for analyzing the immune system's function in patients with neurodegenerative diseases. By isolating single cell types from patients' peripheral blood, in vitro analyses can be conducted including RNA sequencing, immunofluorescence, and phagocytic analysis. In this chapter, we discuss PBMC separation and isolation of macrophages in pure culture in vitro. We also outline methods for performing RNA-seq on cultured macrophages and other techniques for investigating the role of macrophages in neurodegenerative disease pathophysiology.

Hydrogen-rich water improves sleep consolidation and enhances forebrain neuronal activation in mice.

Study Objectives: Sleep loss contributes to various health issues and impairs neurological function. Molecular hydrogen has recently gained popularity as a nontoxic ergogenic and health promoter. The effect of molecular hydrogen on sleep and sleep-related neural systems remains unexplored. This study investigates the impact of hydrogen-rich water (HRW) on sleep behavior and neuronal activation in sleep-deprived mice. Methods: Adult C57BL/6J mice were implanted with electroencephalography (EEG) and electromyography (EMG) recording electrodes and given HRW (0.7-1.4 mM) or regular water for 7 days ad libitum. Sleep-wake cycles were recorded under baseline conditions and after acute sleep loss. Neuronal activation in sleep- and wake-related regions was assessed using cFos immunostaining. Results: HRW increased sleep consolidation in undisturbed mice and increased non-rapid-eye movement and rapid-eye-movement sleep amount in sleep-deprived mice. HRW also decreased the average amount of time for mice to fall asleep after light onset. Neuronal activation in the lateral septum, medial septum, ventrolateral preoptic area, and median preoptic area was significantly altered in all mice treated with HRW. Conclusions: HRW improves sleep consolidation and increases neuronal activation in sleep-related brain regions. It may serve as a simple, effective treatment to improve recovery after sleep loss.

Polyunsaturated Fatty Acids Mend Macrophage Transcriptome, Glycome, and Phenotype in the Patients with Neurodegenerative Diseases, Including Alzheimer's Disease.

BACKGROUND: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-ß (Aß) into endosomes, and degrade Aß, whereas macrophages of patients with Alzheimer's disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of Aß. OBJECTIVE: To clarify the pathogenesis of sporadic AD and therapeutic effects of polyunsaturated fatty acids (PUFA) with vitamins B and D and antioxidants on monocyte/macrophage (MM) migration in the AD brain, MM transcripts in energy and Aß degradation, MM glycome, and macrophage clearance of Aß. METHODS: We followed for 31.3 months (mean) ten PUFA-supplemented neurodegenerative patients: 3 with subjective cognitive impairment (SCI), 2 with mild cognitive impairment (MCI), 3 MCI/vascular cognitive impairment, 2 with dementia with Lewy bodies, and 7 non-supplemented caregivers. We examined: monocyte migration in the brain and a blood-brain barrier model by immunochemistry and electron microscopy; macrophage transcriptome by RNAseq; macrophage glycome by N-glycan profiling and LTQ-Orbitrap mass spectrometry; and macrophage phenotype and phagocytosis by immunofluorescence. RESULTS: MM invade Aß plaques, upload but do not degrade Aß, and release Aß into vessels, which develop cerebrovascular amyloid angiopathy (CAA); PUFA upregulate energy and Aß degradation enzyme transcripts in macrophages; PUFA enhance sialylated N-glycans in macrophages; PUFA reduce oxidative stress and increase pro-resolution MM phenotype, mitochondrial membrane potential, and Aß phagocytosis (p < 0.001). CONCLUSION: Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, Aß phagocytosis, and Aß degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance Aß clearance, and benefit the cognition of early-stage AD patients.

Cardiac risk assessment, morbidity prediction, and outcome in the vascular intensive care unit.

OBJECTIVES: The aim of this study is to examine the predictive value of the Lee revised cardiac risk index (RCRI) for a standard vascular intensive care unit (ICU) population as well as assessing the utility of transthoracic echocardiography and the impact of prior coronary artery disease (CAD) and coronary revascularization on patient outcome. DESIGN: This is a retrospective review of prospectively maintained Vascubase and prospectively collected ICU data. MATERIALS AND METHODS: Data from 363 consecutive vascular ICU admissions were collected. Findings were used to calculate the RCRI, which was then correlated with patient outcomes. All patients were on optimal medical therapy (OMT) in the form of cardioselective ß-blocker, aspirin, statin, and folic acid. RESULTS: There was no relationship found between a reduced ejection fraction and patient outcome. Mortality was significantly increased for patients with left ventricular hypertrophy (LVH) as identified on echo (14.9% vs 6.5%, P = .028). The overall complication rates were significantly elevated for patients with valvular dysfunction. Discrimination for the RCRI on receiver-operating characteristic analysis was poor, with an area under the receiver-operating characteristic curve of .621. Model calibration was reasonable with an Hosmer-Lemeshow C statistic of 2.726 (P = .256). Of those with known CAD, 41.22% of the patients receiving best medical treatment developed acute myocardial infarction (AMI) compared to 35.3% of those who previously underwent percutaneous cardiac intervention and 23.5% of those who had undergone coronary artery bypass grafting. There was 3-fold increase in major adverse clinical events in patients with troponin rise and LVH. CONCLUSIONS: The RCRI's discriminatory capacity is low, and this raises difficulties in assessing cardiac risk in patients undergoing vascular intervention. The AMI is highest in the OMT group without prior cardiac intervention, which mandates protocols to identify patients requiring cardiac intervention prior to vascular procedures.

Factors associated with persistent sequelae after fasciotomy for acute compartment syndrome.

PURPOSE: To determine factors associated with persistent sequelae after fasciotomy for acute compartment syndrome. METHODS: Records of 57 men and 3 women aged 8 to 84 (mean, 31.9) years who underwent fasciotomy of the lower (n=48) or upper (n=12) limbs for acute compartment syndrome following limb trauma were retrospectively reviewed. 58 of the fasciotomies were therapeutic and 2 were prophylactic. The mean follow-up was 3.9 (range, 1-8) years. Patients were assessed through a telephone survey for persistent sequelae (parasthaesia, dysasthaesia, and/or motor weakness), using a scale of one to 4 to indicate asymptomatic, mild, moderate, and severe, respectively. Associations of persistent sequelae with the aetiology, mechanism of injury, site of fasciotomy, time to fasciotomy (from admission to anaesthesia induction), number of operations, method of closure, time to closure, and perioperative complications were assessed. RESULTS: 18 patients were asymptomatic and 42 reported having persistent sequelae including motor weakness (n=26), parasthaesia (n=28), and dysasthaesia (n=30). In terms of severity, these sequelae were mild (n=10), moderate (n=12), or severe (n=20). Persistent sequelae were associated with higher number of operations, post-fasciotomy complications, closures with skin grafting, and increased time to closure. CONCLUSION: To reduce the risk of persistent sequelae after fasciotomy, careful preoperative planning and meticulous perioperative care is needed to avoid multiple operations and post-fasciotomy complications. Patients whose wounds healed by secondary intention showed the best outcome.