Sleep apnea in relation to metabolism: An urgent need to study underlying mechanisms and to develop novel treatments for this unmet clinical need

Stroke is the commonest cause of disability. Novel treatments require an improved understanding of the underlying mechanisms of recovery. Fractal approaches have demonstrated that a single metric can describe the complexity of seemingly random fluctuations of physiological signals. We hypothesize that fractal algorithms applied to electroencephalographic (EEG) signals may track brain impairment after stroke. Sixteen stroke survivors were studied in the hyperacute (<48 h) and in the acute phase (∼1 week after stroke), and 35 stroke survivors during the early subacute phase (from 8 days to 32 days and after ∼2 months after stroke): We compared resting-state EEG fractal changes using fractal measures (i.e., Higuchi Index, Tortuosity) with 11 healthy controls. Both Higuchi index and Tortuosity values were significantly lower after a stroke throughout the acute and early subacute stage compared to healthy subjects, reflecting a brain activity which is significantly less complex. These indices may be promising metrics to track behavioral changes in the very early stage after stroke. Our findings might contribute to the neurorehabilitation quest in identifying reliable biomarkers for a better tailoring of rehabilitation pathways.

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Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00094.2015 ◽

2015 ◽

Vol 309 (7) ◽

pp. H1101-H1111 ◽

Cited By ~ 54

Author(s):

Luciano F. Drager ◽

Vsevolod Y. Polotsky ◽

Christopher P. O'Donnell ◽

Sergio L. Cravo ◽

Geraldo Lorenzi-Filho ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Cardiovascular Risk ◽

Sleep Apnea ◽

Animal Models ◽

Metabolic Dysfunction ◽

Significant Progress ◽

Glucose And Lipid Metabolism ◽

Obstructive Sleep ◽

Underlying Mechanisms ◽

Made In

Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant pathophysiological disturbance in OSA–intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field.

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Comorbid sleep apnea, post-traumatic stress disorder, and insomnia: underlying mechanisms and treatment implications—a commentary on El Solh et al.’s Impact of low arousal threshold on treatment of obstructive sleep apnea in patients with post-traumatic stress disorder

Sleep And Breathing ◽

10.1007/s11325-020-02107-z ◽

2020 ◽

Author(s):

Douglas M. Wallace ◽

Alexander Sweetman

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Stress Disorder ◽

Post Traumatic Stress ◽

Arousal Threshold ◽

Obstructive Sleep ◽

Post Traumatic ◽

Underlying Mechanisms

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Impaired Glucose Metabolisms of Patients with Obstructive Sleep Apnea and Type 2 Diabetes

Journal of Diabetes Research ◽

10.1155/2018/6714392 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Ye Zhang ◽

Yanpeng Xing ◽

Haibo Yuan ◽

Xiaokun Gang ◽

Weiying Guo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Plasma Cortisol ◽

Sleep Disordered Breathing ◽

Model Assessment ◽

Obstructive Sleep ◽

Underlying Mechanisms ◽

Disordered Breathing

Aims. Obstructive sleep apnea (OSA) is a very common disorder which is associated with metabolic comorbidities. The aims of this study were to analyze clinical data of patients with OSA and evaluate influence of sleep-disordered breathing on glycometabolism and its underlying mechanisms. Methods. We designed a cross-sectional study involving 53 OSA patients in The First Hospital of Jilin University from March 2015 to March 2016. They underwent a full-night polysomnography, measurement of fasting blood glucose and blood lipid profiles. Besides, we chose 20 individuals with type 2 diabetes mellitus (T2DM) as a subgroup for an in-depth study. This group additionally underwent a steamed bread meal test and measurement of HbA1c, C-reactive protein, tumor necrosis factor-α, interleukin 6, morning plasma cortisol, and growth hormone. Results. The two groups which with or without T2DM showed no significant differences in baseline characteristics. As for OSA patients with T2DM, the severe OSA group had higher homeostasis model assessment of insulin resistance (HOMA-IR) (P=0.013) than the mild-to-moderate OSA group, whereas had lower morning plasma cortisol levels (P=0.005) than the mild-to-moderate OSA group. AHI was positive correlated with HOMA-IR (r=0.523, P=0.018), yet negative correlated with morning plasma cortisol (r=−0.694, P=0.001). However, nadir SpO2 was positive correlated with morning plasma cortisol (rs=0.646, P=0.002), while negative correlated with HOMA-IR (rs=−0.489, P=0.029). Conclusions. Our study showed that sleep-disordered breathing exerted negative influence on glucose metabolisms. The impairment of hypothalamic-pituitary-adrenal axis activity may be one of the underlying mechanisms of the glycometabolic dysfunctions in OSA with T2DM patients.

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Bacteria, Lipopolysaccharides, Amyloid and the Role of Iron Dysregulation in Parkinson’s Disease

10.20944/preprints202011.0380.v1 ◽

2020 ◽

Author(s):

Marthinus Janse van Vuuren ◽

Theodore Albertus Nell ◽

Jonathan Ambrose Carr ◽

Douglas B Kell ◽

Etheresia Pretorius

Keyword(s):

Systemic Inflammation ◽

Cell Damage ◽

Vascular Dysfunction ◽

Alpha Synuclein ◽

Motor Deficits ◽

Novel Treatments ◽

Randomized Controlled Clinical Trials ◽

Iron Dysregulation ◽

Neuro Inflammation ◽

Underlying Mechanisms

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuro-inflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby lipopolysaccharides may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments which may relieve the characteristic non-motor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

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α-synuclein in the retina leads to degeneration of dopamine amacrine cells impairing vision

10.1101/760603 ◽

2019 ◽

Author(s):

Marrocco Elena ◽

Esposito Federica ◽

Tarallo Valeria ◽

Carboncino Anna ◽

Alvino Filomena Grazia ◽

...

Keyword(s):

Visual Acuity ◽

Ganglion Cells ◽

Amacrine Cells ◽

Dopamine Neurons ◽

Maze Task ◽

Novel Treatments ◽

Adult Mice ◽

Underlying Mechanisms ◽

And Function ◽

Human Wild Type

AbstractIntroductionα-synuclein aggregates have been identified in the retina of Parkinson’s disease patients associated to vision impairment. In this study, we sought to determine the effects of α-synuclein overexpression on the survival and function of dopaminergic (DA) amacrine cells in the retina.MethodsAdult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type α-synuclein in the inner retina. Following systemic injections of levodopa (L-DOPA), retinal responses and visual acuity driven behavior were measured by electroretinography (ERG) and water maze task, respectively. Amacrine cells and ganglion cells were counted at 1, 2 and 3 months post-injection.Resultsα-synuclein led to an early loss of DA cells, which was associated with the decrease of light-adapted ERG responses and visual acuity. Systemic injections of L-DOPA rescued these retinal and visual abnormalities.ConclusionsThe data show that α-synuclein affects dopamine neurons in the retina. The approach provides a novel accessible mode of modeling the underlying mechanisms implicated in synucleinophaties pathogenesis and for testing novel treatments.

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Amyloid-Based Therapeutics: Findings Translated into Novel Treatments

CNS Spectrums ◽

10.1017/s109285290002705x ◽

2008 ◽

Vol 13 (S16) ◽

pp. 36-38 ◽

Cited By ~ 1

Author(s):

Paul S. Aisen

Keyword(s):

Vitamin E ◽

Memory Impairment ◽

Cholinesterase Inhibitors ◽

Treatment Options ◽

Nmda Receptor Antagonist ◽

Novel Treatments ◽

Therapeutic Class ◽

Positive Treatment ◽

Underlying Mechanisms ◽

With Memory

For decades following the 1906 identification of Alzheimer’s disease (AD), it was believed that the disorder was untreatable. Only in the late 1970s, with the introduction of the cholinergic hypothesis of the underlying mechanisms of AD, were treatment options considered possible. The first positive treatment study was conducted in 1985. In 1993, tacrine, a cholinesterase inhibitor, was approved for the treatment of AD; three similar drugs soon followed. Memantine, an NMDA receptor antagonist, was approved in 2003, representing a second therapeutic class for AD.Cholinesterase inhibitors were the first therapeutic options successfully employed, and there is strong evidence these agents confer benefits. The addition of memantine to the standard course of therapy can be beneficial as well, particularly at the moderate stages of the disorder (Mini-Mental State Exam score of ≤14). For patients without cardiovascular disease, diabetes, or statin use, 1,000 IU vitamin E BID is a consideration to mitigate the effects of AD. However, there is presently concern over the risks involved in vitamin E therapy. Unfortunately, there are no established treatments for mild cognitive impairment (MCI). Vitamin E is ineffective in treating MCI, and cholinesterase inhibitors, while possibly risky, are only minimally effective. The need for effective treatment remains expansive. The benefits of the available agents are modest, and there are currently no treatments for individuals with memory impairment who do not yet meet the diagnostic criteria for AD.

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Abstract 17375: The Potential Role of Stress-Associated Neurobiological Metabolism in the Cardiovascular Sequelae of Sleep Apnea

Circulation ◽

10.1161/circ.142.suppl_3.17375 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ahmed Ghoneem ◽

Michael Osborne ◽

Shady Abohashem ◽

Hadil Zureigat ◽

Tawseef Dar ◽

...

Keyword(s):

Sleep Apnea ◽

Central Sleep Apnea ◽

Sleep Fragmentation ◽

Novel Treatments ◽

Positron Emission ◽

Classification Of Diseases ◽

Icd 10 ◽

International Statistical Classification

Introduction: Obstructive and central sleep apnea (SA) induce sleep fragmentation and associates with HTN and cardiovascular diseases (CVDs). Sleep fragmentation is known to increase stress. Further, heightened stress-associated neurobiological metabolism (particularly amygdalar activity - AmygA), potentiates atherosclerosis. However, it is unknown: 1) whether SA increases AmygA in humans, or 2) whether AmygA mediates the link between SA and its CV consequences (HTN and CVD). Hypothesis: SA associates with higher AmygA which in turn associates with hypertension (HTN) and myocardial infarction (MI). Methods: We studied a cohort of 36424 participants within the Partners Biobank. Diagnoses of MI and sleep apnea and relevant clinical data were obtained from International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes. A subset of 1520 patients provided clinically indicated 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. AmygA was measured using validated measures. Results: Of 36424 participants, 6596 (18.1%) had SA, 20881(57.3%) had HTN and 4033 (11.1%) had MI. OSA significantly associated with HTN (OR [95%CI]: 3.2 [2.95, 4.48], p<0.0001) and MI (1.30 [1.21, 1.41], p<0.001) in multivariable models. SA associated with AmygA (β [95%CI]: 0.183 [0.058, 0.337], p=0.006). AmygA associated with HTN (1.18 [1.02, 1.38], p= 0.028). Further, AmygA associated with MI (1.28 [1.11, 1.46], p=0.0005). Moreover, AmygA mediated the association between SA and HTN and between SA and MI (p<0.05 for both, figs 1a and 1b). Conclusion: Our findings suggest that SA increases the risk of HTN & MI via a mechanism that involves heightened amygdalar activity. This potential mechanism may inform novel treatments.

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