Insomnia in Forensic Detainees: Is Salience Network the Common Pathway for Sleep, Neuropsychiatric, and Neurodegenerative Disorders?

Forensic hospitals throughout the country house individuals with severe mental illness and history of criminal violations. Insomnia affects 67.4% of hospitalized patients with chronic neuropsychiatric disorders, indicating that these conditions may hijack human somnogenic pathways. Conversely, somnolence is a common adverse effect of many antipsychotic drugs, further highlighting a common etiopathogenesis. Since the brain salience network is likely the common denominator for insomnia, neuropsychiatric and neurodegenerative disorders, here, we focus on the pathology of this neuronal assembly and its likely driver, the dysfunctional neuronal and mitochondrial membrane. We also discuss potential treatment strategies ranging from membrane lipid replacement to mitochondrial transplantation. The aims of this review are threefold: 1. Examining the causes of insomnia in forensic detainees with severe mental illness, as well as its role in predisposing them to neurodegenerative disorders. 2. Educating State hospital and prison clinicians on frontotemporal dementia behavioral variant, a condition increasingly diagnosed in older first offenders which is often missed due to the absence of memory impairment. 3. Introducing clinicians to natural compounds that are potentially beneficial for insomnia and severe mental illness.

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) comprise a group of illnesses marked by memory and behavioral dysfunction that can occur in up to 50% of HIV patients despite adequate treatment with combination antiretroviral drugs. Iron dyshomeostasis exacerbates HIV-1 infection and plays a major role in Alzheimer's disease pathogenesis. In addition, persons living with HIV demonstrate a high prevalence of neurodegenerative disorders, indicating that HAND provides a unique opportunity to study ferroptosis in these conditions. Both HIV and combination antiretroviral drugs increase the risk of ferroptosis by augmenting ferritin autophagy at the lysosomal level. As many viruses and their proteins exit host cells through lysosomal exocytosis, ferroptosis-driving molecules, iron, cathepsin B and calcium may be released from these organelles. Neurons and glial cells are highly susceptible to ferroptosis and neurodegeneration that engenders white and gray matter damage. Moreover, iron-activated microglia can engage in the aberrant elimination of viable neurons and synapses, further contributing to ferroptosis-induced neurodegeneration. In this mini review, we take a closer look at the role of iron in the pathogenesis of HAND and neurodegenerative disorders. In addition, we describe an epigenetic compensatory system, comprised of bromodomain-containing protein 4 (BRD4) and microRNA-29, that may counteract ferroptosis by activating cystine/glutamate antiporter, while lowering ferritin autophagy and iron regulatory protein-2. We also discuss potential interventions for lysosomal fitness, including ferroptosis blockers, lysosomal acidification, and cathepsin B inhibitors to achieve desirable therapeutic effects of ferroptosis-induced neurodegeneration.

PTSD as an Endothelial Disease: Insights From COVID-19.

SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds that of the general and special populations, the virus may predispose to this disorder by directly interfering with the stress-processing pathways. The SARS-CoV-2 interactome has identified several antigens that may disrupt the blood-brain-barrier by inducing premature senescence in many cell types, including the cerebral endothelial cells. This enables the stress molecules, including angiotensin II, endothelin-1 and plasminogen activator inhibitor 1, to aberrantly activate the amygdala, hippocampus, and medial prefrontal cortex, increasing the vulnerability to stress related disorders. This is supported by observing the beneficial effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in both posttraumatic stress disorder and SARS-CoV-2 critical illness. In this narrative review, we take a closer look at the virus-host dialog and its impact on the renin-angiotensin system, mitochondrial fitness, and brain-derived neurotrophic factor. We discuss the role of furin cleaving site, the fibrinolytic system, and Sigma-1 receptor in the pathogenesis of psychological trauma. In other words, learning from the virus, clarify the molecular underpinnings of stress related disorders, and design better therapies for these conditions. In this context, we emphasize new potential treatments, including furin and bromodomains inhibitors.

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis.

Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling.

The amyloid hypothesis, the assumption that beta-amyloid toxicity is the primary cause of neuronal and synaptic loss, has been the mainstream research concept in Alzheimer's disease for the past two decades. Currently, this model is quietly being replaced by a more holistic, "systemic disease" paradigm which, like the aging process, affects multiple body tissues and organs, including the gut microbiota. It is well-established that inflammation is a hallmark of cellular senescence; however, the infection-senescence link has been less explored. Microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. Infectious agents have previously been associated with Alzheimer's disease, but the cause vs. effect issue could not be resolved. A recent study may have settled this debate as it shows that gingipain, a Porphyromonas gingivalis toxin, can be detected not only in Alzheimer's disease but also in the brains of older individuals deceased prior to developing the illness. In this review, we take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. We also surmise that novel Alzheimer's disease findings, including neuronal somatic mosaicism, iron dyshomeostasis, aggressive glial phenotypes, and loss of aerobic glycolysis, can be explained by the infection-senescence model. In addition, we discuss potential cellular senescence targets and therapeutic strategies, including iron chelators, inflammasome inhibitors, senolytic antibiotics, mitophagy inducers, and epigenetic metabolic reprograming.