Inflammation as a Mechanism of Bipolar Disorder Neuroprogression.

Bipolar disorder (BD) is a severe, debilitating psychiatric condition with onset in adolescence or young adulthood and often follows a relapsing and remitting course throughout life. The concept of neuroprogression in BD refers to the progressive path with an identifiable trajectory that takes place with recurrent mood episodes, which eventually leads to cognitive, functional, and clinical deterioration in the course of BD. Understanding the biological basis of neuroprogression helps to explain the subset of BD patients who experience worsening of their disorder over time. Additionally, the study of the neurobiological mechanisms underpinning neuroprogression will help BD staging based on systems biology. Replicated epidemiological studies have suggested inflammatory mechanisms as primary contributors to the neuroprogression of mood disorders. It is known that dysregulated inflammatory/immune pathways are often associated with BD pathophysiology. Hence, in this chapter, we focus on the evidence for the involvement of inflammation and immune regulated pathways in the neurobiological consequences of BD neuroprogression. Herein we put forth the evidence of immune markers from autoimmune disorders, chronic infections, and gut-brain axis that lead to BD neuroprogression. Further, we highlighted the peripheral and central inflammatory components measured along with BD progression.

Postmortem evidence of brain inflammatory markers in bipolar disorder: a systematic review.

Bipolar disorder (BD) is a chronic affective disorder with extreme mood swings that include mania or hypomania and depression. Though the exact mechanism of BD is unknown, neuroinflammation is one of the numerous investigated etiopathophysiological causes of BD. This article presents a systematic review of the data regarding brain inflammation evaluating microglia, astrocytes, cytokines, chemokines, adhesion molecules, and other inflammatory markers in postmortem BD brain samples. This systematic review was performed according to PRISMA recommendations, and relevant studies were identified by searching the PubMed/MEDLINE, PsycINFO, EMBASE, LILACS, IBECS, and Web of Science databases for peer-reviewed journal articles published by March 2019. Quality of included studies appraised using the QUADAS-2 tool. Among the 1814 articles included in the primary screening, 51 articles measured inflammatory markers in postmortem BD brain samples. A number of studies have shown evidence of inflammation in BD postmortem brain samples. However, an absolute statement cannot be concluded whether neuroinflammation is present in BD due to the large number of studies did not evaluate the presence of infiltrating peripheral immune cells in the central nervous system (CNS) parenchyma, cytokines levels, and microglia activation in the same postmortem brain sample. For example, out of 15 studies that evaluated microglia cells markers, 8 studies found no effect of BD on these cells. Similarly, 17 out of 51 studies evaluating astrocytes markers, 9 studies did not find any effect of BD on astrocyte cells, whereas 8 studies found a decrease and 2 studies presented both increase and decrease in different brain regions. In addition, multiple factors account for the variability across the studies, including postmortem interval, brain area studied, age at diagnosis, undergoing treatment, and others. Future analyses should rectify these potential sources of heterogeneity and reach a consensus regarding the inflammatory markers in postmortem BD brain samples.

Long-Term Cognitive Outcomes After Sepsis: a Translational Systematic Review.

Sepsis is systemic inflammatory response syndrome with a life-threatening organ dysfunction that is caused by an unbalanced host immune response in an attempt to eliminate invasive microorganisms. We posed questions, "Does sepsis survivor patients have increased risk of neuropsychiatric manifestations?" and "What is the mechanism by which sepsis induces long-term neurological sequelae, particularly substantial cognitive function decline in survivor patients and in pre-clinical sepsis models?" The studies were identified by searching PubMed/MEDLINE (National Library of Medicine), PsycINFO, EMBASE (Ovid), LILACS (Latin American and Caribbean Health Sciences Literature), IBECS (Bibliographical Index in Spanish in Health Sciences), and Web of Science databases for peer-reviewed journals that were published until January 2018. A total of 3555 papers were included in the primary screening. After that, 130 articles were selected for the study. A number of pre-clinical studies have shown an auto amplification of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6 in the first few hours after sepsis induction, also increased blood-brain barrier permeability, elevated levels of matrix metalloproteinases, increased levels of damage-associated molecular patterns were demonstrated. In addition, the rodents presented long-term cognitive impairment in different behavioral tasks that were prevented by blocking the mechanism of action of these inflammatory mediators. Clinical studies have showed that sepsis survivors presented increased bodily symptoms such as fatigue, pain, visual disturbances, gastrointestinal problems, and neuropsychiatric problems compared to before sepsis. Sepsis leaves the survivors with an aftermath of physiological, neuropsychiatric, and functional impairment. Systematic review registration: CRD42017071755.

A systematic review of evidence for the role of inflammatory biomarkers in bipolar patients.

Bipolar disorder (BD) is a neuropsychiatric disorder that is characterized by a phasic course of affective episodes interspersed with a euthymic state. Epidemiological, clinical, genetic, post-mortem and preclinical studies have shown that inflammatory reactions and immune modulation play a pivotal role in the pathophysiology of BD. It is conceptualized that biomarkers of inflammation and immune responses should be employed to monitor the disease process in bipolar patients. The objective of this systematic review is to analyse the inflammatory markers involved in human studies and to explore each individual marker for its potential clinical application and summarize evidence regarding their role in BD. A systematic review of human studies to measure inflammatory markers was conducted, and the studies were identified by searching PubMed/MEDLINE, PsycINFO, EMBASE, and Web of Science databases for peer-reviewed journals that were published until September 2015. In this review, we included peripheral markers, genetic, post-mortem and cell studies with inflammatory biomarker analysis in BD. One hundred and two (102) papers met the inclusion criteria. The pro-inflammatory cytokines were elevated and the anti-inflammatory cytokines were reduced in BD patients, particularly during manic and depressive phases when compared to the controls. These changes tend to disappear in euthymia, indicating that inflammation may be associated with acute phases of BD. Even though there are promising findings in this field, further clinical studies using more established detection techniques are needed to clearly show the benefit of using inflammatory markers in the diagnosis, follow-up and prognosis of patients with BD.

Ventricular assist devices and sleep-disordered breathing.

Congestive heart failure is one of the leading causes of morbidity and mortality in the United States, and left ventricular assist devices have revolutionized treatment of end-stage heart failure. Given that sleep apnea results in significant morbidity in these patients with advanced heart failure, practicing sleep physicians need to have an understanding of left ventricular assist devices. In this review, we summarize what is known about ventricular assist devices as they relate to sleep medicine.

Animal models of Parkinson's disease: a gateway to therapeutics?

Parkinson's disease (PD) is a progressive, neurodegenerative disorder of unknown etiology, although a complex interaction between environmental and genetic factors has been implicated as a pathogenic mechanism of selected neuronal loss. A better understanding of the etiology, pathogenesis, and molecular mechanisms underlying the disease process may be gained from research on animal models. While cell and tissue models are helpful in unraveling involved molecular pathways, animal models are much better suited to study the pathogenesis and potential treatment strategies. The animal models most relevant to PD include those generated by neurotoxic chemicals that selectively disrupt the catecholaminergic system such as 6-hydroxydopamine; 1-methyl-1,2,3,6-tetrahydropiridine; agricultural pesticide toxins, such as rotenone and paraquat; the ubiquitin proteasome system inhibitors; inflammatory modulators; and several genetically manipulated models, such as α-synuclein, DJ-1, PINK1, Parkin, and leucine-rich repeat kinase 2 transgenic or knock-out animals. Genetic and nongenetic animal models have their own unique advantages and limitations, which must be considered when they are employed in the study of pathogenesis or treatment approaches. This review provides a summary and a critical review of our current knowledge about various in vivo models of PD used to test novel therapeutic strategies.

Genetics of amyotrophic lateral sclerosis: an update.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.