Showing papers in "International Review of Neurobiology in 2020"
TL;DR: These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain, and in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them.
Abstract: The impact of stress on brain health begins in the womb. Both animal and human studies have found that prenatal maternal stress affects the brain and behavior of the offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk for the child having a range of emotional, behavioral and/or cognitive problems in later life. These include depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), and/or conduct disorders. There is an increased risk for other outcomes also, including preterm delivery and reduced telomere length, possibly indicative of an accelerated life history. The causal role of prenatal maternal stress on the etiology of the neurodevelopmental disorders is supported by large population cohorts, which have controlled for a wide range of potential confounders, including postnatal maternal mood. More recently, research has begun to explore the biological correlates and mediators of these findings. These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain. Further, in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them. The structural changes include cortical thinning and an enlarged amygdala. While these studies have been conducted on smaller sample sizes and could not control for many confounders, the observed brain changes do plausibly underlie many of the emotional, behavioral and cognitive changes found to be associated with prenatal stress.
116 citations
TL;DR: Evidence linking exposure to diverse types of psychosocial stress, including early-life stress, cumulative stressful experiences, and low socioeconomic status is reviewed, with accelerated epigenetic aging as a putative mediator of the effects ofPsychosocial environment on health and disease.
Abstract: Aging is the single most important risk factor for diseases that are currently the leading causes of morbidity and mortality. However, there is considerable inter-individual variability in risk for aging-related disease, and studies suggest that biological age can be influenced by multiple factors, including exposure to psychosocial stress. Among markers of biological age that can be affected by stress, the present article focuses on the so-called measures of epigenetic aging: DNA methylation-based age predictors that are measured in a range of tissues, including the brain, and can predict lifespan and healthspan. We review evidence linking exposure to diverse types of psychosocial stress, including early-life stress, cumulative stressful experiences, and low socioeconomic status, with accelerated epigenetic aging as a putative mediator of the effects of psychosocial environment on health and disease. The chapter also discusses methodological differences that may contribute to discordant findings across studies to date and plausible mechanisms that may underlie the effects of stress on the aging epigenome. Future studies examining the effects of adversity on epigenetic and other indicators of biological weathering may provide important insights into the pathogenesis of aging-related disease states.
48 citations
TL;DR: Findings suggest that cellular and molecular changes occurring within and around the cerebral vasculature are among the key drivers of neurodegenerative disease pathogenesis.
Abstract: The cerebral vasculature serves as the crossroads of the CNS, supporting exchange of nutrients, metabolic wastes, solutes and cells between the compartments of the brain, including the blood, brain interstitium, and cerebrospinal fluid (CSF). The blood-brain barrier (BBB) regulates the entry and efflux of molecules into brain tissue. The cells of the neurovascular unit regulate cerebral blood flow, matching local metabolic demand to blood supply. The blood-CSF barrier at the choroid plexus secretes CSF, which supports the brain and provides a sink for interstitial solutes not cleared across the BBB. Recent studies have characterized the glymphatic system, a brain-wide network of perivascular spaces that supports CSF and interstitial fluid exchange and the clearance of interstitial solutes to the CSF. The critical role that these structures play in maintaining brain homeostasis is illustrated by the established and emerging roles that their dysfunctions play in the development of neurodegenerative diseases, such as Alzheimer's disease (AD). Loss of BBB and blood-CSF barrier function is reported both in rodent models of AD, and in human AD subjects. Cerebrovascular dysfunction and ischemic injury are well established contributors to both vascular dementia and to a large proportion of cases of sporadic AD. In animal models, the slowed glymphatic clearance of interstitial proteins, such as amyloid β or tau, are proposed to contribute to the development of neurodegenerative diseases, including AD. In total, these findings suggest that cellular and molecular changes occurring within and around the cerebral vasculature are among the key drivers of neurodegenerative disease pathogenesis.
43 citations
TL;DR: Roles of senescent cells in neurodegenerative diseases and potential implications of senolytic agents as an innovative treatment are considered and agents that selectively target these cells are targeted in preclinical models are considered.
Abstract: Aging is the major predictor for developing multiple neurodegenerative diseases, including Alzheimer's disease (AD) other dementias, and Parkinson's disease (PD). Senescent cells, which can drive aging phenotypes, accumulate at etiological sites of many age-related chronic diseases. These cells are resistant to apoptosis and can cause local and systemic dysfunction. Decreasing senescent cell abundance using senolytic drugs, agents that selectively target these cells, alleviates neurodegenerative diseases in preclinical models. In this review, we consider roles of senescent cells in neurodegenerative diseases and potential implications of senolytic agents as an innovative treatment.
38 citations
TL;DR: The present review considers the accumulating evidence linking stress, attenuation of the CAR and reduced cognitive function, and seeks to contextualize the many findings to study populations, cognitive measures, and CAR methodologies employed.
Abstract: There is evidence that stress-induced disruption of the circadian rhythm of cortisol secretion, has negative consequences for brain health. The cortisol awakening response (CAR) is the most prominent and dynamic aspect of this rhythm. It has complex regulatory mechanisms making it distinct from the rest of the cortisol circadian rhythm, and is frequently investigated as a biomarker of stress and potential intermediary between stress and impaired brain function. Despite this, the precise function of the CAR within the healthy cortisol circadian rhythm remains poorly understood. Cortisol is a powerful hormone known to influence cognition in multiple and complex ways. Studies of the CAR and cognitive function have used varied methodological approaches which have produced similarly varied findings. The present review considers the accumulating evidence linking stress, attenuation of the CAR and reduced cognitive function, and seeks to contextualize the many findings to study populations, cognitive measures, and CAR methodologies employed. Associations between the CAR and both memory and executive functions are discussed in relation to its potential role as a neuroendocrine time of day signal that synchronizes peripheral clocks throughout the brain to enable optimum function, and recommendations for future research are provided.
37 citations
TL;DR: The concept of microglial activation as a marker of neuroinflammation and the potential use of anti-inflammatory treatments in depression are described.
Abstract: Compelling evidence have highlighted the role of inflammation as a possible mechanism linking environmental stress to the development of depression. In particular, the communication between the peripheral and the brain immune system might lead to brain inflammatory processes, in turn causing impaired neurogenesis and neural plasticity. As a consequence, measuring brain inflammation and its possible correlation with peripheral inflammatory processes has become the focus (and a challenge) for a number of recent studies. In this chapter we review the evidence on the link between stress, peripheral and brain inflammation and the way to measure it, through preclinical, post-mortem and clinical models of depression and in healthy humans. We describe the concept of microglial activation as a marker of neuroinflammation and the potential use of anti-inflammatory treatments in depression. The paper concludes by highlighting the unresolved questions and challenges for future studies.
37 citations
TL;DR: A review of the case for mitochondrial and metabolism dysfunction in AD and the challenges of proving that a primary mitochondrial cascade is pertinent to the disease is presented in this article, which supports the view that mitochondria are more relevant to the causes of AD than its consequences.
Abstract: Alzheimer's disease (AD) features mitochondrial dysfunction and altered metabolism. Other pathologies could drive these changes, or alternatively these changes could drive other pathologies. In considering this question, it is worth noting that perturbed AD patient mitochondrial and metabolism dysfunction extend beyond the brain and to some extent define a systemic phenotype. It is difficult to attribute this systemic phenotype to brain beta-amyloid or tau proteins. Conversely, mitochondria increasingly appear to play a critical role in cell proteostasis, which suggests that mitochondrial dysfunction may promote protein aggregation. Mitochondrial and metabolism-related characteristics also define AD endophenotypes in cognitively normal middle-aged individuals, which suggests that mitochondrial and metabolism-related AD characteristics precede clinical decline. Genetic analyses increasingly implicate mitochondria and metabolism-relevant genes in AD risk. Collectively these factors suggest that mitochondria are more relevant to the causes of AD than its consequences, and support the view that a mitochondrial cascade features prominently in AD. This chapter reviews the case for mitochondrial and metabolism dysfunction in AD and the challenges of proving that a primary mitochondrial cascade is pertinent to the disease.
36 citations
TL;DR: It is clear that early adversity sculpts the stress system, but it is not understood which dimensions have the most impact and at what points in early development, and the mechanisms of social buffering are not yet clear.
Abstract: Adverse experiences during childhood can have long-lasting impacts on physical and mental health. At the heart of most theories of how these effects are transduced into health impacts is the activity of stress-mediating systems, most notably the hypothalamic-pituitary-adrenocortical (HPA) axis. Here we review the anatomy and physiology of the axis, models of stress and development, the development of the axis prenatally through adolescence, the role of experience and sensitive periods in shaping its regulation, the social regulation of the axis at different points in development, and finally conclude with suggestions for future research. We conclude that it is clear that early adversity sculpts the stress system, but we do not understand which dimensions have the most impact and at what points in early development. It is equally clear that secure attachment relationships buffer the developing stress system; however, the mechanisms of social buffering and how these may change with development are not yet clear. Another critical issue that is not understood is when and for whom adversity will result in hypo- vs hyperactivity of stress-mediating systems. These and other issues are important for advancing our understanding of how early adversity "gets under the skin" and shapes human physical and mental health.
34 citations
TL;DR: Understanding how stress influences prefrontal cortex and behaviors mediated by it, as well as sex differences in this effect, will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in executive function and emotion regulation.
Abstract: Stress alters both cognitive and emotional function, and increases risk for a variety of psychological disorders, such as depression and posttraumatic stress disorder. The prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Therefore, understanding how stress-induced changes in the structure and function of the prefrontal cortex are related to stress-induced changes in behavior may elucidate some of the mechanisms contributing to stress-sensitive disorders. This review focuses on data from rodent models to describe the effects of chronic stress on behaviors mediated by the medial prefrontal cortex, the effects of chronic stress on the morphology and physiology of the medial prefrontal cortex, mechanisms that may mediate these effects, and evidence for sex differences in the effects of stress on the prefrontal cortex. Understanding how stress influences prefrontal cortex and behaviors mediated by it, as well as sex differences in this effect, will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in executive function and emotion regulation.
30 citations
TL;DR: This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients using novel therapeutic advances in gliomas.
Abstract: Glioblastoma Multiforme (GBM) is one the most common intracranial tumors discovered by Burns (1800) and Abernethy (1804) based on gross morphology of the autopsied material and referred to as "medullary sarcoma" and later "fungus medullare" (Abernethy, 1804; Burns, 1800). Virchow in 1863 was the first German pathologist using histomorphological techniques discovered that GBM is a tumor of glial origin. Virchow (1863/65) also then used the term Glioma for the first time and classified as low-grade glioma and high-grade glioma very similar to that of today according to World health organization (WHO) classification (Jellinger, 1978; Virchow, 1863/65). After almost >50 years of this discovery, Baily and Cushing (1926) based on modern neuropathological tools provide the classification of gliomas that is still valid today (Baily & Cushing, 1926). Although, our knowledge about development of gliomas has advanced through development of modern cellular and molecular biological tools (Gately, McLachlan, Dowling, & Philip, 2017; Omuro & DeAngelis, 2013), therapeutic advancement of GBM still requires lot of efforts for the benefit of patients. This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients. These novel therapeutic approaches rely on enhanced penetration of drug therapy into the tumor tissues by use of nanomedicine for both the diagnostic and therapeutic purposes, referred to as "theranostic nanomedicine" (Alphandery, 2020; Zhao, van Straten, Broekman, Preat, & Schiffelers, 2020). Although, the blood-brain barrier (BBB) is fenestrated around the periphery of the tumor tissues, the BBB is still tight within the deeper tissues of the tumor. Thus, drug delivery is a challenge for gliomas and requires new therapeutic advances (Zhao et al., 2020). Associated edema development around tumor tissues is another factor hindering therapeutic effects (Liu, Mei, & Lin, 2013). These factors are discussed in details using novel therapeutic advances in gliomas.
29 citations
TL;DR: The current status of therapeutic candidates targeting diverse mechanisms and strategies including Aβ and tau, proteins involved in Aβ production and trafficking, neuroinflammation, neurotransmitters, neuroprotective agents antimicrobials, and gene and stem cell therapy are presented.
Abstract: Amyloid-β (Aβ) senile plaques and neurofibrillary tangles of tau are generally recognized as the culprits of Alzheimer's disease (AD) and related dementia. About 25 years ago, the amyloid cascade hypotheses postulated a direct correlation of plaques with the development of AD, and it has been the dominant theory since then. In this period, more than 200 clinical trials focused mainly on targeting components of the Aβ cascade have dramatically failed, some of them in Phase III. With a greater than 99.6% failure rate at a cost of several billion from governments, industry, and private funders, therapeutic strategies targeting amyloid and tau are now under scrutiny. Therefore, it is time to reevaluate alternatives to targeting Aβ and tau as effective therapeutic strategies for AD. The diagnosis of AD is currently based on medical examination of symptoms including tests to assess memory impairment, attention, language, and other thinking skills. This is complemented with brain scans, such as computed tomography, magnetic resonance imaging, or positron emission tomography with the help of imaging probes targeting Aβ or tau deposits. This approach has contributed to the tunnel vision focus on Aβ and tau as the main culprits of AD. However, events upstream of these proteopathies (age-related impaired neuronal bioenergetics, lysosome function, neurotrophic signaling, and neuroinflammation, among others) are almost surely where the development of alternative therapeutic interventions should be targeted. Here, we present the current status of therapeutic candidates targeting diverse mechanisms and strategies including Aβ and tau, proteins involved in Aβ production and trafficking (ApoE, α/β/γ-secretases), neuroinflammation, neurotransmitters, neuroprotective agents antimicrobials, and gene and stem cell therapy. There are currently around 33 compounds in Phase III, 78 in Phase II, and 32 more in Phase I trials. With the current world health crisis of increased dementia in a rapidly aging population, effective AD therapies are desperately needed.
TL;DR: This review describes neuroprotective effects mediated by pre- and post-conditioning-induced processes that act via the quantitative features of the hormetic dose response that lead to the development of acquired resilience that can protect neuronal systems from endogenous and exogenous stresses and insult.
Abstract: This review describes neuroprotective effects mediated by pre- and post-conditioning-induced processes that act via the quantitative features of the hormetic dose response. These lead to the development of acquired resilience that can protect neuronal systems from endogenous and exogenous stresses and insult. Particular attention is directed to issues of dose optimization, inter-individual variation, and potential ways to further study and employ hormetic-based preconditioning approaches in medical and public health efforts to treat and prevent neurodegenerative disease.
TL;DR: An overview of studies that demonstrate that stress and dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, are important additional risk factors for suicide are presented.
Abstract: Suicide is a global health issue accounting for at least 800,000 deaths per annum. Numerous models have been proposed that differ in their emphasis on the role of psychological, social, psychiatric and neurobiological factors in explaining suicide risk. Central to many models is a stress-diathesis component which states that suicidal behavior is the result of an interaction between acutely stressful events and a susceptibility to suicidal behavior (a diathesis). This article presents an overview of studies that demonstrate that stress and dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, are important additional risk factors for suicide. Evidence for other putative stress-related suicide risk factors including childhood trauma, impaired executive function, impulsivity and disrupted sleep are considered together with the impact of family history of suicide, perinatal and epigenetic influences on suicide risk.
TL;DR: This review compares available ketogenic interventions and discusses the potential of the potent oral Ketone Ester for future therapeutic use in AD and other NDDs characterized by inefficient glucose utilization.
Abstract: To meet its high energy demands, the brain mostly utilizes glucose. However, the brain has evolved to exploit additional fuels, such as ketones, especially during prolonged fasting. With aging and neurodegenerative diseases (NDDs), the brain becomes inefficient at utilizing glucose due to changes in glia and neurons that involve glucose transport, glycolytic and Krebs cycle enzyme activities, and insulin signaling. Positron emission tomography and magnetic resonance spectroscopy studies have identified glucose metabolism abnormalities in aging, Alzheimer's disease (AD) and other NDDs in vivo. Despite glucose hypometabolism, brain cells can utilize ketones efficiently, thereby providing a rationale for the development of therapeutic ketogenic interventions in AD and other NDDs. This review compares available ketogenic interventions and discusses the potential of the potent oral Ketone Ester for future therapeutic use in AD and other NDDs characterized by inefficient glucose utilization.
TL;DR: It is hypothesized that sodium glucose cotransporter 2 (SGLT2) inhibition, mediated by sustained glucose loss, restores mTOR cycling through nutrient-driven, nightly periods of transient mTOR inhibition (and restoration of catabolic cellular housekeeping processes) interspersed by daily periods of temporary mTOR activation (and anabolism) accompanying eating, thereby preventing or even reducing the progress of AD pathology.
Abstract: With the lack of success and increasing urgency for therapies capable of impacting Alzheimer's disease (AD) and its progression, there are increasing efforts to expand testing of new mechanistic hypotheses to attack the disease from different angles. Three such hypotheses are the "Mitochondrial Cascade (MC)" hypothesis, the "Endo-Lysosomal Dysfunction (ELD)" hypothesis and the "Type 3 Diabetes (T3D)" hypothesis. These hypotheses provide a rationale for new pharmacological approaches to address the mitochondrial, endo-lysosomal and metabolic dysfunction associated with AD. It is increasingly evident that there is critical interplay between the metabolic dysfunction associated with obesity/metabolic syndrome/type 2 diabetes mellitus (T2DM) and patient susceptibility to AD development. A candidate for a common mechanism linking these metabolically-driven disease states is chronically-activated mechanistic target of rapamycin (mTOR) signaling. Unrestrained chronic mTOR activation may be responsible for sustaining metabolic, lysosomal and mitochondrial dysfunction in AD, driving both the breakdown of the blood-brain barrier via endothelial cell dysfunction and hyperphosphorylation of tau and formation of amyloid plaques in the brain. It is hypothesized that sodium glucose cotransporter 2 (SGLT2) inhibition, mediated by sustained glucose loss, restores mTOR cycling through nutrient-driven, nightly periods of transient mTOR inhibition (and restoration of catabolic cellular housekeeping processes) interspersed by daily periods of transient mTOR activation (and anabolism) accompanying eating. In this way, a flexible mTOR dynamic is restored, thereby preventing or even reducing the progress of AD pathology. The first study to investigate the effect of SGLT2 inhibition in patients with AD is ongoing and focuses on the impact on energy metabolism in the brain following treatment with the SGLT2 inhibitor dapagliflozin.
TL;DR: The past and current findings that link AD and PD with T2DM, emphasizing the common pathological mechanisms are summarized and the efficacy of antidiabetic drugs in the prevention and/or treatment of AD andPD is discussed.
Abstract: Medical and scientific communities have been striving to disentangle the complexity of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), in order to develop a cure or effective treatment for these diseases. Along this journey, it has become important to identify the early events occurring in the prodromal phases of these diseases and the disorders that increase the risk of neurodegeneration highlighting common pathological features. This strategy has led to a wealth of evidence identifying diabetes, mainly type 2 diabetes mellitus (T2DM) as a main risk factor for the onset and progression of AD and PD. Impaired glucose metabolism, insulin resistance, and mitochondrial dysfunction are features common to both type 2 diabetes mellitus (T2DM), and AD and PD, and they appear before clinical diagnosis of the two neurodegenerative diseases. These could represent the strategic nodes of therapeutic intervention. Following this line of thought, a conceivable approach is to repurpose antidiabetic drugs as valuable agents that may prevent or reduce the risk of cognitive decline and neurodegeneration. This review summarizes the past and current findings that link AD and PD with T2DM, emphasizing the common pathological mechanisms. The efficacy of antidiabetic drugs, namely intranasal insulin, metformin, and thiazolidinediones, in the prevention and/or treatment of AD and PD is also discussed.
TL;DR: Evidence for an association between childhood poverty and brain structure/function is examined from a lifespan perspective and existing studies that link childhood poverty, brain development, and physical and mental health outcomes are examined.
Abstract: Experiencing poverty in childhood has been associated with increased risk for physical and mental health difficulties later in life. An emerging body of evidence suggests that brain development may be one mediator of this relation. In this chapter, we discuss evidence for an association between childhood poverty and brain structure/function. First, we examine the association from a lifespan perspective discussing studies at multiple developmental stages from the prenatal period to late adulthood. Second, we examine existing studies that link childhood poverty, brain development, and physical and mental health outcomes. Third, we discuss studies linking childhood poverty and environmental risks and protective factors. Lastly, we discuss suggestions for future studies including advances in network neuroscience, population neuroscience, using multiple imaging modalities, and the use of longitudinal neuroimaging studies. Overall, associations between childhood poverty, brain development, and development over the life course may help to both better understand and eventually reveal salient intervention strategies to mitigate social disparities in health.
TL;DR: Three subtypes of structural exposures of chronic stress exposure for psychotic disorders are identified, including urban environments, population density and crime exposure, and underlying neural mechanisms of over-pruning and protracted PFC development are identified.
Abstract: Chronic stress exposure has been established as a key vulnerability factor for developing psychotic disorders, including schizophrenia. A structural, or systems level perspective, has often been lacking in conceptualizations of chronic stress for psychotic disorders. The current review thus identified three subtypes of structural exposures. Stimulation exposures included urban environments, population density and crime exposure, with intermediary mechanisms of lack of safety and high attentional demands. Underlying neural mechanisms included threat neural circuits. Discrepancy exposures included environmental ethnic density, income inequality, and social fragmentation, with intermediary mechanisms of lack of belonging and social exclusion, and neural mechanisms including the oxytocin system. Deprivation exposures included environments lacking socioeconomic, educational, or material resources, with intermediary mechanisms of lack of needed environmental enrichment, and underlying neural mechanisms of over-pruning and protracted PFC development. Delineating stressor etiology at the systems level is a necessary step in reducing barriers to effective interventions and health policy.
TL;DR: How mitophagy is altered in Alzheimer's, Parkinson's, and Huntington's diseases, as well as in amyotrophic lateral sclerosis, is evaluated, and the potential of restoring mitophagic as a therapeutic intervention is evaluated.
Abstract: Neurodegenerative diseases are highly debilitating illnesses and a growing cause of morbidity and mortality worldwide. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes underlying neurodegeneration. Defective mitophagy has been highlighted as the cause of the accumulation of damaged mitochondria, which consequently leads to cellular dysfunction and/or death in neurodegenerative diseases. Here, we highlight the recent advances in the molecular mechanisms of mitochondrial homeostasis and mitophagy in neurodegenerative diseases. In particular, we evaluate how mitophagy is altered in Alzheimer's, Parkinson's, and Huntington's diseases, as well as in amyotrophic lateral sclerosis, and the potential of restoring mitophagy as a therapeutic intervention. We also discuss the interlinked connections between mitophagy and innate immunity (e.g., the involvement of Parkin, interferons and TRIM21) as well as the opportunity these pathways provide to develop combinational therapeutic strategies targeting them and related molecular mechanisms in such neurodegenerative diseases.
TL;DR: The pathways of stress and anxiety involve the hypothalamic pituitary adrenal axis and explain at least in part how stress may lead to worsening seizure control.
Abstract: Stress is ubiquitous in chronic medical conditions; however, the connections to psychiatric and neurologic conditions are not always clearly established. Epilepsy is a unique illness that is intimately intertwined with stress and anxiety not only as a result of the disease process but also as a cause of disease exacerbation. Anxiety and depression also involve stress management and often overlap with epilepsy. Anxiety symptoms themselves may be present as intrinsic aspects of seizure phenomena, either during the events or closely related to them. The pathways of stress and anxiety involve the hypothalamic pituitary adrenal (HPA) axis and explain at least in part how stress may lead to worsening seizure control. Ultimately, the study of stress, anxiety, and epilepsy offers insight into mind and body connections, and furthers understanding of neuropsychiatric illness.
TL;DR: The relationship between these common pathological processes in AD and PD is reviewed from the perspective of the "pro-inflammatory" signaling of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex.
Abstract: Evidence increasingly suggests that type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases share many pathological processes, including oxidative stress, local inflammation/neuroinflammation and chronic, low-grade (systemic) inflammation, which are exacerbated by aging, a common risk factor for T2DM and NDDs. Here, we focus on the link between chronic inflammation driven by peripheral metabolic disease and how this may impact neurodegeneration in AD and PD. We review the relationship between these common pathological processes in AD and PD from the perspective of the "pro-inflammatory" signaling of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex. Since the need for effective disease-modifying therapies in T2DM, AD and PD is significant, the relationship between these diseases is important as a positive clinical impact on one may benefit the others. We briefly consider how novel strategies may target neuro-inflammation and provide potential therapies for AD and PD.
TL;DR: This review will detail how ketone bodies, particularly d-β-hydroxybutyrate (βHB), may serve as a potential adjunctive nutritional therapy for two of the world's most devastating conditions.
Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are, respectively, the most prevalent and fastest growing neurodegenerative diseases worldwide. The former is primarily characterized by memory loss and the latter by the motor symptoms of tremor and bradykinesia. Both AD and PD are progressive diseases that share several key underlying mitochondrial, inflammatory, and other metabolic pathologies. This review will detail how these pathologies intersect with ketone body metabolism and signaling, and how ketone bodies, particularly d-β-hydroxybutyrate (βHB), may serve as a potential adjunctive nutritional therapy for two of the world's most devastating conditions.
TL;DR: The possible contributions of the range and nature of stress in PD are discussed and the current knowledge about the role of stress-related responses on motor and non-motor symptoms, the underlying pathophysiology, and the potential implications for treatment is summarized.
Abstract: Stress is ubiquitous with many factors contributing to its effects, including psychological responses and associated biological factors, including cortisol related physiological responses, and inflammation. Also in Parkinson's disease there is growing evidence for the role of stress in some key symptoms, even stretching to the prodromal stage. Here we discuss the possible contributions of the range and nature of stress in PD and we aim to summarize the current knowledge about the role of stress-related responses on motor and non-motor symptoms, the underlying pathophysiology, and the potential implications for treatment.
TL;DR: The heuristic model proposes that long-term effects of stress and ELA on the brain contribute to dysregulation of the stress response, emotional reactivity, reward systems, cognitive dysregulation, and delay discounting that lead to impulsive and high-risk behaviors, such as drug use and relapse.
Abstract: Preclinical, clinical, and population research demonstrates that stress and early life adversity (ELA) increase vulnerability to initiate, maintain, and relapse in addiction. Individuals with addiction problems have higher prevalence of trauma exposure than nondrug users; and this association extends to young populations (e.g., adolescents). Mechanisms for these associations likely involve multiple systems, including changes in the mesolimbic reward functions, HPA axis stress response, and other stress- and reward-related pathways. Other brain morphological and functional changes are also likely involved and directly contribute to the neurohormonal and behavioral alterations observed during adulthood in those exposed to ELA. Stress-related risk is influenced by sex, genetic factors, and resilience, among other factors. Our heuristic model proposes that long-term effects of stress and ELA on the brain contribute to dysregulation of the stress response, emotional reactivity, reward systems, cognitive dysregulation, and delay discounting that lead to impulsive and high-risk behaviors, such as drug use and relapse.
TL;DR: Evidence suggests that the interplay between neuro-endocrine and psychological factors may have a significant role in balance function, and in healthy individuals vestibular stimulation has been shown to trigger the stress response as indicated by increased blood cortisol levels.
Abstract: In this chapter we review the existing literature regarding the interactions between stress and the mechanisms that maintain balance. Evidence suggests that the interplay between neuro-endocrine and psychological factors may have a significant role in balance function. For example, in healthy individuals vestibular stimulation has been shown to trigger the stress response as indicated by increased blood cortisol levels, whereas in patients with vestibular pathology factors such as resilience and anxiety may be the key focus of interactions with stress. Critically, factors such as anxiety are known to influence clinical outcomes, despite our mechanistic understanding of these processes remaining in their infancy.
TL;DR: The potential of salivary cortisol as both a product and mediator of brain function, instrumental in disturbing brain health, is highlighted, with a particular emphasis on necessary methodological rigor for integration of stress-related risk factors and resilience across the life course.
Abstract: The validation of accurate and meaningful assessment of cortisol in saliva samples has proved revolutionary in stress research. Its many advantages have expanded the scope of investigation from traditional laboratory and clinical settings to include multidisciplinary and community-based research. These developments have given rise to a wealth insight into the links between stress and health. Here we highlight the potential of salivary cortisol as both a product and mediator of brain function, instrumental in disturbing brain health. However, the subtleties of salivary cortisol as a measure can be underestimated, leading to misinterpretation of findings. These issues are explored, with a particular emphasis on necessary methodological rigor. Notwithstanding great promise, there is undeniably more to learn so we conclude by making recommendations for future research including use of salivary cortisol in the development of integrative predictive models of stress-related risk factors and resilience across the life course.
TL;DR: Compared the expression levels of signaling pathway proteins involved in interaction of receptors with the ECM in CSCs and DGCs, it is observed that C SCs may have highly invasive nature.
Abstract: Glioblastoma multiforme (GBM) is the most common primary tumor of the human brain. It is characterized by invasive growth and strong resistance to treatment, and the median survival time of patients is 15 months. The invasive growth of this tumor type is associated with tumor cells with an aggressive phenotype, while its treatment resistance is attributed to cancer stem cells (CSCs). It remains unclear if CSCs have a more invasive nature than differentiated glioblastoma cells (DGCs), and what contribution CSCs make to the aggressive phenotype of GBM. Interaction with the extracellular matrix (ECM) is a key factor in the development of invasion. The aim of the present study was to compare the expression levels of signaling pathway proteins involved in interaction of receptors with the ECM in CSCs and DGCs. The U-87MG GBM cell line was used in the present study CSCs were extracted from gliomaspheres through magnetic-activated cell sorting based on the expression of cluster of differentiation 133 (CD133); CD133-negative DCGs were used as a control. HPLC and mass spectrometry were also used, and biological and molecular functions, signaling pathways and protein-protein interactions were analyzed using publicly available databases. Increased expression levels of the following 10 proteins involved in interaction with the ECM were identified in CSCs, compared with expression levels in DGCs: COL6A1, COL6A3, FN1, ITGA2, ITGA5, ITGAV, ITGB1, ITGB3, LAMB1 and LAMC1. The proteome of CSCs was observed to have >2-fold higher expression of these key proteins, when compared with the DGC proteome. Increased expression levels of four proteins (FERMT2, LOXL2, HDAC2 and FBN1) involved in activating signaling in response to receptor interaction with the ECM was also observed, indicating that CSCs may have highly invasive nature. LOXL2 expression level was >9-fold higher in CSCs compared to DGCs, suggesting that this protein may have potential as an marker for CSCs and as a target for this cell type in GBM.
TL;DR: Recommendations are provided for the use of salivary cortisol as a marker of early monitoring of brain health and effectiveness of stress-alleviating interventions.
Abstract: Stress leads to ill-health and disease, and with today's fast-pace western society, engaging in strategies to relieve stress is crucial for good health across the life-course. Activities such as focusing on positive characteristics, art/music therapies, mindfulness, yoga and engaging with nature and/or physical activity have been shown to reduce stress and enhance well-being. It is thought that patterns of cortisol secretion, which are regulated by the brain, are a key mediator of stress-disease and well-being-health links. Measurement of cortisol in saliva is a non-invasive and ecologically valid tool for detecting early changes in brain health, as well as evaluating the effectiveness of strategies in relieving stress and improving brain health as well as monitoring stress-related brain changes. This chapter will review the evidence that engaging in stress-relieving strategies promotes regulation and/or restoration of patterns of cortisol secretion. If such strategies are found to be effective in healthy populations, they could potentially inform ways of promoting brain health and the prevention or delay of clinical disorders involving disorders in the brain (e.g., Parkinson's disease) and symptoms experienced with such disorders. To inform this field of research, recommendations are provided for the use of salivary cortisol as a marker of early monitoring of brain health and effectiveness of stress-alleviating interventions.
TL;DR: This chapter will discuss epigenetic mechanisms of brain histone acetylation, histone methylation, and DNA methylation that contribute to adult stress-induced depressive-like behavior in rodents.
Abstract: Stressful life events are a major contributor to the development of major depressive disorder. Environmental perturbations like stress change gene expression in the brain, leading to altered behavior. Gene expression is ultimately regulated by chromatin structure and the epigenetic modifications of DNA and the histone proteins that make up chromatin. Studies over the past two decades have demonstrated that stress alters the epigenetic landscape in several brain regions relevant for depressive-like behavior in rodents. This chapter will discuss epigenetic mechanisms of brain histone acetylation, histone methylation, and DNA methylation that contribute to adult stress-induced depressive-like behavior in rodents. Several biological themes have emerged from the examination of the brain transcriptome after stress such as alterations in the neuroimmune response, neurotrophic factors, and synaptic structure. The epigenetic mechanisms regulating these processes will be highlighted. Finally, pharmacological and genetic manipulations of epigenetic enzymes in rodent models of depression will be discussed as these approaches have demonstrated the ability to reverse stress-induced depressive-like behaviors and provide proof-of-concept as novel avenues for the treatment of clinical depression.
TL;DR: The recent applications of advanced multimodal imaging such as diffusion MRI sequences, amide proton transfer MRI Sequence, perfusion MRI sequence, MR spectroscopy and multinuclides PET/CT in the evaluation of post-radiotherapy treatment response in glioma patients are discussed.
Abstract: Gliomas are the most common malignant primary brain tumor, and their prognosis is extremely poor. Radiotherapy is an important treatment for glioma patients, but the changes caused by radiotherapy have brought difficulties in clinical image evaluation because differentiating glioma recurrence from post-radiotherapy changes including pseudo-progression (PD) and radiation necrosis (RN) remains a challenge. Therefore, accurate and reliable imaging evaluation is very important for making clinical decisions. In recent years, advanced multimodal imaging techniques have been applied to achieve the goal of better differentiating glioma recurrence from post-radiotherapy changes for minimizing errors associated with interpretation of treatment effects. In this review, we discuss the recent applications of advanced multimodal imaging such as diffusion MRI sequences, amide proton transfer MRI sequences, perfusion MRI sequences, MR spectroscopy and multinuclides PET/CT in the evaluation of post-radiotherapy treatment response in glioma patients and highlight their potential role in differentiating post-radiotherapy changes from glioma recurrence.