Depression, dementia and immune dysregulation.

Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer's disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia. We propose that chronic stress and inflammation combine to compromise vascular and brain function. The resulting increases in proinflammatory cytokines and microglial activation drive brain pathology leading to depression and mild cognitive impairment, which may progress to dementia. We present evidence that by treating the inflammatory changes, depression can be reversed in many cases. Importantly, there is evidence that anti-inflammatory and antidepressant treatments may reduce or prevent dementia in people with depression. Thus, we propose a model in which chronic stress and inflammation combine to increase brain permeability and cytokine production. This leads to microglial activation, white matter damage, neuronal and glial cell loss. This is first manifest as depression and mild cognitive impairment, but can eventually evolve into dementia. Further research may identify clinical subgroups with inflammatory depression at risk for dementia. It would then be possible to address in clinical trials whether effective treatment of the depression can delay the onset of dementia.

Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells.

Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry. When MPs were added to cultured endothelial cells or normal rat kidney cells they induced cell death in a time and dose dependent manner. Analysis of pellets by electron microscopy indicates that cell death signals are carried by particles in the range of 400 nm in diameter or less. Cell death involved the activation of caspase 3 and was not a consequence of oxidative stress. Inhibition of the Fas/FasL signaling pathway also did not improve cell survival. MPs were found to contain caspase 3 and treating the MPs with a caspase 3 inhibitor significantly reduced cell death. A TNF-α receptor blocker and a TRAIL neutralizing antibody also significantly reduced cell death. Levels of circulating MPs are elevated in a rodent model of chronic cerebral ischemia. MPs with a diameter of 400 nm or less activate the TNF-α and TRAIL signaling pathways and may deliver caspase 3 to cultured cells.

Microparticles: biomarkers and beyond.

Membrane microparticles are submicron fragments of membrane shed into extracellular space from cells under conditions of stress/injury. They may be distinguished from other classes of extracellular vesicles (i.e. exosomes) on the basis of size, content and mechanism of formation. Microparticles are found in plasma and other biological fluids from healthy individuals and their levels are altered in various diseases, including diabetes, chronic kidney disease, pre-eclampsia and hypertension among others. Accordingly, they have been considered biomarkers of vascular injury and pro-thrombotic or pro-inflammatory conditions. In addition to this, emerging evidence suggests that microparticles are not simply a consequence of disease, but that they themselves may contribute to pathological processes. Thus microparticles appear to serve as both markers and mediators of pathology. The present review examines the evidence for microparticles as both biomarkers of, and contributors to, the progression of disease. Approaches for the detection of microparticles are summarized and novel concepts relating to the formation of microparticles and their biological effects are examined.

The Physiological and Molecular Links Between Physical Activity and Brain Health: A Review.

There is currently an epidemic of sedentary behavior throughout the world, leading to negative impacts on physical health and contributing to both mortality and burden of disease. The consequences of this also impact the brain, where increased levels of cognitive decline are observed in individuals who are more sedentary. This review explores the physiological and molecular responses to our sedentary propensity, its contribution to several medical conditions and cognitive deficits, and the benefits of moderate levels of physical activity and exercise. Also presented is the recommended level of activity for overall physical health improvement.

Gene therapy strategies for glaucoma from IOP reduction to retinal neuroprotection: Progress towards non-viral systems.

Glaucoma is the result of the gradual death of retinal ganglion cells (RGCs) whose axons form the optic nerve. Elevated intraocular pressure (IOP) is a major risk factor that contributes to RGC apoptosis and axonal loss at the lamina cribrosa, resulting in progressive reduction and eventual anterograde-retrograde transport blockade of neurotrophic factors. Current glaucoma management mainly focuses on pharmacological or surgical lowering of IOP, to manage the only modifiable risk factor. Although IOP reduction delays disease progression, it does not address previous and ongoing optic nerve degeneration. Gene therapy is a promising direction to control or modify genes involved in the pathophysiology of glaucoma. Both viral and non-viral gene therapy delivery systems are emerging as promising alternatives or add-on therapies to traditional treatments for improving IOP control and providing neuroprotection. The specific spotlight on non-viral gene delivery systems shows further progress toward improving the safety of gene therapy and implementing neuroprotection by targeting specific tissues and cells in the eye and specifically in the retina.

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery.

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

Primary prevention of stroke: blood pressure, lipids, and heart failure.

Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment and rehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is a heterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs from coronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease on risk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heart failure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases rather than individual risk factors. Lifestyle interventions serve as a basis for primary prevention of cardiovascular diseases. It is estimated that 70% of strokes are potentially preventable by lifestyle modification but prospective evidence is needed to support these hypotheses derived from epidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additional measures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids.

Perspectives on the complex links between depression and dementia.

This review highlights that depression is a growing health problem for the individual, and because of its high frequency in most societies, a growing burden on health care budgets. The focus of the review is the physiological links between depression and dementia, specifically Alzheimer's disease. It suggests that depression is a significant risk factor for cognitive decline and explores the pathways that may lead depressed individuals to suffer this outcome. This review shows that depression and a number of its precursors activate pro-inflammatory mediators. These lead to cerebral small vessel disease with the consequent reduction in cerebral blood flow, which is known to precede cognitive decline. Thus, the impact of depression on the physiological events that lead to dementia is identical to the impact of other dementia risk factors recently reviewed. Depression is distinct, however, in being a relatively treatable condition, but the impact of treating depression on later cognitive decline is not always positive, leading to the hypothesis that only the antidepressants that attenuate inflammation alleviate subsequent cognitive decline.

A Proposed Hypothesis on Dementia: Inflammation, Small Vessel Disease, and Hypoperfusion Is the Sequence That Links All Harmful Lifestyles to Cognitive Impairment.

There is growing consensus that certain lifestyles can contribute to cognitive impairment and dementia, but the physiological steps that link a harmful lifestyle to its negative impact are not always evident. It is also unclear whether all lifestyles that contribute to dementia do so through the same intermediary steps. This article will focus on three lifestyles known to be risk factors for dementia, namely obesity, sedentary behavior, and insufficient sleep, and offer a unifying hypothesis proposing that lifestyles that negatively impact cognition do so through the same sequence of events: inflammation, small vessel disease, decline in cerebral perfusion, and brain atrophy. The hypothesis will then be tested in a recently identified risk factor for dementia, namely hearing deficit. If further studies confirm this sequence of events leading to dementia, a significant change in our approach to this debilitating and costly condition may be necessary, possible, and beneficial.

Stroke: working toward a prioritized world agenda.

BACKGROUND AND PURPOSE: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. METHODS: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

Stroke: working toward a prioritized world agenda.

BACKGROUND AND PURPOSE: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. METHODS: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

Living beyond our physiological means: small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis.

BACKGROUND AND PURPOSE: It is our premise that the pathophysiology of small vessel disease in the brain is similar to small vessel disease in other heavily perfused tissues and that the presence of small vessel disease elsewhere in the body foretells its presence in the brain as well as its consequences on cognitive function. The hypothesis presented in this article is that small vessel disease is a systemic condition of aging that is exacerbated by vascular risk factors, which results from dysfunction of arteriolar perfusion. This condition, which we term systemic arteriolar dysfunction, affects the brain as well as a number of extracranial systems. SUMMARY OF REVIEW: Recent literature is synthesized to suggest a possible etiology of this condition, highlighting the multiple pathways that may conspire to produce the endothelial and other vascular changes seen in systemic arteriolar dysfunction. CONCLUSIONS: Regardless of the etiology, we emphasize that small vessel disease is a systemic condition with major healthcare consequences, requiring a new paradigm in the way we practice medicine. Because this condition can be decelerated by control of vascular risk factors, doing so may significantly reduce morbidity, mortality, and healthcare costs.

Age disparities in stroke quality of care and delivery of health services.

BACKGROUND AND PURPOSE: Limited information is available on the effect of age on stroke management and care delivery. Our aim was to determine whether access to stroke care, delivery of health services, and clinical outcomes after stroke are affected by age. METHODS: This was a prospective cohort study of patients with acute ischemic stroke in the province of Ontario, Canada, admitted to stroke centers participating in the Registry of the Canadian Stroke Network between July 1, 2003 and March 31, 2005. Primary outcomes were the following selected indicators of quality stroke care: (1) use of thrombolysis; (2) dysphagia screening; (3) admission to a stroke unit; (4) carotid imaging; (5) antithrombotic therapy; and (6) warfarin for atrial fibrillation at discharge. Secondary outcomes were risk-adjusted stroke fatality, discharge disposition, pneumonia, and length of hospital stay. RESULTS: Among 3631 patients with ischemic stroke, 1219 (33.6%) were older than 80 years. There were no significant differences in stroke care delivery by age group. Stroke fatality increased with age, with a 30-day risk adjusted fatality of 7.1%, 6.5%, 8.8%, and 14.8% for those aged 59 or younger, 60 to 69, 70 to 79, and 80 years or older, respectively. Those aged older than 80 years had a longer length of hospitalization, increased risk of pneumonia, and higher disability at discharge compared to those younger than 80. This group was also less likely to be discharged home. CONCLUSIONS: In the context of a province-wide coordinated stroke care system, stroke care delivery was similar across all age groups with the exception of slightly lower rates of investigations in the very elderly. Increasing age was associated with stroke severity and stroke case-fatality.

Small Vessel Disease.

Small vessel disease (SVD) refers to conditions where damage to arterioles and capillaries is predominant, leading to reduced, or interrupted perfusion of the affected organ. Data suggest that when this condition is evident in any organ, it is already systemic in its occurrence and consequences. SVD affects primarily organs that receive significant portions of cardiac output such as the brain, the kidney, and the retina. Thus, SVD is a major etiologic cause in debilitating conditions such as renal failure, blindness, lacunar infarcts, and dementia. The factors that lead to this devastating condition include all the known vascular risk factors when they are not strictly controlled, but lifestyles that include sedentary existence, obesity, and poor sleep patterns are also recognized drivers of SVD. In addition, depression is now recognized as a vascular risk factor. Inflammation is a mediator of SVD, but it is not known which factor(s) predominate in its etiology. This article emphasizes the need for more investigations to define this link further and suggests clinical and societal responses that might reduce the major impacts of this condition on populations.

ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitro.

Spreading depression (SD) is a self-propagating wave of neuronal and glial depolarization that may occur in virtually any gray matter region in the brain. One consequence of SD is an increased tolerance to ischemia. It has been shown that during cortical SD ATP is released into the extracellular space and activation of purinergic receptors leads to the induction of ischemic tolerance. In the present study we show that depolarization of cultured neurons induces ischemic tolerance which is mediated by purinergic receptor activation. Depolarization causes the release of ATP into the extracellular medium, which may be prevented by treatment with the connexin hemichannel blockers flufenamic acid and quinine, but not the pannexin hemichannel blocker carbenoxolone. Knockdown of connexin 36 expression by siRNA greatly reduces the amount of ATP released during depolarization and the subsequent degree of ischemic tolerance. We conclude that during depolarization neurons release ATP by way of connexin 36 hemichannels.

Vascular disease: the tsunami of health care.

The gap between existing knowledge and the patient care provided in stroke has become more apparent. The translational gap is evidence of our scientific progress, but the sheer magnitude of our implementation gap is astounding. For instance, almost 5 decades ago we recognized the risk factors for stroke, yet in Canada until recently fewer than 20% of cases of hypertension were effectively controlled. We recognize that continued exposure to risk factors will not only lead to clinically evident strokes, but far more frequently to silent strokes resulting in cognitive decline. In addition, the same risk factors cause damage to other organs. This growing gap between existing knowledge and its translational delivery is leading our politicians to demand more practical returns. As scientific and clinical opinion leaders in stroke, we have a huge opportunity now to lead the process of narrowing the translational gap. We need to keep our emphasis on individual research excellence but temper it with a social mission to improve stroke prevention, care and rehabilitation. Toward this end, the Canadian Stroke Network partnered with the Heart and Stroke Foundation of Canada to develop the 'Canadian Stroke Strategy', an approach to focus research, increase training of stroke specialists, coordinate the care of patients, and bring 'systems change' to respond to the growing gap in all facets of stroke care. Lessons learned from both successes and failures can inform our translational efficiency in the future and facilitate collective progress in stroke care.

Transient expression of Nxf, a bHLH-PAS transactivator induced by neuronal preconditioning, confers neuroprotection in cultured cells.

Cortical spreading depression (CSD) induces waves of neuronal depolarization that confer neuroprotection to subsequent ischemic events in the rat brain. To gain insights into the molecular mechanisms elicited by CSD, we used representational difference analysis (RDA) to identify mRNAs induced by potassium depolarization in vivo. Using this approach, we have isolated a cDNA encoding the SIM2-related bHLH-PAS protein Nxf. Our results confirm that Nxf mRNA and protein are rapidly and transiently expressed in cortical neurons following CSD. Reporter assays show that Nxf is a transcriptional activator that associates with the bHLH-PAS sub-class co-factor ARNT2. Adenovirus-mediated expression of epitope-tagged Nxf results in cell death and the direct activation of the Bax gene in cultured cells. However, RNA interference studies show that endogenous Nxf is required for optimal neuroprotection by preconditioning in cultured F-11 cells. Together, our data indicate that Nxf is a novel bHLH-PAS transactivator transiently induced by preconditioning and that its sustained expression is detrimental. The identification of Nxf may represent an important step in our understanding of the molecular mechanisms of brain preconditioning and injury.

Cortical spreading depression releases ATP into the extracellular space and purinergic receptor activation contributes to the induction of ischemic tolerance.

Cortical Spreading Depression (CSD) is a well-studied model of preconditioning that provides a high degree of tolerance to a subsequent ischemic event in the brain. The present study was undertaken in order to determine whether the release of ATP during CSD could contribute to the induction of ischemic tolerance. Direct measurement of ATP levels during CSD indicates that with each CSD wave ATP is released into the extracellular space at levels exceeding 100 microM. Cultures of rat primary cortical neurons exposed to low levels of extracellular ATP developed tolerance to subsequent oxygen-glucose deprivation (OGD) or metabolic hypoxia. The preconditioning effect requires new protein synthesis and develops with time, suggesting that a complex genomic response is required for the induction of tolerance. Multiple purinergic receptors are involved in mediating tolerance, with P2Y receptor activation having the greatest effect. Although extracellular adenosine or glutamate may make a small contribution, most of the tolerance was found to be induced independently of adenosine or glutamate receptor activation. Multiple signal transduction pathways mediate the response to extracellular ATP with the protein kinase A pathway and activation of phospholipase C contributing the most. The results are consistent with the proposal that CSD releases ATP into the extracellular space and the subsequent activation of P2Y receptors makes a major contribution to the induction of ischemic tolerance in the brain.