Jerzy Leszek

Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins

A molecular test for Alzheimers disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimers and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimers disease 2–6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimers disease.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

A number of distinct β-amyloid (Aβ) variants or multimers have been implicated in Alzheimers disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Aβ-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Aβ and amyloidogenic non-Aβ species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21–89 years. Antibody reactivity was most prominent against oligomeric assemblies of Aβ and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Aβ1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Aβ, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Aβ toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Aβ the monkeys developed high titers not only against Aβ peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Aβ antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

Metabolic syndrome, mild cognitive impairment and Alzheimer's disease—The emerging role of systemic low-grade inflammation and adiposity

The past decade has shed new light on the etiology of Alzheimers disease (AD), which is the consequence of interactions between numerous lesions. There is a growing body of evidence that the most beneficial effects of treatment might only be achieved in the preclinical stage of dementia, prior to the immense hallmarks of neurodegeneration. In view of this, several studies have focused on mild cognitive impairment (MCI) as a state, which represents a less severe form of the neuropathological process. However, early treatment interventions initiated in MCI have failed to slow down progression of the disease. Thus, great effort has been made to indicate modifiable risk factors for MCI. Consistent with the role of vascular malfunction in AD, this approach has shown the predictive value of the metabolic syndrome (MetS), which is a multidimensional entity and includes visceral obesity, dyslipidemia, hyperglycemia and hypertension. Despite the positive results of several epidemiological studies, the exact mechanisms underlying the connection between MetS and AD remain uncertain and various theories are being assessed. MetS, similarly to AD, has been attributed to a low-grade chronic inflammation. There is a general consensus that the aberrant inflammatory response underlying MetS may arise from a deregulation of the endocrine homeostasis of adipose tissue. Hence, it might be assumed that the subclinical inflammation of adipose tissue may interact with the impaired central inflammatory response, leading to neurodegeneration. This article reviews the role of low-grade inflammation of adipose tissue in the pathophysiology of cognitive impairment and translates several considerable and unexplored findings from studies focused on subjects with MetS and animal models mimicking the phenotype of MetS into the etiology of AD.

Antioxidants in Health, Disease and Aging

There is growing scientific agreement that antioxidants, particularly the polyphenolic forms, may help lower the incidence of disease, such as certain cancers, cardiovascular and neurodegenerative diseases, DNA damage, or even have anti-aging properties. On the other hand, questions remain as to whether some antioxidants or phytochemicals potentially could do more harm than good, as an increase in glycation-mediated protein damage (carbonyl stress) and some risk has been reported. Nevertheless, the quest for healthy aging has led to the use of antioxidants as a means to disrupt age-associated deterioration in physiological function, dysregulated metabolic processes or prevention of many age-related diseases. Although a diet rich in polyphenolic forms of antioxidants does seem to offer hope in delaying the onset of age-related disorders, it is still too early to define their exact clinical benefit for treating age-related disease. Regardless of where the debate will end, it is clear that any deficiency in antioxidant vitamins or adequate enzymatic antioxidant defenses can manifest in many disease states and shift the redox balance in some diseases. This updated review critically examines general antioxidant compounds in health, disease and aging with hope that a better understanding of the many mechanisms involved with these diverse compounds may lead to better health and novel treatment approaches for age-related diseases.

Flavones from Root of Scutellaria Baicalensis Georgi: Drugs of the Future in Neurodegeneration?

Flavonoids are natural, plant-derived compounds which exert diverse biological activities, also valuable neuroprotective actions within the brain and currently are intensively studied as agents able to modulate neuronal function and to prevent age-related neurodegeneration. Among them, flavones isolated from Scutellaria baicalensis root exhibit strong neuroprotective effects on the brain and are not toxic in the broad range of tested doses. Their neuroprotective potential has been shown in both oxidative stress-induced and amyloid-beta and alpha-synuclein-induced neuronal death models. Baicalein, the main flavone present in Scutellaria baicalensis root, strongly inhibited aggregation of neuronal amyloidogenic proteins in vitro and induces dissolution of amyloid deposits. It exerts strong antioxidative and anti-inflammatory activities and also exhibits anti-convulsive, anxiolytic, and mild sedative actions. Importantly, baicalein, and also another flavone: oroxylin A, markedly enhanced cognitive and mnestic functions in animal models of aging brains and neurodegeneration. In the preliminary study, wogonin, another flavone from Scutellaria baicalensis root, has been shown to stimulate brain tissue regeneration, inducing differentiation of neuronal precursor cells. This concise review provides the main examples of neuroprotective activities of the flavones and reveals their potential in prevention and therapyof neurodegenerative diseases.

Mitochondrion-Specific Antioxidants as Drug Treatments for Alzheimer Disease

Age-related dementias such as Alzheimer disease (AD) have been linked to vascular disorders like hypertension, diabetes and atherosclerosis. These risk factors cause ischemia, inflammation, oxidative damage and consequently reperfusion, which is largely due to reactive oxygen species (ROS) that are believed to induce mitochondrial damage. At higher concentrations, ROS can cause cell injury and death which occurs during the aging process, where oxidative stress is incremented due to an accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms. Neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, causing a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion whos DNA has been compromised. Therefore, mitochondria specific antioxidants such as acetyl-L-carnitine and R-alphalipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and amyloid beta oxidation and making these antioxidants very powerful alternate strategies for the treatment of AD.

Inflammatory Response in the CNS: Friend or Foe?

Inflammatory reactions could be both beneficial and detrimental to the brain, depending on strengths of their activation in various stages of neurodegeneration. Mild activation of microglia and astrocytes usually reveals neuroprotective effects and ameliorates early symptoms of neurodegeneration; for instance, released cytokines help maintain synaptic plasticity and modulate neuronal excitability, and stimulated toll-like receptors (TLRs) promote neurogenesis and neurite outgrowth. However, strong activation of glial cells gives rise to cytokine overexpression/dysregulation, which accelerates neurodegeneration. Altered mutual regulation of p53 protein, a major tumor suppressor, and NF-κB, the major regulator of inflammation, seems to be crucial for the shift from beneficial to detrimental effects of neuroinflammatory reactions in neurodegeneration. Therapeutic intervention in the p53-NF-κB axis and modulation of TLR activity are future challenges to cope with neurodegeneration.

The medical perspective on burnout

ObjectiveThe aim of this study was to review recent medical findings related to burnout, its diagnosis, treatment, characteristic pathophysiological features, and preventive measures.Materials and MethodsA systematic review of the scientific literature in PubMed/Medline was performed. The most recent and important findings were reported.ResultsBurnout was found to be a risk factor for myocardial infarction and coronary heart disease. It was also related to reduced fibrinolytic capacity, decreased capacity to cope with stress and hypothalamic-pituitary-adrenal (HPA) axis hypoactivity. Severe burnout symptoms are associated with a lower level or smaller increase of the cortisol awakening response (CAR), higher dehydroepiandrosterone-sulphate (DHEAS) levels, lower cortisol/DHEAS ratios and stronger suppression as measured by the dexamethasone suppression test (DST). More and more literature works suggest that the evaluation of the HPA axis should be brought to the attention of primary care physicians. There is no universal agreement on specific treatment and diagnostic measures to evaluate the wide range of HPA axis disorders. The cost-effective evaluation of adrenal hormones via saliva samples by a primary care physician may significantly alter the course of therapy in numerous chronic disease patients. Psychiatric disorders may have similar symptoms, but they have distinctive hormonal profiles. Having burnout recognized as a medical condition would help in differentiating burnout from similar clinical syndromes, such as depression or anxiety, and provide appropriate treatment to burnout patients. Proper treatment is essential for a fast and full recovery.ConclusionChronic stress-related disorders often fall outside the category of a “true” disease and are often treated as depression or not treated at all. The evaluation of adrenal hormones via saliva samples helps to predict burnout. Burnout screening techniques, dietary and nutritional guidelines and lifestyle changes for supporting the HPA function need to be developed. The presented material includes hormonal, dietary, and pharmaceutical perspectives.

Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer's disease: a new approach to therapy.

Vascular and metabolic dysfunctions and mitochondrial failure are now believed to be contributors to Alzheimer’s disease (AD) pathogenesis. Vascular dysfunction includes reduced cerebral blood flow (CBF), blood-brain barrier (BBB) disturbances and cerebral amyloid angiopathy (CAA). Mitochondrial failure results in deregulation of Ca 2+ homeostasis and elevated reactive oxygen species (ROS) generation, both of which are linked to neurotoxicity. Increased levels of ROS stimulate proinflammatory gene transcription and release of cytokines, such as IL-1, IL-6, and TNF-α, and chemokines, thereby inducing neuroinflammation. Conversely, inflammatory reactions activate microglia and astrocytes to generate large amounts of ROS, so neuroinflammation could be perceived as a cause and a consequence of chronic oxidative stress. The interaction between oxidative stress and neuroinflammation leads to amyloid-β (Aβ) generation. The deposition of Aβ peptide in the brain generates a cascade of pathological events, including the formation of neurofibrillary tangles (NFTs), inflammatory reactions, increased oxidative stress and mitochondrial dysfunction, which are causative factors of cell death and dementia. The purpose of this paper is to provide current evidence on vascular dysfunction and mitochondrial failure, both in neurons and glia and in brain vascular wall cells in the context of potential application for treatment of AD and other neurodegenerations.

Vascular factors and epigenetic modifications in the pathogenesis of Alzheimer's disease

Alzheimers disease (AD) is a debilitating illness with no known cure. Nowadays accumulating evidence suggested that the vascular endothelium and chronic hypoperfusion may play important role in pathobiology of AD. The vascular endothelium which regulates the passage of macromolecules and circulating cells from blood to tissue, is a major target of oxidative stress, playing a critical role in the pathophysiology of vascular diseases. Since the vascular endothelium, neurons and glia are all able to synthesize, store and release reactive oxygen species (ROS) and vascular active substances in response to certain stimuli, their contribution to the pathophysiology of AD can be very important. New evidence indicates that continuous formation of free ROS induces cellular damage and decreases antioxidant defenses. Specifically, oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesion. We summarize the reports that sporadic, late-onset of AD results from vascular etiology. Recently an involvement of epigenetic alterations in the etiology of AD is also intensively investigated. Gaining a more complete understanding of the essential components and underlying mechanisms involved in epigenetic regulation could lead to novel treatments for a number of neurological and psychiatric conditions.