BACKGROUND AND PURPOSE Organized systems of care have the potential to improve acute stroke care delivery. The current report describes the experience of implementing a countywide system of spoke-and-hub Stroke Neurology Receiving Centers (SNRC) that incorporated several comprehensive stroke center recommendations. METHODS Observational study of patients with suspected stroke <5 hours duration transported by Emergency Medical System personnel to an SNRC during the first year of this system. RESULTS A total of 1,360 patients with suspected stroke were evaluated at 9 hub SNRCs, of which 553 (40.7%) had a discharge diagnosis of ischemic stroke. Of these 553, intravenous (IV) tPA was given to 110 patients (19.9% of ischemic strokes). Care at the 6 neurointerventional-ready SNRC was a major focus, where 25.1% (99/395) of the patients with ischemic stroke received acute IV or intraarterial reperfusion therapy, and where provision of such therapies was less common with milder stroke, higher age, and Hispanic origin. The door-to-needle time for IV tPA met the <60 minute target in only 25% of patients and was 37% longer (p=0.0001) when SNRCs were neurointerventional-ready. CONCLUSIONS A stroke system that incorporates features of comprehensive stroke centers can be effectively implemented, and with substantial rates of acute reperfusion therapy administration. Experiences potentially useful to broader implementation of comprehensive stroke centers are considered.

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

Alzheimer's disease, the most common form of dementia, is marked by progressive cognitive and functional impairment believed to reflect synaptic and neuronal loss. Recent preclinical data suggests that lipopolysaccharide (LPS)-activated microglia may contribute to the elimination of viable neurons and synapses by promoting a neurotoxic astrocytic phenotype, defined as A1. The innate immune cells, including microglia and astrocytes, can either facilitate or inhibit neuroinflammation in response to peripherally applied inflammatory stimuli, such as LPS. Depending on previous antigen encounters, these cells can assume activated (trained) or silenced (tolerized) phenotypes, augmenting or lowering inflammation. Iron, reactive oxygen species (ROS), and LPS, the cell wall component of gram-negative bacteria, are microglial activators, but only the latter can trigger immune tolerization. In Alzheimer's disease, tolerization may be impaired as elevated LPS levels, reported in this condition, fail to lower neuroinflammation. Iron is closely linked to immunity as it plays a key role in immune cells proliferation and maturation, but it is also indispensable to pathogens and malignancies which compete for its capture. Danger signals, including LPS, induce intracellular iron sequestration in innate immune cells to withhold it from pathogens. However, excess cytosolic iron increases the risk of inflammasomes' activation, microglial training and neuroinflammation. Moreover, it was suggested that free iron can awaken the dormant central nervous system (CNS) LPS-shedding microbes, engendering prolonged neuroinflammation that may override immune tolerization, triggering autoimmunity. In this review, we focus on iron-related innate immune pathology in Alzheimer's disease and discuss potential immunotherapeutic agents for microglial de-escalation along with possible delivery vehicles for these compounds.

Dehydration is one of the ten most frequent diagnoses responsible for the hospital admission of elderly in the United States. It is associated with increased mortality, morbidity and an estimated cost of 1.14 billion per year (Xiao et al., 2004; Schlanger et al., 2010; Pretorius et al., 2013; Frangeskou et al., 2015). Older individuals are predisposed to dehydration encephalopathy as a result of decreased total body water (TBW) and diminished sensation of thirst. We hypothesize that thirst blunting in older individuals is the result of a defective microRNA-6842-3p failing to silence the expression of the vesicular GABA transporters (VGAT) and alpha 7 cholinergic nicotinic receptors in the subfornical organ (SFO) of the hypothalamus. We hypothesize further that resultant dehydration facilitates protein misfolding and aggregation, predisposing to neurocognitive disorders. We completed a search of predicted microRNA targets, utilizing the public domain tool miRDB and found that microRNA-6842-3p modulates the SLC6A1 and CHRNA7 genes both of which were previously hypothesized to inhibit the thirst sensation by their action on SFO. The primary aim of this article is to answer two questions: Can prevention and correction of dehydration in elderly lower age-related cognitive deterioration? Can exosomal miR-6842 in the peripheral blood predict dehydration encephalopathy in elderly?

The interaction between living organisms and the environment requires a balancing act between genomic and epigenomic forces. Inflammation and cellular proliferation are kept in check by the genes, which code for their components and the microRNAs, which are capable of silencing the transcription of these genes. Acetylcholine (ACh) may play a unique role in the maintenance of this equilibrium, as the epigenomic inhibition of the gene coding for nicotinic receptors, and disinhibits the gene causing anergia in immune cells. We hypothesize that age-induced ACh deficiency is the result of an epigenomic dysfunction of microRNA-6775 (miR-6775), which silences the transcription of CHRNA7 gene [coding for alpha 7 nicotinic cholinergic receptors (nAChRs)]. When silenced, this gene induces decreased expression of alpha 7 nAChRs, which may predispose elderly individuals to inflammation, neuroinflammation, and delirium. We hypothesize further that miR-6775-induced hypocholinergia augments the expression of RNF 128, the gene related to anergy in lymphocytes (GRAIL). This gene favors regulatory T cells (Tregs), promoters of immunologic tolerance, which may predispose to both cancer and sepsis-induced immunosuppression.

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Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and progressive insulin resistance, leading to macro and microvascular dysfunction. Passive heating has potential to improve glucose homeostasis and act as an exercise mimetic. We assessed the effect of acute passive heating before or during an oral glucose tolerance test (OGTT) in people with T2DM. Twelve people with T2DM were randomly assigned to 3 conditions:1) 3 h OGTT (CON); 2) 1 h passive heating (40 °C water) 30 min before an OGTT (HOT-OGTT); and 3) 1 h passive heating (40 °C water) 30 min after commencing an OGTT (OGTT-HOT). Blood [glucose], insulin sensitivity, extracellular heat shock protein 70 (eHSP70), total energy expenditure (TEE), heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were recorded. Passive heating did not alter blood [glucose] (CON, 1,677 (386) a.u.; HOT-OGTT, 1,797 (340) a.u.; OGTT-HOT, 1,662 (364) a.u.; P = 0.28), insulin sensitivity (P = 0.15), or SBP (P = 0.18), but did increase [eHSP70] in both heating conditions (CON, 203.48 (110.81) pg·mL-1; HOT-OGTT, 402.47 (79.02) pg·mL-1; OGTT-HOT, 310.00 (60.53) pg·mL-1; P < 0.001), increased TEE (via fat oxidation) in the OGTT-HOT condition (CON, 263 (33) kcal; HOT-OGTT, 278 (40) kcal; OGTT-HOT, 304 (38) kcal; P = 0.001), increased HR in both heating conditions (P < 0.001) and reduced DBP in OGTT-HOT condition (P < 0.01). Passive heating in close proximity to a glucose challenge does not alter glucose tolerance but does increase [eHSP70] and TEE, and reduce blood pressure in people with T2DM.