Comorbidities in patients with vascular dementia and Alzheimer's disease with Neuropsychiatric symptoms.

INTRODUCTION: This study aimed to examine baseline risk factors in Alzheimer's Disease (AD) and Vascular dementia (VaD) patients with neuropsychiatry symptoms (NPS), and determine whether specific risk factors differ by subtypes of dementia for AD and VaD patients with NPS. METHODS: A retrospective data analysis was conducted to evaluate similarities and differences in the risk factors for AD and VaD with NPS. The analysis included 2949 patients with VaD and 6341 patients with clinical confirmation of AD and VaD with or without NPS collected between February 2016 and August 2021. The multivariate logistic regression analysis was used to determine the risk factors associated with AD and VaD with NPS, by predicting the increasing odds (odds ratios (ORs) of an association of a specific baseline risk factor with AD or VaD with NPS. The validity of the regression models was tested using a Hosmer-Lemeshow test, while the Receiver Operating Curve (ROC) was used to test the sensitivity of the models. RESULTS: In the adjusted analysis TSH (OR = 1.781, 95 % CI, p = 0.0025) and CHF (OR = 1.620, 95 %, p = 0.016) were associated with VaD with NPS, while a history of emergency department(ED) admission (OR = 0.277, 95 % CI, p = 0.003) likely to be associated with VaD patients without NPS. For AD patients, a history of CVA (OR = 1.395, 95 % CI, p = 0.032) and cancer (OR = 1.485, 95 % CI, p = 0.013) were associated with AD patients with NPS. DISCUSSION: The findings of this study indicate that an abnormal thyroid gland and CHF were linked to VaD patients with behavioral disturbances, while CVA and cancer were linked to AD patients with behavioral disturbances. These findings suggest the need to develop management strategies for the care of patients with AD and VaD with NPS.

Sex Differences in Severity and Risk Factors for Ischemic Stroke in Patients With Hyperlipidemia.

Objective: This study aims to determine sex differences in poststroke hypertriglyceridemia (serum triglyceride levels ⩾ 200 mg/dl) and high stroke severity in ischemic stroke patients. Method: Our study analyzed data from 392 males and 373 females with hypertriglyceridemia. Stroke severity on admission was measured using the National Institute of Health Stroke Scale (NIHSS) with a value ⩽7 indicating a more favorable post-stroke prognosis while a score of >7 indicates poorer post-stroke outcomes. Logistic regression models adjusted for demographic and risk factors. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each clinical risk factor were used to predict the increasing odds of an association of a specific clinical baseline risk factor with the male or female AIS with hypertriglyceridemia. Results: In the adjusted analysis, male patients with hypertriglyceridemia, diastolic blood pressure (OR = 1.100, 95% CI, 1.034-1.171, P = .002), and Ischemic stroke mortality (OR = 6.474, 95% CI, 3.262-12.847, P < .001) were significantly associated with increased stroke severity. In female patients with hypertriglyceridemia, age (OR = 0.920, 95% CI, 0.866-0.978, P = .008) was associated with reduced stroke severity, while ischemic stroke mortality score (OR = 37.477, 95% CI, 9.636-145.756, P < .001) was associated with increased stroke severity. Conclusion: Increased ischemic stroke mortality risk score was associated with increased severity in both male and female AIS patients with hypertriglyceridemia. Our findings provide information about sex differences in specific risk factors that can be managed to improve the care of male and female ischemic stroke patients with hypertriglyceridemia.

Sex differences in clinical risk factors in obese ischemic stroke patients with a history of smoking.

Clinical risk factors associated obesity and smoking, as well as their combined effect, are not fully understood. This study aims to determine sex differences in risk factors in a population of acute ischemic stroke (AIS) patients who are obese and with a history of previous or current smoking. METHODS: A retrospective analysis of risk factors in male and female AIS patients with baseline data of obesity and current or previous history of smoking, smoking, and obesity alone was determined. The primary predictor and outcome are risk factors associated with male and female AIS patients. Baseline risk factors were analyzed using a multivariate regression analysis to determine specific risk factors linked with the combined effect of obesity and current or previous history of smoking''. RESULTS: Male obese AIS patients who are current or previous smokers were more likely to be older patients(OR = 1.024, 95% CI, 1.022-1.047, P = 0.033) that present with coronary artery disease (OR = 1.806, 95% CI, 1.028-3.174, P = 0.040), a history of alcohol use (OR = 2.873, 95% CI, 1.349-6.166, P = 0.006), elevated serum creatinine (OR = 4.724, 95% CI, 2.171-10.281, P < 0.001) and systolic blood pressure (OR = 1.029, 95% CI, 1.011-1.047, P < 0.002). Females were more associated with depression (OR = 0.432, 95% CI, 0.244-0.764, P = 0.004), previous TIA (OR = 0.319, 95% CI, 0.142-0.714, P < 0.005), and higher levels of HDL (OR = 0.938, 95% CI, 0.915-0.962, P < 0.001). CONCLUSION: Our results reveal sex differences in risk factors in obese AIS patients with a current or past history of smoking. This finding emphasizes the need to develop management strategies to improve the care of obese AIS patients who are either current or former smokers.

Risk Factors Associated With Exclusion of Obese Patients Ischemic Stroke With a History of Smoking From Thrombolysis Therapy.

The objective of this study is to determine risk factors that may contribute to exclusion decision from recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke (AIS) with a combined current or history of smoking and obesity. This study was conducted on data from 5469 patients with AIS collected from a regional stroke registry. Risk factors associated with inclusion or exclusion from rtPA were determined using multivariate logistic regression analysis. The adjusted odds ratios and 95% confidence interval for each risk factor were used to predict the increasing odds of an association of a specific risk factor with exclusion from rtPA. In the adjusted analysis, obese patients with AIS with a history of smoking (current and previous) excluded from rtPA were more likely to present with carotid artery stenosis (OR = 0.069, 95% CI 0.011-0.442), diabetes (OR = 0.604, 95% CI 0.366-0.997), higher total cholesterol (OR = 0.975, 95% CI 0.956-0.995), and history of alcohol use (OR = 0.438, 95% CI 0.232-0.828). Higher NIHSS score (OR = 1.051, 95% CI 1.017-1.086), higher triglycerides (OR = 1.004, 95% CI 1.001-1.006), and higher high-density lipoprotein (OR = 1.028, 95% CI 1.000-1.057) were associated with the inclusion for rtPA. Our findings reveal specific risk factors that contribute to the exclusion of patients with AIS with a combined effect of smoking and obesity from rtPA. These findings suggest the need to develop management strategies to improve the use of rtPA for obese patients with AIS with a history of smoking.

The crayfish model (Orconectes rusticus), epigenetics and drug addiction research.

Fundamental signs of epigenetic effects are variations in the expression of genes or phenotypic traits among isogenic mates. Therefore, genetically identical animals are in high demand for epigenetic research. There are many genetically identical animals, including natural parthenogens and inbred laboratory lineages or clones. However, most parthenogenetic animal taxa are very small in combined epigenetic and drug addiction research. Orconectes rusticus has a unique phylogenetic position, with 2-3 years of life span, which undergoes metamorphosis that creates developmental stages with distinctly different morphologies, unique lifestyles, and broad behavioral traits, even among isogenic mates reared in the same environment offer novel inroads for epigenetics studies. Moreover, the establishment of crayfish as a novel system for drug addiction with evidence of an automated, operant self-administration and conditioned-reward, withdrawal, reinstatement of the conditioned drug-induced reward sets the stage to investigate epigenetic mechanisms of drug addiction. We discuss behavioral, pharmacological and molecular findings from laboratory studies that document a broad spectrum of molecular and, behavioral evidence including potential hypotheses that can be tested with the crayfish model for epigenetic study in drug addiction research.

Drug-sensitive Reward in Crayfish: Exploring the Neural Basis of Addiction with Automated Learning Paradigms.

Results of recent work from our labs and those of others have broadened perspectives on addiction beyond a human-specific, cognitive phenomenon. Addictive plant alkaloids are defensive compounds which have arisen to counter herbivory. With insects the true targets of the coevolutionary arms race, humans may be little more than collateral damage when impacted by 'human' drugs of abuse. The present paper summarizes recent contributions, with a primary focus on our own research in crayfish, where we characterize the behavioral and neural consequences resulting from chronic and acute exposure to psychostimulant and addictive drugs. Substituted phenethylamines, like amphetamine and cocaine, exhibit a wide range of effects in crayfish with direct parallels to those described from mammalian preparations. Unconditioned effects include intoxication and psychostimulation, where repeated exposure is accompanied by tolerance and sensitization, respectively. Psychostimulants exhibit powerful reinforcing properties in conditioned place preference, subject to extinction and reinstatement. Crayfish readily self-administer amphetamines using instrumental learning approaches. With a nervous system modular and uniquely accessible to neural probing, crayfish offer unique opportunities for studying the basic biological mechanisms of drug effects, for exploring how the appetitive disposition is implemented, and for examining how this is related to the rewarding action of drugs of abuse.

The Sensitivity of the Crayfish Reward System to Mammalian Drugs of Abuse.

The idea that addiction occurs when the brain is not able to differentiate whether specific reward circuits were triggered by adaptive natural rewards or falsely activated by addictive drugs exist in several models of drug addiction. The suitability of crayfish (Orconectes rusticus) for drug addiction research arises from developmental variation of growth, life span, reproduction, behavior and some quantitative traits, especially among isogenic mates reared in the same environment. This broad spectrum of traits makes it easier to analyze the effect of mammalian drugs of abuse in shaping behavioral phenotype. Moreover, the broad behavioral repertoire allows the investigation of self-reinforcing circuitries involving appetitive and exploratory motor behavior, while the step-wise alteration of the phenotype by metamorphosis allows accurate longitudinal analysis of different behavioral states. This paper reviews a series of recent experimental findings that evidence the suitability of crayfish as an invertebrate model system for the study of drug addiction. Results from these studies reveal that unconditioned exposure to mammalian drugs of abuse produces a variety of stereotyped behaviors. Moreover, if presented in the context of novelty, drugs directly stimulate exploration and appetitive motor patterns along with molecular processes for drug conditioned reward. Findings from these studies indicate the existence of drug sensitive circuitry in crayfish that facilitates exploratory behavior and appetitive motor patterns via increased incentive salience of environmental stimuli or by increasing exploratory motor patterns. This work demonstrates the potential of crayfish as a model system for research into the neural mechanisms of addiction, by contributing an evolutionary, comparative context to our understanding of natural reward as an important life-sustaining process.

Effects of chronic cocaine, morphine and methamphetamine on the mobility, immobility and stereotyped behaviors in crayfish.

The worth of crayfish as a model system for studies of addiction was not previously recognized because a drug-reward phenomenon had not been documented in this model system. In our previous experiments, we demonstrate that the crayfish natural reward pathways are sensitive to human drugs of abuse. This finding supports crayfish as a suitable model to characterize specific behaviors that are relevant in drug addiction research, and the current study builds on our previous findings. The aim of the present study was to investigate unconditioned neurobehavioral effects of repeated treatment regimens using cocaine, morphine, and methamphetamine for three consecutive days. We analyzed mobility, immobility and characterized stereotypic behaviors following intracardial infusions of 2.0µg/g or 10.0µg/g doses of cocaine, morphine, and methamphetamine for three days. The results showed that systemic cocaine, morphine, and methamphetamine increased mobility at a low dose of 2.0µg/g more effectively than a high dose of 10.0µg/g, while simultaneously showing that the high dose exerted a more prominent effect in increasing immobility. Moreover, systemic cocaine, morphine, and methamphetamine injections have discerning effects towards a group of defined unconditioned stereotyped behavioral patterns associated with each drug, rather than a shared universal behavioral effect. These findings provide insight into the behavioral and pharmacological basis responsible for the unconditioned effects of these drugs in crayfish.

A new insight into the ability to resist Ischemic brain injury: Does hibernation matter?: An Editorial comment for 'Arctic ground squirrel hippocampus tolerates oxygen glucose deprivation independent of hibernation season even when not hibernating and after ATP depletion, acidosis and glutamate efflux'.

Read the commented article 'Arctic ground squirrel hippocampus tolerates oxygen glucose deprivation independent of hibernation season even when not hibernating and after ATP depletion, acidosis and glutamate efflux' on doi: 10.1111/jnc.13996.

The rewarding properties of methamphetamine in an invertebrate model of drug addiction.

The rewarding properties of drugs in the mammalian system depend on their ability to activate appetitive motivational states. The associated underlying mechanism is strongly conserved in evolution and invertebrates have recently emerged as a powerful new model in addiction research. The natural reward system in crayfish has surprisingly proven sensitive to human drugs of abuse, providing a new model for research into the basic biological mechanisms of drug addiction. In this study, we examined the presence of natural reward systems in crayfish, and then characterized its sensitivity to 2.5 µg/g, 5.0 µg/g and 10.0 µg/g doses of methamphetamine (METH). Using the conditioned place preference (CPP) paradigm, we demonstrated that irrespective of the number of doses of METH injected into the pericardial system, crayfish seek out a particular tactile environment that had previously been paired with the METH. This study demonstrates that crayfish offer a comparative and complementary approach in addiction research. It contributes an evolutionary context to our understanding of a key component in learning and of natural reward as an important life-sustaining process.

Correction to "Molecular and Physiological Factors of Neuroprotection in Hypoxia-tolerant Models: Pharmacological Clues for the Treatment of Stroke".

[This corrects the article on p. 1 in vol. 9, PMID: 25780340.].

Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models.

The treatment and prevention of hypoxic/ischemic brain injury in stroke patients remain a severe and global medical issue. Numerous clinical studies have resulted in a failure to develop chemical neuroprotection for acute, ischemic stroke. Over 150 estimated clinical trials of ischemic stroke treatments have been done, and more than 200 drugs and combinations of drugs for ischemic and hemorrhagic strokes have been developed. Billions of dollars have been invested for new scientific breakthroughs with only limited success. The revascularization of occluded cerebral arteries such as anti-clot treatments of thrombolysis has proven effective, but it can only be used in a 3-4.5h time frame after the onset of a stroke, and not for every patient. This review is about novel insights on how to resist tissue hypoxia from unconventional animal models. Ability to resist tissue hypoxia is an extraordinary ability that is not common in many laboratory animals such as rat and mouse models. For example, we can learn from a naked mole-rat, Chrysemys picta, how to actively regulate brain metabolic activity to defend the brain against fluctuating oxygen tension and acute bouts of oxidative stress following the onset of a stroke. Additionally, a euthermic arctic ground squirrel can teach us how the brain of a stroke patient can remain well oxygenated during tissue hypoxia with no evidence of cellular stress. In this review, we discuss how these animals provide us with a system to gain insight into the possible mechanisms of tissue hypoxia/ischemia. This issue is of clinical significance to stroke patients. We describe specific physiological and molecular adaptations employed by different animals' models of hypoxia tolerance in aquatic and terrestrial environments. We highlight how these adaptations might provide potential clues on strategies to adapt for the clinical management of tissue hypoxia during conditions such as stroke where oxygen demand fails to match the supply.

Molecular and Physiological Factors of Neuroprotection in Hypoxia-tolerant Models: Pharmacological Clues for the Treatment of Stroke.

The naked mole-rat possesses several unique physiological and molecular features that underlie their remarkably and exceptional resistance to tissue hypoxia. Elevated pattern of Epo, an erythropoietin (Epo) factor; c-fos; vascular endothelial growth factor (VEGF); and hypoxia-inducible factors (HIF-1α) contribute to the adaptive strategy to cope with hypoxic stress. Moreover, the naked mole-rat has a lower metabolic rate than any other eutherian mammal of comparable size that has been studied. The ability to actively reduce metabolic rate represents a strategy widely used in the face of decreased tissue oxygen availability. Understanding the different molecular and physiological factors that induce metabolic suppression could guide the development of pharmacological agents for the clinical management of stroke patient.

Exploratory behavior and withdrawal signs in crayfish: chronic central morphine injections and termination effects.

Functional and evolutionary conservation of neural circuits of reward seeking >is a symbol of survival. It is found in most animals from insects to humans. Exploration is a component of a wide range of drug-elicited behaviors that reflects an appetitive motivational state when animals seek natural rewards such as food, water, and shelter for survival. Not only does the characterization of exploratory behaviors indicate the specific components of appetitive motor patterns, it also reveals how exploratory behavioral patterns are implemented via increased incentive salience of environmental stimuli. The current work demonstrates that novel stimuli appear to directly augment exploration in crayfish, while injections of morphine directly into the brain of crayfish enhanced robust arousal resulting in increased locomotion and exploration of the environment. Elimination of morphine suppressed exploratory motor patterns. Crayfish displayed atypical behavioral changes evident of withdrawal-like states when saline is injected into the brain. With proven evidence of rewarding to the exposure to mammalian drugs of abuse, modularly organized and experimentally accessible nervous system makes crayfish exceptionally suitable for characterizing the central workings of addiction at its key behavioral and neuroanatomic locations.

Morphine-conditioned cue alters c-Fos protein expression in the brain of crayfish.

With a highly organized stereotypic behavior and a simplified neuronal system that is characterized by cellular modularity, crayfish (Orconectes rusticus) represents an excellent model that we used in this study to explore how a drug-conditioned-cue alters c-Fos protein expression in the brain of an invertebrate species. The first set of experiments revealed that a single injection of different doses of morphine (3.0 µg/g, 6.0 µg/g and 12.0 µg/g) into the circulatory system of crayfish significantly increased locomotor activity. Repeated injections of morphine increased locomotion at lower doses (3.0 µg/g and 6.0 µg/g), and decreased locomotion at a higher dose of 12.0 µg/g. The second experiment revealed that a repeated or single injection of morphine serves as reward when paired with a distinct visual environment. In the third experiment, we found that the c-Fos profile of morphine treated crayfish in an unconditioned environment did not show a significant increase from the basal level comparable to saline treated crayfish. The brains of crayfish were more active during exposure to the cue-elicited drug conditioned environment than the unconditioned environment. These results indicate that chronic morphine treatment alone is not sufficient to induce changes in the expression of c-Fos; instead, morphine-environment pairing in a specific context contributes to the expression of alterations in c-Fos regulation. The enhancement of c-Fos expression in the brain of crayfish seems to reflect the sensory or anticipatory facets of conditioning that suggests that potential and even unanticipated hypotheses in drug addiction can emerge from studies of addiction in crayfish.

Global change effects on plant chemical defenses against insect herbivores.

This review focuses on individual effects of major global change factors, such as elevated CO2, O3, UV light and temperature, on plant secondary chemistry. These secondary metabolites are well-known for their role in plant defense against insect herbivory. Global change effects on secondary chemicals appear to be plant species-specific and dependent on the chemical type. Even though plant chemical responses induced by these factors are highly variable, there seems to be some specificity in the response to different environmental stressors. For example, even though the production of phenolic compounds is enhanced by both elevated CO2 and UV light levels, the latter appears to primarily increase the concentrations of flavonoids. Likewise, specific phenolic metabolites seem to be induced by O3 but not by other factors, and an increase in volatile organic compounds has been particularly detected under elevated temperature. More information is needed regarding how global change factors influence inducibility of plant chemical defenses as well as how their indirect and direct effects impact insect performance and behavior, herbivory rates and pathogen attack. This knowledge is crucial to better understand how plants and their associated natural enemies will be affected in future changing environments.