The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Nonalcoholic Fatty Liver Disease in Morbidly Obese Subjects: Correlation Among Histopathologic Findings,Biochemical Features,and Ultrasound Evaluation

Nonalcoholic fatty liver disease (NAFLD) has become an important health issue lately. The aim of this study is to determine its prevalence among obese subjects which undergo Roux-en-Y gastric bypass (RYGB). It is a cross-sectional retrospective study involving 164 subjects who underwent RYGB. Clinical, biochemical, and histopathologic features were evaluated. The most common histopathologic features observed were steatohepatitis with fibrosis (29.9 %) and isolated fibrosis (29.3 %). Increased alkaline phosphatase was associated to NAFLD. Dyslipidemia and type 2 diabetes mellitus were associated to NAFLD. Ultrasound had a global accuracy of 78 % to detect NAFLD. Higher prevalence of severe forms of NAFLD was observed compared to previous reports. Most routine biochemical studies had poor correlation with NAFLD and ultrasound was useful but not definitive to detect NAFLD.     

Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats

Rationale

Abuse of synthetic cathinones, popularized as “bath salts,” has increased dramatically in the USA since their debut in 2010. Preclinical behavioral studies may clarify determinants of the abuse-related effects produced by these compounds.

Objectives

This study examined behavioral effects of (±)-methcathinone, (±)-3,4-methylenedioxypyrovalerone (MDPV), (±)-3,4-methylenedioxymethcathinone (methylone), and (±)-4-methylmethcathinone (mephedrone) in rats using intracranial self-stimulation (ICSS).

Methods

Male Sprague–Dawley rats (n?=?18) with electrodes targeting the medial forebrain bundle responded for multiple frequencies of brain stimulation and were tested in two phases. First, dose–effect curves for methcathinone (0.1–1.0 mg/kg), MDPV (0.32–3.2 mg/kg), methylone (1.0–10 mg/kg), and mephedrone (1.0–10 mg/kg) were determined. Second, time courses were determined for effects produced by the highest dose of each compound.

Results

Methcathinone produced dose- and time-dependent facilitation of ICSS. MDPV, methylone, and mephedrone produced dose- and time-dependent increases in low rates of ICSS maintained by low brain stimulation frequencies, but also produced abuse-limiting depression of high ICSS rates maintained by high brain stimulation frequencies. Efficacies to facilitate ICSS were methcathinone ≥ MDPV ≥ methylone > mephedrone. Methcathinone was the most potent compound, and MDPV was the longest acting compound.

Conclusions

All compounds facilitated ICSS at some doses and pretreatment times, which is consistent with abuse liability for each of these compounds. However, efficacies of compounds to facilitate ICSS varied, with methcathinone displaying the highest efficacy and mephedrone displaying the lowest efficacy to facilitate ICSS.     

Visual Search and Emotion: How Children with Autism Spectrum Disorders Scan Emotional Scenes

This study assessed visual search abilities, tested through the flicker task, in children diagnosed with autism spectrum disorders (ASDs). Twenty-two children diagnosed with ASD and 22 matched typically developing (TD) children were told to detect changes in objects of central interest or objects of marginal interest (MI) embedded in either emotion-laden (positive or negative) or neutral real-world pictures. The results showed that emotion-laden pictures equally interfered with performance of both ASD and TD children, slowing down reaction times compared with neutral pictures. Children with ASD were faster than TD children, particularly in detecting changes in MI objects, the most difficult condition. However, their performance was less accurate than performance of TD children just when the pictures were negative. These findings suggest that children with ASD have better visual search abilities than TD children only when the search is particularly difficult and requires strong serial search strategies. The emotional–social impairment that is usually considered as a typical feature of ASD seems to be limited to processing of negative emotional information.     

Descending Facilitation Maintains Long-Term Spontaneous Neuropathic Pain

Neuropathic pain is frequently characterized by spontaneous pain (ie, pain at rest) and, in some cases, by cold- and touch-induced allodynia. Mechanisms underlying the chronicity of neuropathic pain are not well understood. Rats received spinal nerve ligation (SNL) and were monitored for tactile and thermal thresholds. While heat hypersensitivity returned to baseline levels within approximately 35 to 40 days, tactile hypersensitivity was still present at 580 days after SNL. Tactile hypersensitivity at post-SNL day 60 (D60) was reversed by microinjection of 1) lidocaine; 2) a cholecystokinin 2 receptor antagonist into the rostral ventromedial medulla; or 3) dorsolateral funiculus lesion. Rostral ventromedial medulla lidocaine at D60 or spinal ondansetron, a 5-hydroxytryptamine 3 antagonist, at post-SNL D42 produced conditioned place preference selectively in SNL-treated rats, suggesting long-lasting spontaneous pain. Touch-induced FOS was increased in the spinal dorsal horn of SNL rats at D60 and prevented by prior dorsolateral funiculus lesion, suggesting that long-lasting tactile hypersensitivity depends upon spinal sensitization, which is mediated in part by descending facilitation, in spite of resolution of heat hypersensitivity.PerspectiveThese data suggest that spontaneous pain is present for an extended period of time and, consistent with likely actions of clinically effective drugs, is maintained by descending facilitation.     

Sleep Apnea,Sleep Disturbance,and Fasting Glucose Variability: A Pilot Study

Background

Disturbed sleep and nocturnal altered breathing are related to disturbances of glucose metabolism. The present uncontrolled observational study explores the role of these factors on the variability of fasting glycemia.

Methods

The number and duration of nocturnal awakenings and the fasting glycemia of 97 patients with type 2 diabetes treated with diet, metformin, or gliptins were recorded over seven consecutive days. During the same time period, the main respiratory indexes—oxygen disturbance index, apnea/hypopnea index, and respiratory disturbance index—were recorded for one night.

Results

The three respiratory indexes and the number of nocturnal awakenings are highly correlated with the coefficient of variation of the fasting blood glucose recorded over the 7-day period at p <.005 level. A multiple regression analysis showed that the variables in the model explained 86% of the variability.

Results

Respiratory/sleep disturbances appear to be modulators superimposed on blood glucose levels determined by other factors.     

Analysis of the Applicability of an Ankle-Foot Orthosis during Gait in Poststroke Patients

[Purpose] The aim of this study was to develop and assess the applicability of an experimental ankle-foot orthosis during gait in patients with hemiparesis. [Subjects and Methods] This was a noncontrolled cross-sectional study. Ten adult patients with hemiparesis but who were capable of independent gait were included in the study. Gait assessment was performed using two platforms (EMG System do Brasil), an electromyograph (EMG System do Brasil), and a video camera. The experimental orthosis consisted of a single piece that fit over the foot and 1/3 of the distal tibia and had a steel spring. [Results] There was greater activation of the rectus femoris and vastus lateralis muscles in the stance and mid-stance phases with the use of the experimental ankle-foot orthosis in comparison with the use of a polypropylene ankle-foot orthosis and no orthosis. Regarding spatial and temporal gait parameters, the individuals achieved an increase in stride length with the use of the experimental ankle-foot orthosis in comparison with the use of a polypropylene ankle-foot orthosis. [Conclusion] The results of the present study demonstrate that individuals with hemiparesis achieved an improvement in the stance and mid-stance phases of gait with the use of the experimental ankle-foot orthosis.Key words: Orthosis, Hemiparesis, Gait     

Role of MDCT coronary angiography in the clinical setting: economic implications

Purpose

This study evaluated the incremental value and cost-effectiveness ratio of introducing coronary angiography (CA) with multidetector computed tomography (MDCT-CA) in the diagnostic management of patients with suspected coronary artery disease (CAD) compared with the traditional diagnostic workup.

Material and methods

Five hundred and fifty consecutive patients who underwent MDCT-CA between January 2009 and June 2011 were considered. Patients with atypical chest pain and suspected obstructive CAD were directed to one of two diagnostic pathways: the traditional protocol (examination, stress test, CA) and the current protocol (examination, stress test, MDCT-CA, and CA, if necessary). The costs of each protocol and for the individual method were calculated. Based on the results, the cost-effectiveness ratio of the two diagnostic pathways was compared. A third, modified, diagnostic pathway has been proposed with its relative cost-effectiveness ratio (examination, MDCT-CA, stress test, and CA, if necessary).

Results

Stress test vs. MDCT-CA had an accuracy of 66%, a sensitivity and specificity of 21% and 87%, respectively, and a positive (PPV) and negative (NPV) predictive value of 40% and 70%, respectively. Comparison between conventional CA (CCA) and MDCT-CA showed a sensitivity and specificity of 92% and 89%, respectively, a PPV and NPV of 89%, and an accuracy of 92%. The traditional protocol has higher costs than the second protocol: 1,645 euro against 322 euro (mean), but it shows a better cost-effectiveness ratio. The new proposed protocol has lower costs, mean 261 euro, with a better costeffectiveness ratio than the traditional protocol.

Conclusions

The diagnostic protocol for patients with suspected CAD has been modified by the introduction of MDCT-CA. Our study confirms the greater diagnostic performance of MDCT-CA compared with stress test and its similar accuracy to CCA. The use of MDCT-CA to select patients for CCA has a favourable cost-effectiveness profile.