Hyperpolarized 1- 13Cpyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice

Purpose@#Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer’s disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is unclear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism. Using hyperpolarized (HP) [1- 13C]pyruvate magnetic resonance spectroscopy (MRS), this study intends to evaluate the influence of agmatine on brain metabolism. @*Materials and Methods@#ICR mice were fed a high-fat diet and injected with streptozotocin to develop a T2DM animal model. During a 2-week period, T2DM mice were treated with normal saline or 100 mg/kg of agmatine, and brain HP [1- 13C]pyruvate MRS was performed. The effect of agmatine on lactate generation and NADH/NAD+ redox state was investigated using C6 and neuro-2a (N2a) cells. @*Results@#As a perfusion marker, the total 13C signals in the brain of T2DM mice (p=0.07) and agmatine-treated mice (p<0.05) were reduced. The conversion constant (Kpl) from [1- 13C]pyruvate to [1- 13C]lactate was not distinguishable in the brains of T2DM mice but was significantly increased in the brains of agmatine-treated T2DM mice. Treating C6 and N2a cells with agmatine increased NADH/NAD+ ratio and lactate generation. @*Conclusion@#Agmatine influences the NADH/NAD+ redox state in the brains of T2DM mice, which may be connected with enhanced cognitive performance and increased conversion of HP [1- 13C]pyruvate to HP [1- 13C]lactate.

Association of Plasma Creatine With Inflammation and Cognitive Function in Persons With and Without Alzheimer’s Disease

Objective@#Creatine, energy buffer in high energy demanding systems including muscle and brain, may play a beneficial role against neuroinflammation in Alzheimer’s disease (AD), and thus be a potential biomarker. This study aimed to compare the levels of plasma creatine between persons with and without AD and investigate associations of plasma creatine levels with cognitive function and blood-based inflammatory markers. @*Methods@#We classified elderly participants by cognitive statuses: normal cognition (NC, n=17), mild cognitive impairment (MCI,n=21), and AD (n=21). To assess cognitive function and inflammatory condition, we performed neuropsychological tests and mea-sured plasma C-reactive protein (CRP) levels, respectively. @*Results@#Plasma creatine levels were comparable among participants with AD, MCI, and NC. In overall participants, plasma cre-atine levels were not associated with neuropsychological test scores, but negatively associated with plasma CRP levels. In AD group, plasma creatine levels were negatively associated with neuropsychological test scores and, although not significant, CRP levels (p=0.086). In participants without AD (NC plus MCI), these associations disappeared. @*Conclusion@#Plasma creatine levels may not be useful as a biomarker indicating cognitive statuses. However, our results suggest that, in AD, plasma levels of creatine might reflect the extent of neuroinflammation as well as cognitive deterioration.

Assessment of Cognitive Impairment in a Mouse Model of High-Fat Diet-Induced Metabolic Stress with Touchscreen-Based Automated Battery System

Obesity-related metabolic disorders can affect not only systemic health but also brain function. Recent studies have elucidated that amyloid beta deposition cannot satisfactorily explain the development of Alzheimer's disease (AD) and that dysregulation of glucose metabolism is a critical factor for the sporadic onset of non-genetic AD. Identifying the pathophysiology of AD due to changes in brain metabolism is crucial; however, it is limited in measuring changes in brain cognitive function due to metabolic changes in animal models. The touchscreen-based automated battery system, which is more accurate and less invasive than conventional behavioral test tools, is used to assess the cognition of mice with dysregulated metabolism. This system was introduced in humans to evaluate cognitive function and was recently back-translated in monkeys and rodents. We used outbred ICR mice fed on high-fat diet (HFD) and performed the paired associates learning (PAL) test to detect their visual memory and new learning ability loss as well as to assess memory impairment. The behavioral performance of the HFD mice was weaker than that of normal mice in the training but was not significantly associated with motivation. In the PAL test, the average number of trials completed and proportion of correct touches was significantly lower in HFD mice than in normal diet-fed mice. Our results reveal that HFD-induced metabolic dysregulation has detrimental effects on operant learning according to the percentage of correct responses in PAL. These findings establish that HFD-induced metabolic stress may have an effect in accelerating AD-like pathogenesis.

Long-Term Culture of Organotypic Hippocampal Slice from Old 3xTg-AD Mouse: An ex vivo Model of Alzheimer's Disease

OBJECTIVE: Conventional methods for organotypic hippocampal tissue slice culture (OHSC) have shown several disadvantages or limitations regarding age of animals used, duration of culture and difficulty using neurodegenerative models. Therefore, we tried to establish OHSC from old 3xTg-Alzheimer’s disease (AD) mice for longer period (over 4 weeks) and to validate utility of this system as a valid platform for translational neuroscience of AD. METHODS: OHSC was performed with old 3xTg-AD mice (12–14 months), old wild type mice (12–14 months) and young 3xTg-AD mice (2–4 months) using serum-free medium for 4 weeks. Hippocampal structure was evaluated by 4’, 6-diamidino-2-phenylindole (DAPI) intensity and neuronal metabolism was measured by Alamarblue assay. Pathologic characteristics of AD were also investigated; β-amyloid levels by ELISA, amyloid plaque deposition by Thioflavin-S staining, and glial activation by immunohistochemistry. RESULTS: Following 4-week culture in serum-free media, hippocampal cells and layers were well preserved in cultured slices from old AD mice as was in those from young AD and old wild type mice. On the contrary, excessive regression of total visible cells was observed in conventional serum-containing medium regardless of genotype of mice. In parallel with this well preserved structure, major pathologic characteristics of AD were also well manifested in hippocampal slices from old AD mice. CONCLUSION: Our findings suggest that long-term OHSC from old 3xTg-AD mouse can serve as a promising ex vivo system for studies on pathophysiology of AD, especially with the minimum number of sacrifice of experimental animals.

The burden of HIV-associated neurocognitive disorder (HAND) in the Asia-Pacific region and recommendations for screening.

BACKGROUND: HIV-associated neurocognitive disorder incurs a significant burden on HIV patients in Asia-Pacific countries; however, the incidence is difficult to estimate due to a lack of local epidemiological data. The impact of neurocognitive impairment in HIV patients is often underestimated due to a lack of education and awareness, and there are consequently gaps in the provision of screening and diagnosis to enable earlier intervention to limit neurocognitive impairment. METHOD: This review seeks to redress the imbalance by promoting awareness and education among physicians concerning the neurovirulence of HIV and thereby increase screening efforts to improve diagnosis rates and clinical outcomes for underserved patients in this region. The Asia, Australia, and Middle East (AAME) HAND Advisory Board convened expert regional representatives to review current practice and recommend appropriate measures related to the implementation of standardised screening programmes and treatment recommendations to curb the developing HAND epidemic in the region. In particular, we recommend basic neuropsychological testing protocols that could be efficiently introduced into clinical practice for routine screening. RESULT: We also propose simple guidelines for the management of HAND. We believe that HAND is a significant and under-reported diagnosis in HIV patients that warrants both greater recognition and further clinical investigation of the underlying pathophysiology and the impact of HIV disease progression, with HAND being associated with worse medication adherence and therefore possibly increased risk of ARV treatment failure. DISCUSSION: Widespread screening will lead to greater recognition of HAND and earlier intervention, which may lead to improved management strategies in the future.

Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling

Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-beta-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.

Effects of Color Temperature and Brightness on Electroencephalogram Alpha Activity in a Polychromatic Light-emitting Diode

OBJECTIVE: It has been reported that working and learning efficiency might be increased through artificially controlling the color temperature and brightness of light. However, the neurological bases of these outcomes are not well established. Our study was designed to observe whether electroencephalogram (EEG) alpha frequency, as a candidate biological marker, demonstrates significant changes in response to alterations of specific light parameters. METHODS: Thirty-two healthy subjects performed cognitive tasks under four different polychromatic light conditions: a combination of two different levels of color temperature (2766K vs. 5918K) and brightness (300 lux vs. 600 lux). Spectrum analyses were performed on alpha frequency. RESULTS: Subjects reported that they felt more pleasant in bright conditions and more relaxed in warm color temperature conditions. Our findings indicate that alpha power increases in warm, low-light and cool, high-light conditions, and there is a significant interaction between color temperature and brightness. CONCLUSION: EEGs might serve as a useful biological marker for further research related to the effects of polychromatic light on cognitive function.

Is the GABA System Related to the Social Competence Improvement Effect of Aripiprazole? An 18F-Fluoroflumazenil PET Study

OBJECTIVE: Patients with schizophrenia who are treated with aripiprazole experience some benefits including an improvement of social competence, but the underlying mechanism of this improvement has not been investigated yet. This study aimed to provide preliminary evidence that the GABA system may be involved in the effect of aripiprazole on social competence. METHODS: Seventeen outpatients with schizophrenia (9 taking aripiprazole and 8 taking risperidone) and 18 healthy controls underwent 18F-fluoroflumazenil PET, and GABAA receptor binding potential was compared between the three groups. RESULTS: Voxelwise one-way ANOVA showed that GABAA receptor binding potentials in the right medial prefrontal cortex (p=0.04) and right dorsolateral prefrontal cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone group, and those in the left frontopolar cortex (p=0.03) and right premotor cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone and control groups. CONCLUSION: Our results suggest that aripiprazole administration results in increased GABA transmission in the prefrontal regions, and that these increases may be a neural basis of aripiprazole's clinical benefits on an improvement of social competence.

Biochemical Biomarkers for Alzheimer's Disease in Cerebrospinal Fluid and Peripheral Blood

The diagnosis of Alzheimer's disease (AD) is still obscure even to specialists. To improve the diagnostic accuracy, to find at-risk people as early as possible, to predict the efficacy or adverse reactions of pharmacotherapy on an individual basis, to attain more reliable results of clinical trials by recruiting better defined participants, to prove the disease-modifying ability of new candidate drugs, to establish prognosis-based therapeutic plans, and to do more, is now increasing the need for biomarkers for AD. Among AD-related biochemical markers, cerebrospinal beta-amyloid and tau have been paid the most attention since they are materials directly interfacing the brain interstitium and can be obtained through the lumbar puncture. Level of beta-amyloid is reduced whereas tau is increased in cerebrospinal fluid of AD patients relative to cognitively normal elderly people. Remarkably, such information has been found to help predict AD conversion of mild cognitive impairment. Despite inconsistent findings from previous studies, plasma beta-amyloid is thought to be increased before the disease onset, but show decreasing change as the disease progress. Regarding other peripheral biochemical markers, omics tools are being widely used not only to find useful biomarkers but also to generate novel hypotheses for AD pathogenesis and to lead new personalized future medicine.

Vascular Dementia

Vascular dementia (VaD) is a dementia syndrome produced by vascular damage to the brain and increases in incidence with advancing age. Early Identification and diagnosis of VaD is particularly importent since its course may be modifiable through controlling vascular risk factors. VaD is heterogeneous and consists of several syndromes : multi-infarct dementia, strategic single infarcts dementia, and subcortical vascular dementia. The diagnosis of VaD is based on several features 1) dementia, 2) evidence of cerebrovascular disease, and 3) temporal relationship between dementia and cerebrovascular disease. Treatment of VaD includes control of vascular risk factors, prevention of further vascular injury and treatment of cognitive impairment. Cholinesterase inhibitors provide symptomatic benefits in treatment of VaD.

Screening and Treating Wernicke's Encephalopathy among Alcoholic Patients in a University Hospital / 신경정신의학

OBJECTIVES: The purpose of this study was to investigate the prevalence and clinical characteristics of Wernicke's encephalopathy (WE) patients in alcoholics and to evaluate the utility of Caine's criteria as a screening test. METHODS: We made an admission note including Caine's criteria and applied it to patients who were admitted to an alcohol treatment unit. Demographic, clinical, and laboratory data were collected on 204 alcoholics. Our alcoholics who met more than one of Caine's criteria were considered at risk for WE and were given high-dose thiamine IV therapy. RESULTS: We was diagnosed in 15.2% of the alcoholic patients. Age and head trauma history were risk factors of WE. The sensitivity of Caine's criteria was 97% and specificity was 54%. High-dose thiamine IV therapy appeared to be a safe and cost-effective method to prevent the serious complications of WE. CONCLUSION: Caine's criteria is useful as a screening test for WE among alcoholic patients. High-dose thiamine IV therapy is cost-effective for alcoholic patients who are considered to be at risk for WE.

Effects of Nicotine on Interpersonal Distance of Patients with Schizophrenia in Immersive Virtual Environments: a Preliminary Study / 대한정신약물학회지

OBJECTIVE: Using immersive virtual environment technique, we aimed to preliminarily examine whether nicotine affects the interpersonal distance, as the size of personal space, in schizophrenic patients, which have extraordinarily high smoking rate. METHOD: Ten male schizophrenic patients who were at least moderate current smokers smoked a high (0.9 mg nicotine as an active drug) or low (0.1 mg nicotine as a placebo) nicotine-yielding cigarette after overnight-abstinence in randomized, double blind, cross-over design. Following the smoking session, subjects performed the 'self-introduction task' in virtual environment by introducing themselves consecutively to six different avatars, which varied in gender and facial/verbal expressions (neutral, angry, and happy). In the tasks, subjects were asked to step forward to each avatar until they felt most comfortable to greet the avatar first. The distance was measured by the head-tracking device, which was transmitting real-time data to the computer. Affective valence and arousal to each avatar were also rated by subjects following the tasks. RESULTS: The overall interpersonal distance of the drug group was significantly greater than that of placebo group (Z = -2.93, p = 0.022). The distances with emotionally neutral avatars (male/female) of the six were significantly different between the two groups (Z = -2.19, p = 0.028 ; Z = -2.09, p = 0.037). Within-group analysis revealed a significant difference among the distances with the six avatars in the placebo group (x2 = 17.03, df = 5, p = 0.004), but there was no significant within-group difference in the drug group (x2 = 6.11, df = 5, p = 0.295). CONCLUSION: These preliminary findings suggest that nicotine may increase the size of personal space of schizophrenic patients probably by enhancing the social stimuli perception through affecting the patients' cognitive function.