The Cholinergic Neuronal Phenotype in Alzheimer's Disease

The synthesis, storage and release of acetylcholine (ACh) requires the expression of several specialized proteins, including choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). The VAChT gene is located within the first intron of the ChAT gene. This unique genomic organization permits coordinated activation of expression of the two genes by extracellular factors. Much less is known about factors that reduce the expression of the cholinergic phenotype. A cholinergic deficit is one of the primary features of Alzheimer’s disease (AD), and AD brains are characterized by amyloid deposits composed primarily of Aβ peptides. Although Aβ peptides are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. Indeed, we and others demonstrated that synthetic Aβ peptides, at submicromolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal phospholipid turnover, which might be related to the progressive accumulation of apolipoprotein E (apoE) within amyloid plaques, leading perhaps to the reduction of apoE content in the CSF of AD patients. ApoE is a component of very low density lipoproteins (VLDL). As a first step in investigating a potential neuroprotective function of apoE, we determined the effects of VLDL on ACh content in neuronal cells. We found that VLDL increases ACh levels, and that it can partially offset the anticholinergic actions of Aβ peptides.     

长期大量饮酒对大鼠阴茎组织胆碱乙酰转移酶的影响

目的 探讨长期大量饮酒对大鼠阴茎组织胆碱乙酰转移酶的影响.方法 将30只雄性大鼠随机分为对照组、20%酒精剂量组和40%酒精剂量组.分别以生理盐水、20%和40%食用酒精各2mL给大鼠灌胃,每日1次.3个月后,观察各组大鼠性行为和药物诱发阴茎勃起的变化;用化学发光法测定各组大鼠血清睾酮的含量;用免疫组化法测定阴茎平滑肌中胆碱乙酰转移酶(CAT)的含量.结果 与对照组相比,20%酒精剂量组大鼠药物诱发阴茎勃起实验没有受到酒精影响(P＜0.05),但除射精潜伏期外,酒精抑制了该组大鼠的性行为(P＜0.05),而40%酒精剂量组大鼠的性行为表现和药物诱发阴茎勃起实验均受到抑制(P＜0.05).实验组大鼠血清睾酮含量减少(P＜0.05),40%酒精剂量组大鼠阴茎组织中CAT活性也降低(P＜0.05).结论 大鼠长期大量饮酒后性功能障碍,其机制与血浆睾酮含量降低,阴茎组织中胆碱乙酰转移酶活性降低有关.     

丁基苯酞对缺血脑组织中及低糖低氧刺激后培养的神经细胞中胆碱乙酰化酶活性的影响

 目的:观察丁基苯酞(dl-NBP),d-NBP和l-NBP对脑缺血后皮层和纹状体中以及低糖低氧和NMDA刺激后培养的胎鼠皮层神经元中胆碱乙酰化酶活性变化的影响?方法:大脑中动脉堵塞起始处造成大鼠局灶性脑缺血;胎鼠皮层神经元以低糖低氧培养基培养造成低糖低氧模型;胆碱乙酰化酶活性以分光度法进行测定?结果:脑缺血后缺血区皮层和纹状体中胆碱乙酰化酶活性分别下降了61.3%和58.4%?dl-NBP,d-NBP和l-NBP(10和20mg·kg^-1,ip)于脑缺血后5和60min给药2次皆可显著提高脑组织中胆碱乙酰化酶活性?dl-NBP,d-NBP和l-NBP(0.1～10μmol·L^-1)对低糖低氧及NMDA刺激后神经细胞中胆碱乙酰化酶活性也有明显的提高作用?结论:dl-NMP改善局灶性脑缺血后动物的学习记忆功能可能与其对胆碱能神经功能的改善有关?     

丁基苯酞对缺血脑组织中及低糖低氧刺激后培养的神经细胞中胆碱乙酰化酶活性的影响

目的：观察丁基苯酞（ｄｌＮＢＰ）,ｄＮＢＰ和ｌＮＢＰ对脑缺血后皮层和纹状体中以及低糖低氧和ＮＭＤＡ刺激后培养的胎鼠皮层神经元中胆碱乙酰化酶活性变化的影响。方法：大脑中动脉堵塞起始处造成大鼠局灶性脑缺血;胎鼠皮层神经元以低糖低氧培养基培养造成低糖低氧模型;胆碱乙酰化酶活性以分光度法进行测定。结果：脑缺血后缺血区皮层和纹状体中胆碱乙酰化酶活性分别下降了６１．３％和５８．４％。ｄｌＮＢＰ,ｄＮＢＰ和ｌＮＢＰ（１０和２０ｍｇ·ｋｇ－１,ｉｐ）于脑缺血后５和６０ｍｉｎ给药２次皆可显著提高脑组织中胆碱乙酰化酶活性。ｄｌＮＢＰ,ｄＮＢＰ和ｌＮＢＰ（０．１～１０μｍｏｌ·Ｌ－１）对低糖低氧及ＮＭＤＡ刺激后神经细胞中胆碱乙酰化酶活性也有明显的提高作用。结论：ｄｌＮＭＰ改善局灶性脑缺血后动物的学习记忆功能可能与其对胆碱能神经功能的改善有关。     

谷胱甘肽联合多烯磷脂酰胆碱对妊娠期肝内胆汁淤积症孕妇皮肤瘙痒症状及妊娠结局的影响

目的探讨分析谷胱甘肽联合多烯磷脂酰胆碱对妊娠期肝内胆汁淤积症(ICP)孕妇皮肤瘙痒症状及妊娠结局的影响。方法选取2016年3月至2020年2月我院收治的ICP孕妇62例,随机平均分为两组。对照组在常规治疗基础上采用多烯磷脂酰胆碱治疗,观察组在对照组基础上采用谷胱甘肽治疗。治疗10 d后,比较两组孕妇的Ribaha评分及妊娠结局。结果治疗后,两组的Ribaha评分均低于治疗前,且观察组的Ribaha评分低于对照组(P <0.05);观察组的宫内窘迫、早产、产后出血发生率低于对照组(P <0.05)。结论谷胱甘肽联合多烯磷脂酰胆碱可显著改善ICP孕妇皮肤瘙痒及妊娠结局,值得临床推广应用。     

Estimating driver risk using alcohol biomarkers,interlock blood alcohol concentration tests and psychometric assessments: initial descriptives

Aim To identify alcohol biomarker and psychometric measures that relate to drivers' blood alcohol concentration (BAC) patterns from ignition interlock devices (IIDs). Design, setting, participants, measurements In Alberta, Canada, 534 drivers, convicted of driving under the influence of alcohol (DUI), installed IIDs and agreed to participate in a research study. IID BAC tests are an established proxy for predicting future DUI convictions. Three risk groups were defined by rates of failed BAC tests. Program entry and follow‐up blood samples (n = 302, 171) were used to measure phosphatidyl ethanol (PETH), carbohydrate deficient transferrin (%CDT), gamma glutamyltransferase (GGT) and other biomarkers. Program entry urine (n = 130) was analyzed for ethyl glucuronide (ETG) and ethyl sulphate (ETS). Entry hair samples were tested for fatty acid ethyl esters (FAEE) (n = 92) and ETG (n = 146). Psychometric measures included the DSM‐4 Diagnostic Interview Schedule Alcohol Module, Alcohol Use Disorders Identification Test (AUDIT), the time‐line follow‐back (TLFB), the Drinker Inventory of Consequences (DRINC) and the Temptation and Restraint Inventory (TRI). Findings Except for FAEE, all alcohol biomarkers were related significantly to the interlock BAC test profiles; higher marker levels predicted higher rates of interlock BAC test failures. PETH, the strongest with an overall analysis of variance F ratio of 35.5, had significant correlations with all nine of the other alcohol biomarkers and with 16 of 19 psychometric variables. Urine ETG and ETS were correlated strongly with the IID BAC tests. Conclusions The findings suggest that several alcohol biomarkers and assessments could play an important role in the prediction and control of driver alcohol risk when re‐licensing.     

Cyto- and Chemoarchitecture of Basal Forebrain Cholinergic Neurons in the Common Marmoset (Callithrix Jacchus)

The cyto- and chemoarchitecture of basal forebrain cholinergic neurons (BFCN) was investigated in the lower primate, the common marmoset (Callithrix jacchus). A large population of magnocellular, hyperchromic, and choline acetyltransferase (ChAT)-positive neurons was detected in the marmoset basal forebrain. The distribution of these neurons was similar to those in higher primates. Thus, ChAT-positive neurons were observed in the medial septum (Ch2), the vertical (Ch2) and horizontal (Ch3) limbs of the diagonal band of Broca, and the nucleus basalis of Meynert (Ch4). The Ch4 complex was relatively well differentiated and displayed distinct sectors. We detected anterior (Ch4a, with a medial and a lateral subdivision), intermediate (Ch4i, with a dorsal and a ventral subdivision), and posterior (Ch4p) sectors in the marmoset Ch4. The Ch4i was relatively small while the Ch4p was large. Similar to the rodent, the marmoset Ch1 extended quite a distance posteriorly, and the Ch4p displayed a major interstitial component distributed within the globus pallidus, its medullary laminae, and the internal capsule. Virtually all of the marmoset BFCN displayed acetylcholinesterase activity, and low affinity (p75^NTR) and high affinity (Trk) neurotrophin receptor immunoreactivity. A majority contained immunoreactivity for calbindin-D_28K and calretinin. Many of the Ch4 neurons also displayed tyrosine hydroxylase immunoreactivity. The BFCN lacked galanin immunoreactivity, but were innervated by galanin-positive fibers. None of the marmoset BFCN were NADPH-d-positive. Thus, the BFCN display major anatomical and biochemical differences in the marmoset when compared with higher primates. The marmoset BFCN also display many characteristics common to other primates. This fact, combined with the relatively short life span of the marmoset, indicates that this species may be ideal for studies of age-related changes in the BFCN.     

Effect of combined or separate administration of piracetam and choline on learning and memory in the rat

Different groups of rats received combined or separate administration of different doses of piracetam (P1:100, P2:200, and P4:400 mg/kg) and choline (C1:100 and C2:200 mg/kg). Compared to control treatment, C1 significantly improved performance in a delayed alternation (DA) task, while P1, P2, P4 or P1C1 had no effect. Moreover, rats receiving P2C1 and P4C1 were significantly inferior in acquiring DA to rats receiving the vehicle or separate administration of P1, P2 or C1. The different treatments with combined or separate administration of P and C had no effect on spontaneous locomotor activity and two-way avoidance conditioning. In a recognition-task only groups C1 and P4 were able to discriminate between familiar and new objects. The combined or separate administration of P1 and C1 on NA, DA, DOPAC, 5-HT, 5-HIAA levels, CAT activity and choline uptake were measured in frontal cortex and hippocampus: the only significant effect was a 5-HT increase in the hippocampus of rats treated with C1.     

Modeling the impact of COPD on the brain

Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p ≤ 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.     

Combined DCE‐MRI and single‐voxel 2D MRS for differentiation between benign and malignant breast lesions

Dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) and proton (1H) magnetic resonance spectroscopy (MRS) provide structural and biochemical information, including vascular volume, vascular permeability and tissue metabolism. In this study, we performed analysis of the enhancement characteristic from DCE‐MRI and the biochemical information provided by two‐dimensional (2D) Localized Correlated Spectroscopy (L‐COSY) MRS to determine the sensitivity and specificity of using DCE‐MRI alone compared to the combination with 2D MRS. The metabolite ratios from the 2D MRS spectra were analyzed using multivariate statistical analyses to determine a method capable of automatic separation of the patient cohort into malignant and benign lesions. A total of 24 lesions were studied with 21 diagnosed accurately using the enhancement characteristics alone resulting in sensitivity and specificity of 100% and 73%, respectively. Analysis of the 2D MRS data demonstrated a significant difference (p < 0.05) in 12 of 18 metabolite ratios analyzed for malignant compared to benign lesions. Previous research focused on utilizing the choline signal to noise ratio (SNR) as a marker for malignancy has been verified using 2D MRS in this study. Using Fisher's linear discriminant test using water (WAT)/olefinic fat diagonal (UFD), choline (CHO)/fat (FAT), CHO/UFD, and FAT/methyl fat (FMETD) as predictors the sensitivity and specificity increased to 92% and 100%, respectively. Using the Classification and Regression Tree (CART) statistical analysis the resulting sensitivity and specificity were 100% and 91%, respectively, with the most accurate predictor for differentiating malignant and benign determined to be FAT/FMETD. The cases within the study that presented a indeterminate diagnosis using DCE‐MRI alone were able to be accurately diagnosed when the metabolic information from 2D MRS was incorporated. The results suggest improved breast cancer detection through the combination of morphological and enhancement information from DCE‐MRI and metabolic information from 2D MRS. Copyright © 2010 John Wiley & Sons, Ltd.